Current concepts of tumor-induced angiogenesis

Abstract

Tumor induced angiogenesis is responsible for the nutrition of the growing tumor and can also increase the probability of hematogenous tumor dissemination. Data obtained from morphological analysis of tumor angiogenesis can contribute to the development of new anti-angiogenic therapies. Based on in vitro and in vivo observations several models of angiogenesis were introduced, explaining the mechanism of lumen formation and the timing of basement membrane depositon. (1) Lumen is formed either by cell body curving or by fusion of intracellular vacuoles of nonpolarized endothelial cells. New basement membrane is deposited after lumen formation. (2) Slit-like lumen is immediately formed by migrating polarized endothelial cells. Basement membrane is continuously deposited during endothelial cell migration, only cellular processes of the endothelial cell migrating on the tip of the growing capillary are free of deposited basement membrane material. (3) Development of transluminal bridges in larger vessels a process called intussusceptive growth leads to the division of the vessels. These models, however, describe angiogenesis in tissues rich in connective tissue. Different processes of angiogenesis take place in organs such as liver, lungs, adrenals, which are the most frequent sites of metastasis having high vessel density without sufficient space for capillary sprouting. In the case of liver metastases of Lewis lung carcinoma the proliferation of endothelial cells was elicited only by direct contact between tumor and endothelial cells, leading to the development of large convoluted vessels inside the metastases. These vessels were continuous with the sinusoidal system, suggesting that these metastases have dual blood supply. This observation, among others, is in contrast to the generally accepted view that liver tumors have arterial blood supply. The increasing number of data demonstrating the dual or venous blood supply of liver metastases should be taken into consideration in the therapy of liver metastasis.

A New Mechanism for Pillar Formation during Tumor-Induced Intussusceptive Angiogenesis: Inverse Sprouting

“…During the normal sprouting process, ECs maintain their polarity, migrate surrounded by connective tissue, and form a slit-like lumen. 2 During pillar formation, ECs are surrounded by the vessel lumen and the connective tissue is situated inside the sprout. As in normal sprouting, ECs involved in inverse sprouting also maintain their polarity.…”

“…Angiogenesis is the formation of new blood vessels from pre-existing ones. Several different forms exist, 1 but so far endothelial sprouting 2,3 and intussusceptive angiogenesis 4 -8 have been investigated the most intensively.…”

“…As the final step, proliferating pericytes of the mother vessel migrate along the basement membrane of the sprout, resulting in the maturation of the new vessel. 2 In contrast to endothelial sprouting, the other major angiogenic mechanism, intussusceptive microvascular growth, or intussusceptive angiogenesis, which has been described in a wide variety of normal and pathological conditions, is faster and does not depend primarily on EC proliferation. The most characteristic feature of intussusceptive angiogenesis is the insertion of connective tissue columns, called tissue pillars, into the lumen and the subsequent growth of these pillars, resulting in partitioning of the vessel lumen and the consequent increase in the density of the given capillary network.…”

Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor

“…4 and 5,c,i,and j), rendering the luminal surface irregular and therefore likely to cause turbulent blood flow (Cohen, 1985). Following Paku and Paweletz (1991), we have called these enlarged vessels "mother" vessels. Mother vessels continued to develop over the next 2-3 days in muscle and for somewhat longer at skin injection sites.…”

The use of the orthotopic model to validate antivascular therapies for cancer

“…Given its pivotal role in these processes, tumour vasculature is a highly attractive target in anticancer therapy. Compared with the vasculature in normal tissue, the tumour vasculature is strikingly disorganized and tortuous (Eberhard, 2000;Konerding, 2001;McDonald and Choyke, 2003), its wall is poorly developed, often with discontinuous endothelial-cell lining, has relatively poor investiture with vascular smooth muscle cells, poor connections between pericytes and endothelial cells (Dvorak, 1988;Eberhard, 2000;Hashizume, 2000;Kobayashi, 1993) and an irregular, structurally abnormal basement membrane (Baluk, 2003;Paku and Paweletz, 1991). Endothelial cells themselves are often irregularly shaped, forming an uneven luminal layer, with loose interconnections and focal intercellular openings (Hashizume, 2000).…”