Tumour angiogenesis: vascular growth and survival

Abstract

Angiogenesis starts at the edge of a malignant epithelial tumour concurrently with tumour cell invasion and stromatogenesis, i.e. the formation of specific connective tissue stroma amenable to easy penetration by endothelial and tumour cells. However, as the tumour continues its growth, the edge becomes the inner tumour area, and a new invading tumour front is formed by the multiplying malignant cells which outflank the initial edge. This process, which repeats itself again and again, forms the “relay race” model of tumour vascular growth and regression. At the heart of the tumour unfavourable environmental conditions prevail – hypoxia, acidity, lack of nutrients, failure of waste removal, and apoptosis rather than proliferation. Blood vessels and tumour cells are greatly decreased, but do not vanish, as tumour cells are shifting to anaerobic glycolysis, and blood vessels are turning into anti‐apoptotic pathways – vascular survival ability (VSA). Thus, assessing vascular density (VD) by simply counting “hot spots” at the edge of a tumour, where conditions are most favourable, is futile; it may reflect tumour angiogenic activity (TAA), but is not representative of genuine tumour vasculature. By combining vessel counts at the invading tumour front with those of the inner tumour areas a complete picture of tumour VD can be achieved. The thus formed four patterns of vascularization, designated as “edvin” (edge vsinner tumour area), are: edvin 1: low TAA/low VSA; edvin 4: high TAA/high VSA; edvin 2: low TAA/high VSA; and edvin 3: high TAA/low VSA. It is expected that this scheme will prove useful in the field of chemoradiotherapy and anti‐angiogenic treatment.

The pathology of tumor stromatogenesis

“…Indeed, under the light of an ordinary microscope, over and above other features encountered along the invading tumor front the one that truly dominates is "stromatogenesis", an ever existing but only recently unveiled phenomenon of the metastatic cascade. [14][15][16][17][18] …”

Autophagy patterns and prognosis in uveal melanomas

“…12,13 Experimental studies suggest that hypoxia is a potent stress stimulus triggering autophagy in normal and malignant cells.…”

Angiogenesis and Non Small Cell Lung Cancer

“…Normal tissues act as a barrier for tumor invasion and angiogenesis occurs simultaneously with the formation of new stroma (stroma togenesis). The loose and oedematous stroma is easily amenable to penetration by endothelial and tumor cells and allows endothelial cell migration and tumor cell invasion [8]. Thus, angiogenesis permits growth of the primary tumor and provides a pathway for migrating tumor cells to gain access to the systemic circulation and to establish distant metastases.…”

“…However, new blood vessel formation occurs mainly at the tumor periphery, while inner regions that form the great bulk of the tumor often lack vessels. Also in tumor periphery and inner parts of the tumor regions of extreme microvessel density ("hot spots") alternate with others of vascular sparsity [8]. Secondly, the method does not distinguish between new and old vessels, or whether there is actual blood flow through the new vessels [6].…”

“…Angiogenesis is the development of new capillary beds from the endothelium of pre-existing blood vessels [6]. Studies in animal tumor models have suggested that tumor endothelial cells may also be derived from circulating endothelial precursor cells originating from the bone marrow [8]. Angiogenesis is a multi-step process that involves activation of endothelial cells and production of matrix metalloproteinases (MMPs), which break down the surrounding extracellular matrix [9], proliferation of activated endothelial cells, migration of these cells to remote regions and then assembly into new capillary tubes and the synthesis of a new basement membrane and maturation of vessels with formation of a vascular lumen [10].…”