Vascular endothelial growth factor. Vascular endothelial growth factor (VEGF human)

Vascular Endothelial Growth Factor (VEGF)

A family of growth factors similar in structure and function. VEGF-A, the first of its identified representatives, was referred to as “vasculotropin” (VAS), or vascular permeability factor (VPF). Later, VEGF-B, -C, -D and PIGF (Placenta growth factor) were discovered.

VEGFs are endothelium-specific polypeptides, secreted mitogens that accelerate vascular growth, proliferation and permeability. The expression of VEGFs is stimulated by a number of stimuli, in particular high doses of glucose. VEGFs play a pathogenetic role in microcirculatory dysfunction caused by hyperglycemia. The transduction mechanism of post-receptor responses of VEGFs includes activation of phospholipase C; however, there are possible ways to realize the effect through DAG, regardless of the synthesis of arachidonic acid products.

endothelium polypeptide vessel growth

ENDOTHELIAL VESSEL GROWTH FACTORS. Isoforms. (Vascular Endothelial Growth Factors, VEGF-A, -B, -C, -D)

Structure. General characteristics.

VEGF-A. Four isoforms are formed from a common gene, differing in the number of amino acid residues included: VEGF, VEGF, VEGF, VEGF with an MV from 14 to 42 kDa.

The isoforms have similar biological activities but differ in their affinity for heparin. They realize their activity when interacting with the VEGFR-1, VEGF-2 receptors (FIG.).

VEGF-A has the activity of a growth factor of vascular endothelial cells with pleiotropic functions: increased migration, proliferation, formation of tubular cell structures. Thanks to its unique functions, VEGF-A realizes the correlation of the processes of permeability, inflammation, and angiogenesis. Expression of VEGF-A mRNA was noted in vascular regions and in the ovaries at all stages of embryogenesis, primarily in cells subject to capillarization. Obviously, the factor is not synthesized directly in the endothelium and its influence is paracrine in nature. Expression of VEGF-A is induced in macrophages, T cells, astrocytes, smooth muscle cells, cardiomyocytes, endothelium, and keratinocytes. The factor is expressed by a number of tumors. Hypoxia is one of the main reasons for the activation of VEGF-A.

VEGF-B. Expressed predominantly in the brain, skeletal muscles, and kidneys. When coexpressed with VEGF-A, A/B heterodimers can be formed. In contrast to the first, VEGF-B expression is not induced by hypoxia. The participation of VEGF-B in the vascularization of adult coronary vessels has been noted. Regulates plasminogen activity in endothelial cells. Analysis of the half-life of VEGF-B mRNA suggests a chronic rather than an acute type of regulation. VEGF-B binds only to the VEGFR-1 receptor.

VEGF-C (or VEGF-Related Factor, VRF, or VEGF-2). Expressed in adult cells of the heart, placenta, lungs, kidneys, small intestine and ovaries. During embryonic development, its presence in the mesenchyme of the brain was noted; plays a role in the development of the venous and lymphatic vascular systems. Realizes activity through interaction with VEGFR-2 and - VEGFR-3 receptors. Expression of VEGF-C and flt-4 receptor are related to primary gastric cancer (Liu et al. 2004). Antibodies to the factor can be used for angiogenic testing of antitumor therapy in vivo (Ran et al. 2003).

VEGF-D (or c-fos-Induced Growth Factor, FIGF). Expressed in the lungs, heart, and small intestine of an adult organism; has moderate mitogenic activity against endothelial cells. However, the full functions of the VEGF-D form remain unknown. The activity of the factor is realized primarily through interaction with VEGFR-2 and - VEGFR-3 receptors.

VEGFs receptors. Three receptors mediate the effects of the VEGF family: VEGFR-1 (flt-1); VEGFR-2 (KDR/flk-1); VEGFR-3 (flt-4). Each belongs to class III receptor tyrosine kinases, containing in their structure IgG-like extracellular motifs and an intracellular tyrosine kinase domain. VEGFR-1 and VEGFR-2 are expressed in endothelial cells, participating in angiogenesis. VEGFR-2 is considered as a marker of hematopoietic cells. VEGFR-3 is a specific marker of embryonic prelymphatic vessels; identified in some tumors.

VEGFR-1 VEGFR-2 VEGFR-3

PHYSIOLOGICAL REACTIONS

• Induction of tPA uPA proteases
• Morphogenesis of blood vessels
• Increased vascular permeability
• Chemotaxis of monocytes and macrophages
• Differentiation of vascular endothelial cells
• Mitogenesis: formation of microtubules
• Hematopoietic stem cell labeling
• Morphogenesis of lymphatic vessels
• Differentiation of lymphatic endothelial cells
• Chemotaxis of endothelial cells

New information on the biological and medical aspects of VEGFs.

• · Angiogenesis and neurogenesis in the developing brain are regulated by VEGFs and receptors widely present in neurons and vascular endothelium (Emmanueli et al. 2003). Receptors of the flt-1 type are detected in the hippocampus, agranular cortex and striatum; flk-1 receptors are ubiquitous in neonatal brain structures (Yang et al. 2003).
• · When VEGF and flt-1 and flk-1 receptors are knocked out, high mortality of animals is detected in the embryonic period; Based on these data, neuroprotective functions of VEGFs are postulated, independent of the vascular component, playing the role of a regulator of neurogenesis in adults (Rosenstein et al. 2003; Khaibullina et al. 2004). Exercise-induced neurogenesis of hippocampal cells in rats and mnestic functions are closely related to VEGF expression (Fabel et al. 2003).
• · VEGF increases angiogenesis in ischemic areas of the brain and reduces neurological deficits; blockade of VEGF by specific antibodies in the acute phase of ischemic stroke reduces the permeability of the blood-brain barrier and increases the risk of hemorrhagic transformation (Zhang et al. 2000). Chronic hypoperfusion of rat brain tissue induces long-lasting expression of VEGF mRNA and the peptide itself, which correlates with stimulated angiogenesis (Hai et al. 2003).
• · Short-term global cerebral ischemia leads to an increase in the level of VEGF and VEGF mRNA in adult rats during the first day. Similarly, hypoxic ischemia of the brain of 10-day-old rats leads to a rapid increase in VEGF in neurons. The expression of VEGFs in both cases is associated with the activation of the HIF-1alpha factor (Hypoxia-Inducible Factor-alpha) (Pichiule et al. 2003; Mu et al. 2003).
• · VEGF stimulates the proliferation of vascular endothelial cells during mechanical injury of the spinal cord; these effects are mediated by the expression of the Flk-1 and Ftl-1 receptors. Microinjections of prostaglandin E2 stimulate VEGF activity (Skold et al. 2000). Astrocytosis, activated by damage to brain cells, and subsequent repair processes are accompanied by the expression of Glial fibrillary acidic protein (GFAP); reactive astrocytosis and stimulated VEFG expression constitute the sequential steps of reparative angiogenesis (Salhina et al. 2000).
• · VEGF appears to be one of the factors in changes in the permeability of the blood-brain barrier and the development of cerebral edema after brain injury. Early invasion of VEGF-secreting neutrophils into the parenchyma of the injured area correlates with phasic disruption of the blood-brain barrier permeability preceding the development of edema (Chodobski et al. 2003). In the first 3 hours after contusion, VEGF expression is observed in some astrocytes and activation of the KDD/fik-1 receptor in endothelial vascular cells in the damaged tissue; these processes, associated with increased capillary permeability, lead to edema (Suzuki et al. 2003). Agents that can block the activity of VEGFs and their receptors are of interest for the treatment of cerebral edema (for a review, see Josko & Knefel, 2003).
• · It has been established that VEGF is synthesized in dopaminergic neurons of the rat striatum. A single bolus injection of VEGF into the striatum of adult rats stimulated vascular development; transplantation of 14-day-old ventral mesencephalon cells into a VEGF-pretreated area of ​​the striatum resulted in homogeneous sprouting of small blood vessels. Results obtained in a model of Parkinson's pathology suggest the possibility of using VEGF-expressing transplants to improve brain function (Pitzer et al. 2003).
• · The ability of VEGF to influence angiogenesis explains its involvement in tumor development and metastasis.

Along with other neurotrophic growth factors (TGF-alpha, basic FGF, PD-ECGF), VEGF is associated with the genesis of several types of carcinoma (Hong et al. 2000) and prostate tumors (Kollerman & Helpap, 2001). Increased serum VEGF levels may serve as a marker of tumor growth in some forms of carcinoma (Hayes et al. 2004). The molecular mechanism of VEGF functioning is associated with stimulation of the bcl-2 protein and inhibition of the apoptotic process in adenocarcinoma cells in mice and humans (Pidgeon et al.2001).

PLACENTAL GROWTH FACTOR (Placental Growth Factor, PIGF)

MV 29 kDa. First isolated from a culture of glioma cells. Expressed in the placenta, autocrinely affecting trophoblasts, and to a lesser extent in the heart, lungs, and thyroid gland. Hypoxia does not stimulate the formation of PIGF; however, during hypoxia, PIGF/VEGF-A heterodimers can be coexpressed. Elevated levels of PIGF and the flt-1 receptor are predictors of preeclampsia in pregnant women (Levine et al. 2004). The PIGF-2 isoform (MB 38 kDa) serves as a ligand for the VEGFR-1 receptor; unlike PIGF-1, it contains a heparin-binding domain.

Table of contents

1. Regulation of neoangiogenesis

2. Tumor angiogenesis

Vasculoendothelial growth factor

. Vasculoendothelial growth factor C

. Vasculoendothelial growth factor D

. VEGF receptors

. Fibroblast growth factor

. Epidermal growth factor

. Transforming growth factor α

. Transforming growth factor β

. Platelet-derived growth factor

. Placental growth factor

. Hepatocyte growth factor

. Angiogenin

. Angiopoietins-1 and -2

. Pigment factor of epithelial origin

. Nitric oxide

. Matrix metalloproteinases

. Endostatin

. Stem cell factor

. Leukemia cell inhibitory factor

. Brain-derived neurotropic factor

Section Abbreviations

EGF - epidermal growth factor

FGF - fibroblast growth factor

HGF - hepatocyte growth factor

IGF - insulin-like growth factors

MMPS - matrix metalloproteinases

PDGF - platelet-derived growth factor

PLGF - placental growth factor

TGF - transforming growth factors

TIMP inhibitors

MMP SCF - stem cell factor

VEGF - vasculoendothelial growth factor

Growth factors are polypeptides with a molecular weight of 5-50 kDa, combined into a group of trophic regulatory substances. Like hormones, these factors have a wide range of biological effects on many cells - they stimulate or inhibit mitogenesis, chemotaxis, and differentiation. Unlike hormones, growth factors are usually produced by unspecialized cells found in all tissues and have endocrine, paracrine and autocrine effects. Endocrine factors are produced and transported to distant target cells through the bloodstream. Reaching their “goal”, they interact with specialized high-affinity receptors of target cells. Paracrine factors differ in that they spread by diffusion. Target cell receptors are usually located near producer cells. Autocrine factors affect cells that are the direct source of these factors. Most polypeptide growth factors act in a paracrine or autocrine manner. However, certain factors, such as insulin-like growth factor (IGF), can have endocrine effects.

Regulation of neoangiogenesis

The normal functioning of tissues depends on the regular delivery of oxygen by blood vessels. Understanding how blood vessels form has focused much of the research effort in the last decade. Vasculogenesis in embryos is the process by which blood vessels are formed de novo from endothelial cell precursors. Angiogenesis is the process of formation of new blood vessels from a pre-existing vascular system. It plays an important role in development, normal tissue growth, wound healing, the reproductive cycle in women (development of the placenta and corpus luteum, ovulation) and also plays a major role in various diseases. Particular interest is focused on tumor growth. It is the formation of a new blood supply that allows the tumor to grow. This process, described as tumor angiogenesis, is also integral in the spread of tumor cells and the growth of metastases. The process of neoangiogenesis is necessary for long-term adaptation of tissues under conditions of damage. In this case, a partial release of growth factors into the blood occurs, which has diagnostic significance.

The following stages of neoangiogenesis are distinguished:

1. increased endothelial permeability and destruction of the basement membrane;

2. migration of endothelial cells;

3. proliferation of endothelial cells;

4. “maturation” of endothelial cells and vascular remodeling.

The main mechanism for regulating neoangiogenesis processes is the release of angiogenic factors, the sources of which can be endothelial and mast cells, macrophages, etc. Under the influence of angiogenic factors, endothelial cells are activated (mainly in postcapillary venules) and migrate beyond the basement membrane with the formation of branches of the main vessels. It is assumed that activation of the expression of endothelial adhesion molecules, for example, E-selectin, is of great importance in the mechanism of endothelial cell migration. In a stable state, endothelial cells do not proliferate and only occasionally (once every 7-10 years) divide. Under the influence of angiogenic growth factors and cytokines, the proliferation of endothelial cells is activated, which ends with vessel remodeling, after which the newly formed vessel acquires a stable state.

The growth of new vessels is determined by the balance between its stimulators and inhibitors. At a low ratio of stimulants to inhibitors of vascular formation, neoangiogenesis is blocked or low-intensity; on the contrary, at high ratios, neoangiogenesis is actively triggered.

Stimulators of neoangiogenesis: vasculoendothelial growth factor (VEGF), fibroblast growth factor (FGF), angiogenin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors α (TGF-α) and β (TGF-β), insulin-like growth factor 1 (IGF-1), NO, interleukin-8 and nonspecific factors such as matrix metalloproteinases (MMPs).

Neoangiogenesis inhibitors: endostatin, soluble VEGF receptors (sVEGFR), thrombospondin, angiostatin (plasminogen fragment), vasostatin, restin, MMP inhibitors (TIMP-1, TIMP-2).

Tumor angiogenesis

Unlike normal, normal vasculature, which matures and stabilizes quickly, tumor blood vessels have structural and functional abnormalities. They do not contain pericytes - cells functionally associated with the vascular endothelium and extremely important for the stabilization and maturation of vascular structures. In addition, vascular1. 2. 3. 4. This tumor network has a chaotic organization, with tortuosity and increased vascular permeability, and its survival and proliferation depend on growth factors. These vascular abnormalities, which are largely due to the excessive production of growth factors, create conditions favorable for tumor growth.

Cancer cells are characterized by an increase in the level of neoangiogenesis stimulators. In the absence of a blood supply, tumors obtain oxygen and nutrients by diffusion and usually do not grow more than 1-2 mm in diameter. The onset of angiogenesis leads to the formation of a new blood supply and facilitates the rapid growth and metastasis of the tumor, which has thereby become active. Although many growth factors are involved in tumor angiogenesis, VEGF has been found to be the most potent and dominant of them. Disruption of the blood supply to the tumor can suppress its subsequent growth. It is assumed that blocking tumor growth is possible by suppressing the formation and activity of growth factors of angiogenesis or by directly affecting newly formed, immature blood vessels. This method of influencing the tumor does not cause eradication, but only limits its growth, transforming the disease into a sluggish chronic process. Anti-VEGF therapy suppresses the growth of new tumor vessels and causes reversal of newly formed vascular beds.

Vasculoendothelial growth factor (VEGF, VEGF A)

VEGF is a heterodimeric glycoprotein growth factor produced by various cell types. At least 5 variants of VEGF-A have been identified: VEGF 121, VEGF 165, VEGF 183, VEGF 189, VEGF 206. Other VEGF variants are designated VEGF-B, -C, -D. VEGF 165 is the predominant form in most tissues. Kaposi's sarcoma expresses VEGF 121 and VEGF 165. VEGF 121 and VEGF 165 are soluble forms, whereas VEGF 189 and VEGF 206 are bound to heparin-containing membrane proteoglycans. Unlike other endothelial cell mitogens such as bFGF (the major form) and PDGF, VEGF is synthesized as a 226 amino acid precursor.

VEGF is a potential mitogen for vascular epithelial cells. It has a strong effect on vascular permeability, is a powerful angiogenic protein in various experimental systems, and takes part in neovascularization processes in pathological situations. There is a synergistic effect between VEGF and bFGF on the induction of angiogenesis. The ability of VEGF to influence vascular permeability implies the possibility of the involvement of this growth factor in changing the functions of the blood-brain barrier under subnormal and pathological conditions. VEGF-A also causes vasodilation through the NO synthetase pathway in endothelial cells and can activate monocyte migration.

VEGF-A can be detected in the plasma and serum of patients, but its level in serum is significantly higher. Extremely high levels can be found in the contents of cysts formed in patients with brain tumors or in ascites fluid. Platelets release VEGFA upon aggregation and may be another major source for tumor cells. Various studies have shown that the association of high serum VEGF-A levels with poor prognosis in patients with malignancies may be correlated with elevated platelet counts. Tumors can secrete cytokines and growth factors that stimulate the production of megakaryocytes in the bone marrow and increase platelet counts. This, in turn, may lead to another, indirect increase in VEGF-A delivery to the tumor. Moreover, VEGF-A is involved in many other pathological processes associated with increased angiogenesis or increased vascular permeability. Examples where VEGF-A plays an important role include psoriasis and rheumatoid arthritis, as well as ovarian hyperstimulation syndrome. Diabetic retinopathy is also associated with high intraocular levels of VEGF-A, and inhibition of VEGFA function can lead to infertility due to blockage of corpus luteum function. The importance of VEGF-A for tumor growth has been clearly demonstrated by using VEGF receptors to block proliferation in vivo, as well as blocking antibodies to VEGF or one of the VEGF receptors. As a consequence, interference with VEGF-A function has become a major area of ​​interest for the development of drugs aimed at blocking angiogenesis and metastasis. Currently, more than 110 pharmaceutical companies around the world are involved in the development of such antagonists. Their approaches include antagonists of VEGF-A or its receptors, selective tyrosine kinase inhibitors. Targeting VEGF signaling may have very important therapeutic implications for many diseases and serve as a basis for the development of future (anti)angiogenic therapies.

Vasculoendothelial growth factor C (VEGF-C)

VEGF-C belongs to the VEGF family. It has been shown to have angiogenic and lymphangiogenic properties. The VEGF family and their receptors are involved in the development and growth of vascular endothelium. Two proteins of this family, VEGF-C and -D, exert a regulatory effect on endothelial cells of lymphatic vessels through the VEGFR3 receptor, acting as mitogens.

Expression of VEGF-C is associated with oncohematological diseases. Expression of VEGF-C together with receptors promotes the survival and proliferation of tumor cells. Increased expression of VEGF-C has been shown in gastrointestinal malignancies, where it correlates with invasion, lymph node metastasis and decreased survival.

Vasculoendothelial growth factor D (VEGF-D)

VEGF-D (also known as c-fos-inducible factor, or FIGF) is very similar to VEGF-C. It has structural homology and receptor specificity similar to VEGF-C, so it is believed that VEGF-D and VEGF-C can be classified into the VEGF subfamily. VEGF-D is initially synthesized as a precursor protein containing unique N- and C-terminal propeptides in addition to the central VEGF receptor-binding homology domain (VHD). N- and C-terminal propeptides have not been found in other members of the VEGF family. These propeptides are proteolytically cleaved during biosynthesis, resulting in the formation of a mature, secreted form consisting of monovalent VHD dimers.

Like VEGF-C, VEGF-D binds on the cell surface to tyrosine kinase VEGF receptor 2 (VEGF R2/Flk-1/KDR) and VEGFR3. These receptors are localized on vascular and lymphatic endothelial cells and are responsible for angiogenesis and lymphogenesis. The mature form of VEGFD binds to these receptors with greater affinity than the original pro form of VEGF-D. The expression of the VEGF-D gene in developing embryos, especially in the pulmonary mesenchyme, has been shown. VEGF-D is also localized in tumor cells. In adult tissues, VEGF-D mRNA is expressed in the heart, lungs, skeletal muscle, and small intestine.

VEGF receptors (sVEGFR-1, sVEGFR-2)

Many cytokine receptors exist in a soluble form following proteolytic cleavage and separation from the cell surface. These soluble receptors are able to bind and neutralize cytokines in circulation. There are three receptors for VEGF-A: VEGFR-1 (Flt-1), -2 (KDR) and -3 (Flt-4). All of them contain seven Ig-like repeats in the extracellular domains. VEGFR1-R3 is mainly expressed in proliferating endothelium of the vascular lining and/or infiltrating solid tumors. VEGFR2, however, is more widely represented than VEGFR1 and is expressed in all endothelial cells of vascular origin. VEGFR2 is also present in endothelial and perivascular capillary cells in the lamina seminiferous tubules, Leydig cells, and Sertoli cells. VEGFR2 binds VEGF-A, -C and -D. Unlike VEGFR1, which binds both PlGF and VEGF with high affinity, VEGFR2 binds only VEGF and not PlGF with high affinity.

These receptors play an important role in angiogenesis. sVEGFR-1 is an inhibitor of this process. By binding to VEGF, it prevents VEGF from interacting with target cells. Functional inactivation of VEGFR2 by antibodies can disrupt the process of angiogenesis and prevent tumor cell invasion. In vascular endothelial cells, HIV-1 Tat protein-induced angiogenesis is mediated by VEGFR2. Tat specifically binds and activates VEGFR2. Tat-induced angiogenesis is inhibited by agents that can block VEGFR2.

Fibroblast growth factor (FGF)

The FGF family currently includes 19 different proteins. Two forms were initially characterized: acidic (aFGF) and basic (bFGF).

a and bFGF are products of different genes and have up to 53% homology. The aFGF molecule is represented by a simple polypeptide chain with m.m. 16.8 kDa. Mm. different forms of bFGF range from 16.8 to 25 kDa. No functional differences were found between bFGF forms.

The biological activities of FGF are diverse. They are mitogens for various cells of neuroectodermal and mesenchymal origin, potential mitogens and stimulators of angiogenesis, support and stimulate the differentiation of cells of various neuronal types in vivo and in vitro. In addition to a and bFGF, the family includes the oncoproteins int-2 (FGF-3) and hst (FGF-4), FGF-5, keratinocyte growth factor and vascular endothelial growth factor. FGF-3 and -4 are closely related to bFGF, which itself is likely to be a potential oncogene. Clinical data support a role for bFGF in tumor neoangiogenesis. Thus, an increase in the level of this factor correlates with the degree of aggressiveness of the process in many solid tumors, leukemia, lymphomas in children and adults and can serve as a prognostic factor for the aggressiveness of the tumor process. bFGF is necessary for the development and maintenance of the vascular system during embryogenesis; it is also the main angiogenic factor in early recovery and cardiovascular diseases.

Epidermal growth factor (EGF)

EGF is a globular protein with m.m. 6.4 kDa, consisting of 53 amino acid residues, which acts as a potent mitogen on various cells of endodermal, ectodermal and mesodermal origin. EGF is found in blood, cerebrospinal fluid, milk, saliva, gastric and pancreatic juices. A growth factor in urine known as urogastron is also identical to EGF. The main site of EGF synthesis is the salivary glands. EGF controls and stimulates the proliferation of epidermal and epithelial cells, including fibroblasts, renal epithelium, glial cells, ovarian granulosa cells and thyroid cells in vitro. EGF also stimulates the proliferation of embryonic cells and increased calcium release from bone tissue. It promotes bone resorption and is a strong chemoattractant for fibroblasts and epithelial cells. EGF alone and in combination with other cytokines is the most important factor mediating the processes of wound healing and angiogenesis. It also acts as an inhibitor of gastric acid secretion. High levels of EGF are present in some body fluids, such as saliva, urine, gastric juice, seminal fluid, and milk.

EGF plays an important role in carcinogenesis. Under certain conditions, it can cause cell malignancy. EGF induces the proto-oncogenes c-fos and c-myc. The biological effects of immunoreactive EGF are similar to those of TGF-α. It is important to note that both factors bind to the same receptors. However, the effectiveness of EGF is 50% higher than TGF-α.

Transforming growth factor α (TGF-α)

The main source of TGF-α is carcinomas. Macrophages and keratinocytes (possibly other epithelial cells) also secrete TGF-α. TGF-α stimulates fibroblasts and endothelial development. It is an angiogenic factor. Like EGF, TGF-α is involved in the regulation of cell proliferation, as well as in the regulation of tumor cell growth.

Transforming growth factor β (TGF-β)

The TGF-β family includes a group of homologous heterodimeric proteins TGFβ-1, -2, -3 and -4. The main isoform secreted by cells of the immune system is TGF-β1. All TGF-βs consist of 112 amino acid residues. The structure of TGF-β2 has 50% homology with TGF-β1 over the first 20 amino acid residues and 85% for fragment 21-36. No differences in functional activity were found between TGF-β1 and -β2. TGF-β is produced by many types of cells and tissues: activated T-lymphocytes and macrophages, platelets, kidneys, placenta.

The factor is produced in an inactive form, containing, along with the main dimer, fragments of additional chains of the precursor molecule. Activation occurs in the form of cleavage of these fragments with the help of proteinases (plasmin, cathepsin, etc.). TGF-β also targets a variety of cells because expression of its high-affinity receptor is widespread. When TGFβ acts on the immune system, inhibitory effects predominate. The factor suppresses hematopoiesis, the synthesis of inflammatory cytokines, the response of lymphocytes to IL-2, -4 and -7, and the formation of cytotoxic NK and T cells. At the same time, it enhances the synthesis of proteins of the intercellular matrix, promotes wound healing, and has an anabolic effect.

In relation to polymorphonuclear leukocytes, TGF-β acts as an antagonist of inflammatory cytokines. Turning off the TGF-β gene leads to the development of a fatal generalized inflammatory pathology, which is based on an autoimmune process. Thus, it is an element of the feedback regulation of the immune response and, above all, the inflammatory response. At the same time, TGF-β is also important for the development of the humoral response: it switches the biosynthesis of immunoglobulins to the IgA isotype. Stimulates angiogenesis. Plasma TGF-β levels positively correlate with tumor vascularization.

Platelet Derived Growth Factor (PDGF)

PDGF is one of the potential mitogenic polypeptides found in human blood. Consists of two chains: A and B, linked in AA-, BB- and AB isoforms. These three isoforms differ in both functional properties and mode of secretion. While the AA and AB forms are rapidly secreted from the producer cell, the BB form remains mainly associated with the producing cell. Only dimeric forms of PDGF can bind to receptors. Two different types of receptors have been identified. The α receptor binds either A or B polypeptide, whereas the β receptor binds only B polypeptide. The entire spectrum of biological effects is due to these three PDGF molecules and two receptors, their differential expression and complex intracellular mechanisms regulating their activity. The source of PDGF in serum is platelet α-granules, although macrophages and endothelial cells can also produce this factor. At certain stages, placental cells and smooth muscle cells of the newborn aorta also serve as a source of PDGF.

The AA isoform is preferentially secreted by fibroblasts, vascular smooth muscle cells, osteoblasts, astrocytes, COLO (colon carcinoma) and WLM (Wilm's tumor) cells. BB synthesis is associated with macrophages, islet cells of Langerhans, non-angiogenic epithelium and SW (thyroid carcinoma) cell line. Cells that produce both chains (A and B) include neurons, kidney mesangial cells, glioma and mesothelioma cell lines, and platelets. Initial data suggested that human platelets contained approximately 70% PDGF-AB and 30% -BB. However, more recent studies have shown that up to 70% PDGF-AA may be present, and earlier findings are an artifact. The type of PDGF dimer(s) secreted depends on the mRNA produced and can also be influenced by translation efficiency, secretion, and intracellular degradation.

The structural identity of the B chain and the c-sis proto-oncogene suggests that PDGF may play a role in virus-induced malignant transformation of infected cells. PDGF is involved in the regulation of acute inflammation, wound healing and scar formation. PDGF released from alveolar macrophages is involved in the development of pulmonary fibrosis. It has also been established that PDGF is associated with the development of atherosclerosis, glomerulonephritis, myelofibrosis and keloid formation. Like EGF, PDGF induces the expression of proto-oncogenes such as fos, myc and jun. PDGF is also ubiquitously present in neurons of the CNS, where it is thought to play an important role in cell survival and regeneration, mediating glial cell proliferation and differentiation

Placental growth factor (PlGF)

PlGF - glycoprotein with m.m. 46-50 kDa, belonging to the VEGF family (42% homology with VEGF). PlGF is also homologous, although more distantly, to the PDGF family of growth factors. There are two isoforms of PlGF: -1 and -2, differing in the presence of a heparin-binding domain in PlGF-2. PlGF mediates proliferation of extravillous trophoblast. As its name implies, PlGF was first identified under normal conditions in the human placenta. It is expressed in other tissues such as capillaries and umbilical vein endothelium, bone marrow, uterus, NK cells and keratinocytes. PlGF is also increased in various pathological conditions, including wound healing and tumor formation. Compared to VEGF, the role of PlGF in neovascularization is less clear. It can increase the lifespan, growth and migration of endothelial cells in vitro, and promote vascular formation in some in vivo models. PlGF activity can occur through direct interaction of the factor with VEGFR1. It has been proposed that VEGFR1 acts as a reservoir for VEGF, and that PlGF, upon binding to the receptor, displaces VEGF, releasing it to activate VEGFR2. PlGF can synergistically enhance VEGF-induced angiogenesis and vascular permeability. The concentration of PlGF increases 4 times from the end of the first to the end of the second trimester of physiological pregnancy.

Hepatocyte growth factor (HGF)

HGF, also called scattering factor (SF), consists of two subunits linked by a disulfide bond: α (69 kDa) and β (34 kDa). HGF is a multifunctional cytokine that acts as a mitogen, which is associated with its function in organogenesis and tissue repair. It has the ability to stimulate blood vessel formation and cell proliferation, suggesting its involvement in malignant growth and metastasis in lung, breast, pancreatic, adenocarcinoma, multiple myeloma and hepatocellular carcinoma. In breast cancer tumor cells, HGF strongly induces bcl-x expression and thus inhibits apoptosis. HGF is continuously produced by bone marrow stromal cells and stimulates hematopoiesis.

Angiogenin (ANG)

ANG is a single chain non-glycosylated polypeptide with m.m. 14 kDa, which belongs to the RISBASE family of ribonucleases (ribonucleases with special biological functions). Molecules of this family exhibit not only ribonuclease activity, but also have special biological effects. ANG has 35% sequence identity with pancreatic ribonuclease. It has been shown that at the amino acid level, human angiogenin is 75% identical to mouse ANG and “works” in mouse systems. ANG is expressed by endothelial cells, smooth muscle cells, fibroblasts, columnar intestinal epithelium, lymphocytes, primary adenocarcinoma cells, and some tumor cell lines. The angiogenin receptor is unknown. It is believed that actin, as a receptor or binding molecule, is required for the actions of angiogenin.

Functionally, ANG is most often associated with the process of angiogenesis. It is thought to initially bind to actin, followed by dissociation of the actin-ANG complex followed by activation of tissue plasminogen activator. As a result, plasmin is formed, which promotes the degradation of basement membrane components such as laminin and fibronectin. Destruction of the basement membrane is a necessary precondition for endothelial cell migration during neovascularization. Although ANG appears to act primarily extravascularly or perivascularly, circulating ANG has been detected in normal serum at concentrations on the order of ng/mL. In pathological processes, elevated levels of ANG were detected in patients suffering from pancreatic cancer and arterial occlusion.

Angiopoietins-1 and -2 (Ang)

Ang-1 and -2 are glycoproteins belonging to the family of growth factors that regulate the development of vascular tissue. Ang-1 consists of 498 amino acid residues, Ang-2 - of 467. The AK sequences of Ang-1 and -2 are 60% identical. Both Angs interact with the receptor tyrosine kinase-2 (Tie-2), which is present predominantly on endothelial cells. However, there are at least three alternative splicing variants of Ang-1, with two alternative forms failing to activate Tie-2. Thus, they act as endogenous suppressors of the major active form of Ang-1. In addition, Ang-1 and -2 act as competitors for interaction with the Tie-2 receptor, so Ang-2, depending on the cell type, acts as either a suppressor or an activator of the Tie-2 receptor.

Ang-1 and -2 are highly expressed in the embryo during rapid development of vascular tissue. Deletion of the Ang-1 gene leads to lethal consequences in the embryo due to serious defects in the development of the heart and blood vessels. Although Ang-2 does not play as significant a role as Ang-1 in the formation of the vascular system of the embryo, in its absence vascularization is also impaired, which causes early death. In the adult organism, Ang-1 is synthesized predominantly by endothelial cells, megakaryocytes and platelets, and Ang-2 is expressed locally: by the ovaries, uterus, and placenta. Ang-1 regulates the development and remodeling of blood vessels and increases the survival of endothelial cells. The survival of endothelial cells during the interaction of Ang-1 with Tie-2 involves the PI3K/AKT mechanism, and cell migration during the same interaction (ligand/receptor) occurs with the participation of several kinases (PI3K, PAK, FAK). In contrast, Ang-2, acting alone, initiates endothelial cell death and vessel regression, although synergistically with VEGF it can promote the formation of new vessels. If Ang-1 acts synergistically with VEGF, its overproduction leads to increased tissue vascularization. Thus, Ang-1 and -2, as a rule, act as antagonists that jointly regulate vascular growth.

The action of angiopoietins is not limited to the vascular endothelium of the bloodstream - they can take part in the formation of vessels of the lymphoid system. Ang-1 has other biological effects, for example, it enhances the adhesion and migration of neutrophils and eosinophils, and regulates the permeability of the vascular wall. Ang-1 can also induce the growth and survival of nerve cells and regulate the organization of dendritic cells. Elevated levels of Ang-1 and -2 enhance the angiogenesis of malignancies. High concentrations of circulating Ang-1 are associated with hypertension and cancer pathologies.

Pigment epithelial-derived factor (PEDF)

PEDF (mw 50 kDa, belongs to the serpin family) was first identified as a factor secreted by retinal epithelial cells and promoting neuronal survival in vitro and in vivo. On the other hand, PEDF has been shown to have the property of inducing apoptosis of capillary endothelial cells, thereby maintaining the avascular nature of the retina. In many ophthalmic diseases characterized by dysregulation of retinal innervation and microvasculature, PEDF is an important regulator in ocular diseases. In addition, PEDF has been shown to have multifunctional antitumor activity in experimental neuroblastoma, as PEDF produced by Schwann cells induces a differentiated, less malignant phenotype in neuroblastoma cells, promotes further growth and survival of Schwann cells, and inhibits angiogenesis.

Nitric oxide (NO)

The biological effects of NO have been widely recognized following its identification as an endothelium-dependent relaxing factor (EDRF), responsible for its potent vasodilatory properties. NO has since been identified as a pleiotropic biological mediator that regulates functions ranging from nervous activity to regulation of the immune system. It is a free radical with a short in vivo half-life of about a few seconds. In this regard, the level of more stable NO metabolites, nitrites (NO 2-) and nitrates (NO 3-) is used for the indirect determination of NO in biological fluids. Examples include altered levels associated with sepsis, reproduction, infections, hypertension, exercise, type 2 diabetes, hypoxia, and cancer.

NO is formed by the oxidation of L-arginine with the participation of NADPH. Oxidation occurs with the participation of one of three isoforms of enzymes of the NO synthase (NOS) family with the formation of citrulline. Members of the NOS family include neuronal (nNOS/NOS1), endothelial (eNOS/NOS3), and inducible (iNOS/NOS2) NO synthases. As its name suggests, nNOS is abundantly expressed by neurons of the CNS and PNS and is also found in cells of other tissues, including skeletal muscle myocytes, lung epithelial cells, and skin mast cells; eNOS is expressed by endothelium and can also be detected in neurons, skin fibroblasts, keratinocytes, thyroid follicular cells, hepatocytes and smooth muscle cells. iNOS is expressed in a variety of tissues, including chondrocytes, epithelial cells, hepatocytes, glial tissue, and various cell types of the immune system. In general, eNOS and nNOS expression occurs continuously and is regulated by Ca2+-dependent calmodulin, whereas iNOS synthesis is induced by endotoxin and inflammatory cytokines and is relatively insensitive to Ca2+.

Due to the fact that NO is soluble in lipids, it is not stored, but is synthesized de novo and diffuses freely through membranes. The effects of NO on target cells are mediated through various mechanisms. For example, NO-mediated activation of the enzyme guanylyl cyclase (GC) catalyzes the formation of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP). cGMP is involved in a number of biological functions, such as the regulation of smooth muscle contraction, cell lifetime, proliferation, axonal function, synaptic plasticity, inflammation, angiogenesis, and cyclic nucleotide-gated channel activity. NO is also an antitumor and antimicrobial agent through mechanisms of conversion to peroxynitrite (ONOO-), formation of S-nitrosothiols, and reduction of arginine stores. Another putative role of NO is inhibition of mitochondrial respiration through inhibition of cytochrome oxidase. NO can also modify protein activity through post-translational nitrosylation through attachment via the thiol group of cysteine ​​residues.

Matrix metalloproteinases (MMPs)

Human MMPs are a family of matrix-degrading enzymes. MMPs have the ability to degrade almost all components of the extracellular matrix found in connective tissues (collagen, fibronectin, laminin, proteoglycans, etc.). In addition to similarities at the amino acid sequence level, all MMPs are formed from inactive precursors that are converted into active substrate-degrading proteinases under the influence of extracellular factors. The sources of MMPs formation are fibroblasts, macrophages, smooth muscle cells of the vascular wall, and neutrophils. Any tumor is a powerful inducer of the formation of MMPs in stromal cells. While promoting invasion of tumor growth and metastasis, MMPs are at the same time powerful stimulators of neoangiogenesis. Endogenous and synthetic MMPs inhibitors are used as potential antitumor agents, the main purpose of which is to suppress neoangiogenesis.

Endostatin

Biologically active C-terminal fragment of collagen VIII with m.m. 20 kDa. Belongs to the family of collagen-like proteins. In order to avoid excessive vascular growth under normal conditions, the processes of formation of new and remodeling of original vessels are controlled by appropriate growth factors. During tumor angiogenesis, penetration of blood vessels into the growing tumor mass is observed. Endostatin specifically inhibits endothelial cell proliferation. Accordingly, it inhibits angiogenesis and tumor growth. Endostatin therapy is currently undergoing phase 1 clinical trials.

Other diagnostically significant growth factors

Stem Cell Factor (SCF)

Producers of SCF are bone marrow stromal cells, fibroblasts, endothelial cells, and Sertoli cells. Its main target cells are hematopoietic stem cells, early committed precursors of cells of various hematopoietic lineages and mast cells. SCF activates the differentiation of multipotent progenitor cells synergistically with IL-3, GM-CSF and IL-7 and erythropoietin. It is involved in maintaining the proliferation of the youngest forms of T-lymphocyte precursors in the thymus. In relation to mast cells, it is a major growth factor and chemotactic agent.

SCF has important clinical significance as an inducer of differentiation of lymphocyte and erythrocyte precursors. Determination of SCF is of significant interest in the treatment of myelodysplastic syndrome and after bone marrow transplantation.

Leukemia cell inhibitory factor (LIF)

LIF enhances the proliferation of hematopoietic cell precursors. LIF has been shown to cause the development of cachexia syndrome in cancer patients. The LIF receptor component gp130 (CD130) is part of the receptors for IL-6 and -11.

Brain-derived neurotrophic factor (BDNF)

1 State Educational Institution of Higher Professional Education “Saratov State Medical University named after. IN AND. Razumovsky Ministry of Health and Social Development of Russia", Saratov

Based on the analysis of domestic and foreign literature devoted to the study of vascular endothelial growth factor (VEGF), its leading role in the processes of regulation of angiogenesis, changing the balance of angiogenic and antiangiogenic factors of hypoxia and the “switching on” of angiogenesis in various diseases is shown. Expression of VEGF occurs in malignant neoplasms and is involved in the biology of tumor-transformed tissues. An increase in VEGF expression in tumor tissue is accompanied by an increase in protein levels in the blood serum in patients with kidney cancer and non-muscle-invasive bladder cancer, which can be recommended as a prognostic marker in detecting disease relapse.

vascular endothelial growth factor

angiogenesis

malignant neoplasms

kidney cancer

non-muscle invasive bladder cancer

1. Alekseev B.Ya., Kalpinsky A.S. New opportunities for targeted therapy of metastatic kidney cancer // Oncourology. – 2009. – No. 3. – P. 8–12.

2. Andreeva Yu.Yu. Morphological and molecular biological factors for the prognosis of bladder cancer: abstract. dis. ... dr. honey. Sci. – M., 2009. – 45 p.

3. Danilchenko D.I. Clinical evaluation and implementation of new minimally invasive methods for diagnosing bladder cancer: abstract. dis. ...Dr. med. Sciences: 14.00.40. – St. Petersburg, 2008. – 38 p.

4. Kadagidze Z.G., Shelepova V.M. Tumor markers in modern clinical practice // Vest. Moscow Oncol. General – 2007. – No. 1. – P. 56–9.

5. Karyakin O.B., Popov A.M. Efficacy of sunitinib in patients with disseminated renal cell cancer // Oncourology. – 2008. – No. 1. – pp. 25–28.

6. Kushlinsky N.E., Gershtein E.S. Biological markers of tumors in the clinic - achievements, problems, prospects // Molecular Medicine. – 2008. – No. 3. – pp. 48–55.

7. Kushlinsky N.E., Gershtein E.S., Lyubimova N.V. Biological markers of tumors: methodological aspects and clinical application // Bulletin of the Moscow Oncological Society. – 2007. – No. 1. – P. 5–7.

8. Molecular genetic disorders in the VHL gene and methylation of some suppressor genes in sporadic clear cell kidney carcinomas / D.S. Mikhailenko, M.V. Grigorieva, V.V. Zemlyakova et al. // Oncourology. – 2010. – No. 2. – pp. 32–36.

9. Mikhailenko D.S. Nemtsova M.V. Molecular genetic markers of kidney cancer // Russian Journal of Oncology. – 2007. – No. 4. – pp. 48–51.

10. Regulation of angiogenesis in malignant neoplasms of the kidney and bladder / L.V. Spirina, I.V. Kondakova, E.A. Usynin et al. // Siberian Journal of Oncology. – 2008. – No. 4. – P. 65–70.

11. Stepanova E.V., Baryshnikov A.Yu., Lichinitser M.R. Assessment of angiogenesis of human tumors // Advances in modern biology. – 2000. – T. 120(6). – pp. 599–604.

12. Trapeznikova M.F., Glybin P.A., Morozov A.P. Angiogenic factors in renal cell carcinoma // Oncourology. – 2008. – No. 5. – pp. 82–87.

13. Vascular endothelial growth factor and its type 2 receptor in blood serum, tumor and kidney parenchyma of patients with renal cell cancer / M.F. Trapeznikova, P.V. Glybin, V.G. Tumanyan et al. // Urology. – 2010. – No. 4. – P. 3–7.

14. Filchenkov A.A. Therapeutic potential of angiogenesis inhibitors // Oncology. – 2007. – No. 9. – pp. 321–328.

15. Shakhpazyan N.K. The importance of tumor markers, growth factors, angiogenesis and apoptosis in the diagnosis of superficial bladder cancer: abstract. dis. ...cand. honey. Sci. – Saratov, 2010. – 20 p.

16. Angiogenesis and other markers for prediction of survival in metastatic renal cell carcinoma / F.I. Alamdari, T. Rasmuson, K. Grankvist et al. // Scand J Urol Nephrol. – 2007. – Vol. 41(1). – P. 5–9.

17. Molecular mechanism of tumor vascularization / P. Auguste, S. Lemire, F. Larrieu-Lahargue et al. // Crit. Rev. Oncol. Hematol. – 2005. – Vol. 54(1). – P. 53–61.

18. High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT-PCR mRNA expression profile / M.M. Baldewijns, V.L. Thijssen, G. G. Van den Eynden et al. // Br J Cancer – 2007. – Vol. 96(12). – P. 1888–95.

19. Present strategies in the treatment of metastatic renal cell carcinoma: an update on molecular targeting agents /J. Bellmunt, C. Montagut, S. Albiol et al. // BJU Int. – 2007. – Vol. 99. – P. 274–280.

20. Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer / S. Bernardini, S. Fauconnet, E. Chabannes et al. // J. Urol. – 2001. – Vol. 166. – P. 1275–1279.

21. Bicknell R., Harris A.L. Novel angiogenic signaling pathways and vascular targets // Annu. Rev. Pharmacol. Toxicol. – 2004. – Vol. 44. – P. 219–238.

22. Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles / M. Birkhahn, A.P. Mitra, A.J. Williams et al. // Eur Urol. – 2010. – Vol. 57. – P. 12–20.

23. Cao Y. Tumor angiogenesis and therapy // Biomed. Pharmacother. – 2005. – Vol. 59. – P. 340–343.

24. Carmeliet P. Angiogenesis in life, disease and medicine // Nature. – 2005. – Vol. 438. – P. 932–936.

25. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis // Nature medicine. – 2000. – Vol. 6. – P. 389–395.

26. Carmeliet P., Jain R.K. Angiogenesis in cancer and other diseases. //Nature. – 2000. – Vol. 407. – P. 249–257.

27. Clinical factors associated with outcome in patients with metastatic clearcell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy / T.K. Choueiri, J.A. Garcia, P. Elson et al. //Cancer. – 2007. – Vol. 110. – P. 543–50.

28. Role of cytokeratins, nuclear matrix proteins, Lewis antigen and epidermal growth factor receptor in human bladder tumors / A. Di Carlo, D. Terracciano, A. Mariano et al. // Int. J. Oncol. – 2003. – Vol. 23(3). – P. 757–762.

29. Prognostic significance of vascular endothelial growth factor expression in clear cell renal cell carcinoma / G. Djordjevic, V. Mozetic, D.V. Mozetic et al. // Pathol Res Pract. – 2007. – Vol. 203(2). – P. 99–106.

30. Dhanabal M., Sethuraman N. Endogenous angiogenesis inhibitors as therapeutic agents: historical perspectives and future direction // Recent Patients Anticancer Drug Discov. – 2006. – Vol. 1(2). – P. 223–236.

31. Dor Y., Porat R., Keshet E. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis // Am J Physiol Cell Physiol. – 2001. – Vol. 280(6). – P. 1367–74.

32. Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing // N Engl J Med 1986. Vol. 315. P. 1650-9.

33. Dvorak H.F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy // J. Clin. Oncol. – 2002. – Vol. 20. – P. 4368–80.

34. Angiogenesis in cancer: molecular mechanism, clinical impact / M.E. Einchorn, A. Kleespies, M.K. Angele et al. // Langenbecks Arch. Surg. – 2007. – Vol. 392(2). – P. 371–379.

35. Phase III trial of bevacizumab plus interferon alfa–2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival / B. Escudier, J. Bellmunt, S. Negrie et al. // J Clin Oncol. – 2010. – Vol. 28. – P. 2144–50.

36. Rapamycin inhibits in vitro growth and release of angiogenetic factors in human bladder cancer / G. Fechner, K. Classen, D. Schmidt et al. // Urology. – 2009. – Vol. 73(3). – P. 665–668.

37. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis // Am. J. Physiol. Cell Physiol. – 2001. – Vol. 280. – P. 1358–1366.

38. Ferrara N., Gerber H.P., Le Couter J. The biology of VEGF and its receptors // Nat Med. – 2003. – Vol. 9. - P. 669–76.

39. Ferrara N., Keyt B. Vascular endothelial growth factor: basic biology and clinical implications // EXS. – 1997. – Vol. 79. – P. 209–32.

40. Figg W.D., Folкman J.E. Angiogenesis: An Integrative Approach From Science To Medicine. Edited by New York, "Random House". – 2008. – P. 601.

41. Folkman J. A new link in ovarian cancer angiogenesis: lysophosphatidic acid and vascular endothelial growth factor expression // J Natl Cancer Inst. – 2001. – Vol. 93(10). – P. 734–735.

42. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease // Nat Med. – 1995. – Vol. 1(1). – P. 27–31.

43. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors // Ann. Surg. – 1972. – Vol. 175(3). – P. 409–416.

44. Folkman J. Clinical applications of research on angiogenesis // New England Journal of Medicine. – 1995. – Vol. 333(26). – P. 1757–1763.

45. Folkman J. Role of angiogenesis in tumor growth and metastasis // Semin. Oncol. – 2002. – Vol. 29. – P. 15–18.

46. ​​Folkman J. Tumor angiogenesis: therapeutic implications // N. Engl. J. Med. – 1971. – Vol. 285. – P. 1182–1186.

47. Folkman J. What is the evidence that tumors are angiogenesis dependent? Edited by © Oxford University Press. – 1990. – P. 4–7.

48. Folkman J., Klagsburn M. Angiogenic factors // Science. – 1987. – Vol. 235. – P. 442–7.

49. Furcht L.T. Critical factors controlling angiogenesis: cell products, cell matrix, and growth factors // Lab Invest. – 1986. – Vol. 55(5). – P. 505–9.

50. Grosjean J, Kiriakidis S, Reilly K et al. Vascular endothelial growth factor signaling in endothelial cell survival: a role for NFkappaB // Biochem Biophys Res Commun. – 2006. – Vol. 340. – P. 984–994.

51. Hanna S.C., Heathcote S.A., Kim W.Y. mTOR pathway in renal cell carcinoma // Expert Rev Anticancer Ther. – 2008. – Vol. 8. – P. 283–92.

52. Harper J., Moses M.A. Molecular regulation of tumor angiogenesis: mechanism and therapeutic implication // EXS. – 2006. – Vol. 96. – P. 223–268.

53. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF / J. Holash, P.C. Maisonpierre, D. Compton et al. // Science. – 1999. – Vol. 284. – P. 1994–8.

54. Concentration of vascular endothelial growth factor (VEGF) in the serum of patients with malignant bone tumors / G. Holzer, A. Obermair, M. Koschat et al. // Med Pediatr Oncol. – 2001. – R. 601–4.

55. The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy / K. Inoue, J.W. Slaton, T. Karashima et al. // Clin. Cancer. Res. – 2000. – Vol. 6. – P. 4866–4873.

56. Izzi L., Attisano L. Ubiquitin-dependent regulation of TGF-β signaling in cancer // Neopalasia. – 2006. – Vol. 8. – P. 677–688.

57. Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma / J. Jacobsen, K. Grankvist, T. Rasmuson et. al. //Br. J. Urol. Int. – 2006. – Vol. 97(5). – P. 1102–1108.

58. Activations of HIF-α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex / T. Kamura, S. Sato, K. Iwai et al. //Proc. Natl. Acad. Sci USA. – 2000. – Vol. 97. – P. 10430–10435.

59. Kaya M., Wada T., Akatsuka T. et al. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis // Clin Cancer Res. – 2000. – Vol. 6. – P. 572–577.

60. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors // Nat Rev Cancer. – 2002. – Vol. 2. – P. 727–739.

61. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma / H.L. Kim, D. Seligson, X. Liu et al. // J. Urol. – 2005. – Vol. 173. – P. 1496–1501.

62. Kirstein M.N., Moore M.M., Dudek A.Z. Review of selected patients for cancer therapy targeting tumor angiogenesis // Recent Patients Anticancer Drug Discov. – 2006. – Vol. 1(2). – P. 153–161.

63. Renal cell carcinoma: new frontiers in staging, prognostication and targeted molecular therapy / J.S. Lam, O. Shvarts, J.T. Leppert et al. // J Urol. – 2005. – Vol. 173. – P. 1853–62.

64. Regulation of Notch 1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis / Z.L. Liu, T. Shirakawa, Y. Li et al. // Mol. Cell. Biol. – 2003. – Vol. 23. – P. 14–25.

65. Maxwell P.H., Pugh C.W., Ratcliffe P.J. Activation of the HIF pathway in cancer // Curr Opin Genet Dev. – 2001. – Vol. 11. – P. 293–9.

66. McMahon G. VEGF receptor signaling in tumor angiogenesis // The Oncologist. – 2000. – Vol. 5(11). – P. 3–10.

67. Prognostic role of Fuhrman grade and vascular endothelial growth factor in pT1a clear cell carcinoma in partial nephrectomy specimens / D. Minardi, G. Lucarini, R. Mazzucchelli et al. // J Urology. – 2005. – Vol. 174(4). – P. 1208–12.

68. Expression of cyclooxogenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival / Y. Miyta, S. Koga, S. Kanda et al. // Clin. Cancer Res. – 2003. – Vol. 9. – P. 1741–1749.

69. Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression / T. Quentin, T. Schlott, M. Korabiowska et al. // Anticancer Res. – 2004. – Vol. 24(5A). – P. 2745–56.

70. Papetti M., Herman I.M. Mechanisms of normal and tumor-derived angiogenesis / Am J Physiol Cell Physiol. – 2002. – Vol. 282(5). – P. 947–70.

71. Expression of vascular endothelial growth factor in renal cell carcinomas / V. Paradis, N.B. Lagha, L. Zeimoura et al. //Virchows Arch. – 2000. – Vol. 436(4). mP. 351–6.

72. Parton M., Gore M., Eisen T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer // J Clin Oncol. – 2006. – Vol. 24. – P. 5584–92.

73. Patel P.H., Chadalavada R.S.V., Chaganti R.S.K. et al. Targeting von Hippel-Lindau pathway in renal cell carcinoma // Clin. Cancer Res. – 2006. – Vol. 12(24). – P. 7215–7220.

74. VEGF and VEGFR-1 are coexpressed by epithelial and stromal cells of renal cell carcinoma / J. Rivet, S. Mourah, H. Murata et al. //Cancer. – 2008. – Vol. 112(2). P. 433–42.

75. Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species / R. Roy, G. Louis, K.R. Loughlin et al. // Clinical Cancer Research. – 2008. – Vol. 14(20). – P. 6610–6617.

76. Increased serum levels of vascular endothelial growth factor in patients with renal cell carcinoma / K. Sato, N. Tsuchiya, R. Sasaki et al. // Jpn J. Cancer Res. – 1999. – Vol. 90 (8). – P. 874–879.

77. Serum levels of vascular endothelial growth factor (VEGF) and endostatin in renal cell carcinoma patients compared to a control group / L. Schips, O. Dalpiaz, K. Lipsky et al. //Eur. Urol. – 2007. – Vol. 51(1). – P. 168–173.

78. Tung-Ping Poon R., Sheung-Tat F., Wong J. Clinical implications of circulating angiogenic factors in cancer patients // J Clin One. – 2001. – Vol. 4. – P. 1207–1225.

78. Angiogenesis in renal cell carcinoma: Evaluation of microvessel density, vascular endothelial growth factor and matrix metalloproteinases / X. Zhang, M. Yamashita, H. Uetsuki et al. // Int J Urol. – 2002. – Vol. 9(9). – P. 509–14.

In recent years, numerous studies have appeared in the literature on the study of vascular endothelial growth factor (VEGF) in the diagnosis of various diseases. FRES -
dimer, heparin-binding protein, with a molecular weight of 34-42 kDa. VEGF was isolated by Napoleon Ferrara in 1989 and the gene responsible for the synthesis of this protein has now been identified. VEGF, interacting with two structurally similar membrane tyrosine kinase receptors (VEGF-1 and VEGF-2 receptors), activates them and triggers a signaling cascade of processes that stimulate the growth and proliferation of endothelial cells.

Over the past 10 years, active study of the role of angiogenesis in the development of a number of diseases has begun. Angiogenesis is classified as a typical process leading to the formation of new blood vessels from an existing vasculature. It is necessary for the normal growth of embryonic and postnatal tissues, proliferation of the endometrium, maturation of the follicle and corpus luteum in the ovary, wound healing, and the formation of collateral vessels stimulated by ischemia. The formation of blood vessels is determined by two processes: vasculogenesis and angiogenesis. Vasculogenesis refers to the differentiation of angioblasts (precursors of endothelial cells) in embryos into blood islands that, after fusion, form the cardiovascular system or vascularize endodermal organs. Angiogenesis involves the proliferation and migration of endothelial cells in primary vascular structures and promotes the vascularization of ectodermal and mesenchymal organs and the reconstruction of the capillary network. During the process of angiogenesis, endothelial cells begin to divide (the rate of doubling of their population increases almost 100 times), forming an endothelial bud, which breaks through the basement membrane and penetrates into the connective tissue. Activation of endothelial cells is ensured by growth factors that are formed in the endothelial cells themselves, as well as components of the extracellular matrix. The cessation of the action of these factors returns endothelial cells to a resting state.

The main stimulus for the activation of angiogenesis under physiological and pathological conditions is oxygen deficiency. It is known that hypoxia promotes the accumulation of hypoxia-inducible factors - HIF (HIF-1α and HIF-1β). These factors enter the cell nucleus, bind to the corresponding HIF-responsive site and change the transcription of many genes, including vascular endothelial growth factor genes. The result is an increase in the expression of proangiogenic factors, including VEGF and fibroblast growth factors. There are a number of cells capable of increasing VEGF levels “in vitro” during hypoxia. These include fibroblasts, smooth and striated muscle myocytes, retinal pigment epithelium, astrocytes and endothelial cells, as well as some tumor cells. At the moment when the effect of pro-angiogenic factors exceeds the effect of anti-angiogenic ones, endothelial cells pass from the usual dormant state into an active one and “angiogenesis is turned on.”

Currently, both activators and inhibitors of angiogenesis have been identified, which directly or indirectly activate and suppress the proliferation of endothelial cells and vascular growth. The regulation of angiogenesis is a dynamic process of interaction between inhibitors and activators.

Important after the “switching on of angiogenesis” is the rupture of basement membranes and extracellular matrix, mainly as a result of increased activity of matrix metalloproteinases (MMPs).

MMPs play an important role in the process of angiogenesis. They belong to the family of Zn 2 + - and Ca 2 + -dependent endopeptidases involved in the remodeling of connective tissue through the destruction of its organic components at physiological pH values. MMPs received their name for their ability to specifically hydrolyze the main proteins of the intercellular matrix.

These matrix changes promote migration of endothelial cells into the extravascular space and active proteolysis of the extracellular matrix. As a result, endothelial cells are organized into tubes with a lumen and a new capillary network is formed. The process of capillary growth continues until sufficient proximity to the cell is achieved. Angiogenesis then enters a resting phase (with the exception of angiogenic cycles in the female reproductive system). Each increase in tissue mass is accompanied by neovascularization, which maintains adequate vascular density.

During the development of malignant neoplasms, after a tumor formation reaches a diameter of 2-4 mm, its further growth requires the formation of a network of capillaries from endothelial cells lining small venules. If there is a stable balance between angiogenic and antiangiogenic factors, tumor cells can remain in an inactive state for a long period of time. Tumor growth begins as a result of the predominance of the activity of angiogenesis factors. The capillary network formed during tumor growth is noticeably different from the normal one in morphological structure. The formation of blood vessels in tumors occurs against the background of perverted mitogenic stimulation and an altered extracellular matrix. This leads to the development of defective vessels, predominantly of the capillary type, often having a discontinuous basement membrane and a damaged endothelial lining. The endothelium can be replaced by tumor cells, and sometimes completely absent. Initially, the vascular network appears in the tissues adjacent to the tumor, which subsequently ensures their replacement by tumor cells.

A series of experimental and clinical studies have established that when tumor growth is activated, the expression of VEGF and other growth factors (fibroblast growth factor, epidermal growth factor, transforming growth factor-α) increases. This ensures the development and formation of the vascular bed of the tumor, which contributes to its metastasis.

Currently, research has begun on the concentration of growth factors in blood serum in various diseases. In the last decade, it has been established that activation of angiogenesis accompanies a number of diseases: rheumatoid arthritis, atherosclerotic lesions of the vascular bed, etc. Of greatest interest is the assessment of the quantitative content of the main of them, VEGF, in blood serum in malignant neoplasms. It is believed that the determination of VEGF in the blood serum of cancer patients can be used to assess the effectiveness of ongoing therapy, primarily targeted therapy, in the dynamics of treatment, to provide prognostic information, as an additional study used in differential diagnosis.

Thus, in recent years, a number of studies have been carried out to study the expression of VEGF in tumor tissue cells and in the blood serum of patients with breast, lung, prostate, and osteosarcular cancer.
coma

An important step in understanding the development pathways of kidney cancer (RC) was the recognition of VEGF as the main regulator of tumor angiogenesis. Kidney tumors are heterogeneous in composition and are represented by several types of hereditary forms of renal cell carcinoma. These include clear cell renal cell carcinoma (von Hippel-Lindau syndrome), hereditary papillary renal carcinoma, chromophobe renal cell carcinoma (Birt-Hogg-Dube syndrome). In the carcinogenesis of clear cell carcinomas, the most characteristic event is inactivation of the VHL gene (von Hippel-Lindau syndrome), resulting in abnormal production of many growth factors, including molecules that promote increased angiogenesis. The VHL protein is part of the E3-ubiquitin ligase, which, under normal oxygenation conditions, promotes the attachment of ubiquitin to transcriptomic factors (hipoxia-inducible factor -
HIF-1α, HIF-2α, HIF-3α) . Under hypoxic conditions, the VHL complex as part of the E3 ubiquitin ligase does not bind to transcriptomic factors. Accordingly, the factors HIF-1α and HIF-1β accumulate in cells. And this complex enters the nucleus, binds to the corresponding HIF-responsive site and changes the transcription of many genes, including the gene responsible for the expression of VEGF-A and other angiogenesis factors. Thus, a mutation in the VHL gene leads to the accumulation of factors that stimulate angiogenesis.

It is known that VEGF is not detected in healthy kidney tissue, but increased protein expression occurs in all types of kidney tumors. Microvascular density, together with the level of matrix metalloproteinase-2 expression, indicates large tumors larger than 7 cm.

It has been established that in patients with RP there is a significant increase in the content of VEGF in the blood serum compared to practically healthy individuals. The level of VEGF in the serum obtained from the veins of the kidneys affected by the tumor was significantly different from the level of VEGF in the serum obtained from the contralateral kidneys. In addition, serum VEGF levels changed significantly after nephrectomy. Serum VEGF levels were associated with renal tumor volume and the presence of metastases. It has also been established that when the level of serum VEGF is above 100 pg/ml, the sensitivity of this test for RP is 80%, and the specificity is 72.7%, therefore, the determination of serum VEGF can be considered as a possible marker of RP. A number of studies have shown that changes in VEGF levels cannot be used as an independent prognostic marker in RP. It has also been established that determining the level of VEGF in blood serum can have diagnostic value in identifying patients with rapid progression of the disease. In the works of M.F. Trapeznikova, P.V. Glybina, N.E. Kushlinsky et al. (2009) noted that in tumor tissue during RP there are higher levels of VEGF compared to unchanged kidney tissue. At the same time, the level of VEGF in the tumor significantly increased with a decrease in the degree of cancer differentiation and an increase in the stage of the disease.

Research into the clinical and diagnostic significance of changes in serum VEGF levels in patients with RP continues due to the emergence of new methods of targeted therapy.

Molecular genetic studies have identified potential targets for antitumor effects associated with inactivation of the VHL gene, hyperproduction of HIF or activation of the P3IK-AKT-mTOR signaling pathway, which regulate the processes of neoangiogenesis in tumor tissue: VEGF, platelet growth factor (TGF), tyrosine kinase receptors to growth factors (VEGR, TFRR), as well as the signaling protein mTOR. The effectiveness of 6 targeted agents acting on these targets has been proven for renal cell tumors: monoclonal antibodies to VEGF (bevacizumab), VEFR inhibitors (sunitinib, sorafenib, pazopanib), mTOR inhibitors (temsirolimus, everolimus). Each drug has its own medicinal properties.
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However, to date, the optimal regimen for targeted therapy for advanced RP has not been determined. Moreover, the first results of the use in clinical practice of this fundamentally different group of drugs in the treatment of patients with RP have led to the emergence of new applied problems. Thus, the features of targeted therapy for patients with target-refractory tumors and “unsuitable” patients who were not included in clinical trials have not been established. The indications for palliative nephrectomy and targeted treatment and the main markers of the effectiveness of the treatment have not been determined.

The development of bladder cancer (BC) is also associated with the identification of a number of genetic risk factors in patients. It has been established that for the development of bladder cancer to begin, the presence of a genetic mutation is necessary, which determines the possibility of uncontrolled division of urothelial cells. Mutations specific to breast cancer are: activation of the HRAS1 oncogene, inactivation of the suppressor gene RB1, damage to genes that regulate proliferation (CDKN2A and INK4B), damage to the p53 antioncogene, inactivation of the DNA repair mismatch gene, deletion of the p16 gene, microsatellite instability of the 9p locus, deletion of the TP53 gene , mutation in the 7th exon of the FGFR3 gene. Confirmation of the widespread opinion that bladder cancer is a disease of the entire mucosa is the high frequency of occurrence of many of the above mutations in the same patient, not only in tumor tissue, but also in normal urothelium.

Currently, the most significant factors of angiogenesis in bladder cancer have been identified, for which correlations with the clinical and morphological signs of the disease and its outcome have been identified. These include microvascular density, factors induced by hypoxia (VEGF and others). The main factor in the activation of tumor angiogenesis in bladder cancer is also considered VEGF. In the study Shakhpazyan N.K. (2010) found that in patients with non-muscle-invasive bladder cancer (NMBC), an increase in the level of VEGF in the blood serum is associated with activation of the tumor growth process. Studying the level of VEGF in patients with bladder cancer is advisable, since its level correlates with the density of microvessels in tumor tissue. VEGF is considered a prognostic factor for bladder cancer. As vascular permeability increases, and consequently, the invasiveness and ability to metastasize the tumor, the level of VEGF increases significantly in the blood serum of patients with invasive bladder cancer. Determining its level in the blood serum at the preoperative stage can be a prognostic marker for assessing the risk of relapse in invasive bladder cancer after cystectomy. Quantitative determination of VEGF levels also helps to diagnose tumor metastases (at blood concentrations > 400 pg/ml).

Despite the large number of studies, the clinical and diagnostic value of studying VEGF in blood serum in patients with tumor diseases of the kidneys and bladder has not been determined.

In studies conducted since 2009 on the content of VEGF in blood serum in the laboratory of the Central Scientific Research Laboratory of the State Educational Institution of Higher Professional Education "Saratov State Medical University named after. IN AND. Razumovsky Ministry of Health and Social Development of Russia" shows that studies of the content of VEGF in blood serum can be proposed as laboratory predictors and criteria for predicting the initial stages of the formation of atherosclerotic lesions of the vascular bed, as well as in patients with oncological diseases (RP and NMIBC) to assess the activity of tumor growth and in diagnosis of relapse.

The presented analysis of domestic and foreign literature and our own research results are the basis for the widespread use of quantitative determination of VEGF in blood serum in the practice of clinical diagnostic laboratories. This indicator can be considered one of the main biomarkers characterizing the processes of “angiogenesis” activation in various diseases. In patients with RP and NMIBC, an increase in the level of VEGF in the blood serum can be considered a confirmatory indicator of disease relapse.

Reviewers:

Karyakina E.V., Doctor of Medical Sciences, Professor, Leading Researcher Department of Laboratory and Functional Diagnostics of the Federal State Institution "SarNIITO" of the Ministry of Health and Social Development of Russia, Saratov;

Konopatskova O.M., Doctor of Medical Sciences, Professor of the Department of Faculty Surgery and Oncology named after. S.R. Mirtvortsev State Educational Institution of Higher Professional Education of the Saratov State Medical University named after. IN AND. Razumovsky Ministry of Health Development of Russia, Saratov.

The work was received by the editor on August 26, 2011.

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For 30 years, it has been suggested that angiogenesis, the process of formation of new blood vessels, could become an important target for anticancer therapy. And only recently this opportunity was realized. Clinical data have demonstrated that the humanized monoclonal antibody drug bevacizumab, which targets a key proangiogenic molecule, vascular endothelial growth factor (VEGF), can prolong the life of patients with metastatic colorectal cancer when administered as first-line therapy in combination with chemotherapy drugs. Here we discuss the functions and significance of VECF to demonstrate that VEGF is a reasonable target for anticancer therapy.

What is VEGF?

VEGF is one of the members of a family of structurally related proteins that are ligands for the VEGF receptor family. VEGF influences the development of new blood vessels (angiogenesis) and the survival of immature blood vessels (vascular support) by binding to and activating two closely related membrane tyrosine kinase receptors (VEGF receptor-1 and VEGF receptor-2). These receptors are expressed by endothelial cells in the wall of blood vessels (Table 1). The binding of VEGF to these receptors initiates a signaling cascade that ultimately stimulates vascular endothelial cell growth, survival, and proliferation. Endothelial cells are involved in such diverse processes as vasoconstriction and vasodilation, antigen presentation, and also serve as very important elements of all blood vessels - both capillaries and veins or arteries. Thus, by stimulating endothelial cells, VEGF plays a central role in the process of angiogenesis.

Why is it important to do Vascular Endothelial Growth Factor (VEGF human)?

VEGF is extremely important for the formation of an adequately functioning vascular system during embryogenesis and in the early postnatal period, but in adults its physiological activity is limited. Experiments on mice showed the following:

• Targeted damage to one or two alleles of the VEGF gene leads to the death of the embryo
• Inactivation of VEGF during early postnatal development is also fatal
• Damage to VEGF in adult mice is not accompanied by any obvious abnormalities because its role is limited to follicular development, wound healing, and the reproductive cycle in females.

The limited importance of angiogenesis in adults means that inhibition of VEGF activity represents a feasible therapeutic goal.

Already in July, the first Russian gene therapy drug for the treatment of vascular ischemia in the legs may appear on the market. Last September, neovasculgen (as it is called) was registered with Roszdravnadzor. It is possible that it will soon be offered for government procurement. The biotech company that created the drug, the Human Stem Cell Institute, which develops and tries to promote drugs and services “based on cellular, gene and post-genomic technologies,” speaks of the new product as a breakthrough in science. However, many experts view the new drug differently, arguing that it is actually about “patient confusion.”

In his speech on June 3, the medical director of the Human Stem Cell Institute (HSCI), Roman Deev, noted that currently only three gene therapy drugs are registered in the world, one of which is neovasculgen, and in Europe this is generally the first gene therapy drug. “Out of 1,500 clinical trials in the field of gene therapy, about 20 are aimed at treating patients with vascular pathology, and neovasculgen has already shown its effectiveness, while some drugs have dropped out,” Deev emphasized. It seems that domestic drug manufacturers have something to be proud of! But is the new medicine really effective and safe, and how much will its use cost patients?

The Society of Evidence-Based Medicine Specialists draws attention to the fact that the Human Stem Cell Institute is not a scientific institution, but a commercial organization.

The cost of two injections is about 100 thousand rubles. “The mechanism of action of neovasculgen is based on the principle of therapeutic angiogenesis,” explained HSCI director Artur Isaev. – The drug is a circular DNA molecule that contains a region responsible for the synthesis of vascular endothelial growth factor. Local administration of the drug stimulates the growth and development of new blood vessels.” Researchers are confident that for many patients the drug can become an alternative to amputation. The percentage of “success” of therapy, according to Professor R.E. Kalinin (Ryazan Medical State University), amounted to 93.6%.

In Russia, the system of angioplasty and vascular treatment of blood vessels has not been established. What is considered “high-tech care” to prevent amputations has become routine practice in most countries many years ago.

Things are bad in Russia with medicines too. Senior Researcher at the Institute of Surgery named after. Vishnevsky Leonid Blatun says that despite the availability of advanced ointments and medicines, patients in clinics of the Russian Federation “really have access to only the most outdated means,” since modern means are not included in the standards of treatment.

How safe is neovasculgen? It must be emphasized that when a new gene is introduced into a human cell, the patient may experience cancer risks. This is why drugs with this mode of action have not previously received approval. “The theory that a researcher can act on a cell growth factor, stimulate it by introducing an autogen that will produce protein growth, is generally correct,” says Valentin Vlasov, director of the Institute of Chemical Biology and Fundamental Medicine, Academician of the Russian Academy of Sciences. – That is, with the help of genetic technology, a virus is taken and it delivers the desired gene into the cell.

On this topic

Law enforcement agencies did not initiate a criminal case against Moscow resident Elena Bogolyubova, who ordered a drug not registered in Russia by mail for her terminally ill son.

“I am familiar with the project of the Stem Cell Institute and the drug neovasculgen,” says Valentin Vlasov. – In this case, there is no question of a virus vector. I do not rule out that in a very short time after the injection, protein synthesis occurs with the help of this product, and it does not seem to bring anything bad to the patient, but whether it brings anything good, in order to assert this, a very serious evidence base is needed "

The expert noted that it is quite difficult to draw such a conclusion from the photographs provided: “How to look at them, with what resolution the X-rays were taken, how they were developed - this is all on the conscience of the researchers. It seems that small vessels are branching. The report about the drug was pompous, but I can say that if such an effect exists, it is very short in time, it can only last a few days. And there is no reason to expect a miraculous effect from the drug.” According to Academician Vlasov, scientists need to achieve long-term protein production, and this can only be achieved by “inserting” the desired gene into a cell, but researchers have not yet been able to do this safely for the patient.

Even the journal in which the results of the study of the drug neovasculgen were published looks like it belongs to the same company. According to experts, questions arise from the haste in conducting clinical trials and the lack of randomization in them (a special algorithm for conducting them that excludes interest in the results). The place of administration of the drug and its description – “plasmid construct” – raised doubts.

As a result, experts came to the conclusion that this may be a case of “consumer confusion,” since large vessels in which there is no blood flow are not restored. The researchers promised benefits for patients for two years, but the trial actually lasted only six months. The absence of declared side effects from such a drug is also suspicious. The desire of scientists to find new treatment options is not disputed. But all this requires many years of research and significant evidence before application.

Patients with critical ischemia of the lower extremities in 20–50% of cases experience so-called primary amputations, but only slightly more than half of those operated on retain both legs after a year. Every fifth person dies, and in every fourth case a “major amputation” is performed. Obviously, many patients will literally stand in line for a miracle cure. Among them there will be a huge number of diabetics.

In Russia, the number of patients with diabetes mellitus complicated by diabetic foot syndrome is about 4 million people. Such a complication in half of the cases is the main indicator for amputation. In almost half of patients, treatment for this complication begins late. At the same time, in comparison with European countries, very few low-traumatic endovascular operations on the vessels of the legs are performed in Russia. According to the Russian State Medical University. N.I. Pirogov, in EU countries 8% of complications of peripheral vessels of the legs end in amputation, while in Russia this figure is significantly higher and in diabetes mellitus reaches more than 50%. According to the President of the Russian Academy of Medical Sciences, Director of the Endocrinological Research Center of the Ministry of Health and Social Development Ivan Dedov, about 8-10% of patients with diabetes are affected by diabetic foot syndrome, and up to 50% of them can be classified as at risk. After amputations, the mortality rate of patients doubles, but if such patients are not operated on, they will die of gangrene within two years.