In tumor angiogenesis, two main mechanisms are officially recognized. They are: the formation of vascular structures by associations of endothelial cell precursors (PEK) or angioblasts from circulating peripheral blood (1) and vascular co-optation (2) using preexistent vessels. Determining the dominant phenotype of endothelial cells (EC) involved in the neoangiogenesis of uveal melanoma (UM) is very important due to the different sensitivity of different EC to antiangiogenic therapy and their biological differences. Circulating hemangioblasts of bone marrow origin (synonym: endothelial cell precursors, PEC) involved in the formation of vessels in the tumor can also originate from hematopoietic stem cells and, in conditions of an excess of proangiogenic growth factors, undergo “reverse differentiation” or “dedifferentiation”. This situation is extremely dangerous due to changes in the biological properties of EC: the rate of proliferation increases and high resistance to any type of interventional antiangiogenic therapy, including targeted antiangiogenic drugs, develops. In combination with high resistance to radiation therapy and chemotherapy of tumor cells, such a tumor becomes uncontrollable and quickly leads to death... The purpose of this study: to identify the phenotype of endothelial cells involved in UM angiogenesis by immunohistochemical analysis. The authors conducted immunohistochemical studies on paraffin blocks (n = 98) of enucleated eyes with UM. One of the recommended PEC markers was used: a monoclonal antibody to the VEGFR2-KDR/Flk-1 receptor. It was found that the expression of the VEGFR- 2/Flk-KDR-1 receptor took place only in 22.1 % of the UM. The receptor was expressed exclusively by endothelial cells (EC) of tumor vessels and was not expressed by UM cells. There was no basic expression of the receptor (at stage T1). Peak expression was observed at stage T2. At the next stages of the oncological process, there was a decline in expression. The mean IHC gradation of expression intensity also decreased from stage T2 to stage T4. Flk-positive and negative endothelial cells differed in size, shape, nature of communication with the vascular wall and the presence or absence of a nucleus in the cell. The authors concluded that both mechanisms of angiogenesis take place in UM. A small percentage (22.1 %) Flk+endothelial cells indicate that the dominant mechanism of angiogenesis in UM is co-optation of vessels based on preexistent, and the dominant population of EC is Flk-negative EC.

A prerequisite for the growth, progression and metastasis of malignant tumors of any localization is the development of its own vascular network. Newly formed vessels not only nourish the primary tumor, but also create conditions for the spread of tumor cells through the circulatory system and the formation of distant metastases. Angiogenesis is able to launch a small population of tumors from 100–300 cells that have accumulated genetic aberrations and have begun to express proangigenic molecules. The phenomenon is known as “transformation of tumor cells into angiogenic phenotype”. A tumor with angiogenic phenotype carries a high potential for proliferation and malignization. This pattern has been found in many types of cancer, but studied less in uveal melanoma. Meanwhile, in this aspect, uveal melanoma, metastasizing exclusively in a hematogenic way, with its selective, organotropic nature of metastasis, becomes an attractive model for the study of the molecular “scenario” of tumor angiogenesis studies allow us to say that, UM is subject to the general patterns of the development of malignant tumors. As with many types of tumors, VEGF is an obligate condition for the development and progression of UM. The VEGF molecule’s producers in UM are two cell populations: endothelial vascular cells and tumor cells. VEGF’s expression in UM is cyclical. The cycle is re-initiated, apparently, by increasing cell density in tumor proliferate and the development of hypoxia zones. We found no correlation between the intensity of pigmentation, necrosis, hemorrhage, germination in the corner of the front chamber, ophthalmohypertension on the one hand, and expression of VEGF in UM cells on the other. At the same time, a direct link between the expression of VEGF in tumor cells and EC vessels on the one hand and the thickness, base diameter, as well as the localization of UM, on the other hand, has been revealed. Additionally, VEGF expression in tumor cells was closely correlated with the histological structure of UM, and VEGF expression in EC correlated with the stage of the disease. Thus, the authors showed that UM, like other malignant solid tumors, is prone to transformation into angiogenic phenotype and expression of VEGF.

Thanks to new fundamental data, our understanding of the angiogenesis’ role and its molecular participants has changed. Molecular genetic mechanisms of activation of signaling pathways of proliferation, malignancy, suppression of the tumor cells’ apoptosis, carried out through the interaction of the VEGF molecule with its receptors, have been deciphered. Molecular genetic mechanisms of activation of signaling pathways of proliferation, malignancy, suppression of apoptosis of tumor cells, carried out through the interaction of the VEGF molecule with its receptors, have been deciphered. The doctrine of angiogenesis has changed. Angiogenesis began to be considered in the aspect of the increasing anaplasia mechanism, accelerating proliferation, the formation of a clone of stem tumor cells, highly resistant to chemotherapy and radiation therapy with a high potential for metastasis. It is time to reconsider the role of individual biological markers of angiogenesis in their suitability in predicting disease outcome and evaluating them as a potential target for targeted therapy. In this aspect, uveal melanoma (UM) as a model of an extremely aggressive malignant tumor using its angiogenic phenotype to accelerate hematogenous metastasis is of particular interest. One of the characteristics of the angiogenic phenotype is VEGF-R1/Flt-1. The purpose: to study the expression of the VEGF-R1/Flt-1 receptor as a characteristic of the angiogenic phenotype of UM in correlation with its clinical and morphological indicators and the outcome of the disease. The authors conducted a retrospective study on 98 archival paraffin blocks of the eyes of patients with UM. The following general patterns of Flt expression in UM cells are revealed: Basic expression takes place in the smallest tumor proliferates UM (T1). Moreover, overexpression (IGH-gradation III) of Flt in the nucleus (39.7 %) and cytoplasm (36.3 %) occurred in every third patient with UM in stage T1. The peak of reception for the maximum average percentage of positive cells and the average cellular IGH gradation of expression was recorded at the T2 stage, after which there was a slow decline to the T4 stage. The number of overexpressive Flt in the nucleus and cytoplasm of UM cells increased x 2 times (75.3 %) to the T2 stage. The peak of Flt nuclear expression in terms of the number of immunopositive cells was also recorded at the T2 stage. The authors concluded that VEGF-R1/Flt-1 expression is a very important characteristic of the UM angiogenic phenotype. In the vast majority of UM, there is an expression of the VEGF-R1/Flt-1 receptor in the nucleus and cytoplasm of tumor cells. The revealed correlations of VEGF-R1/Flt-1 expression with the volume and histological type of tumor, disease stage and metastasis allow them to consider Flt-1 an important indicator associated with the pathogenesis and prognosis of uveal melanoma and a potential target for targeted therapy. A prognostic adverse factor in the aspect of the prognosis of the risk of metastases should be considered the index of the ratio Flt C/Flt N ≥ 3.