Antiangiogenic therapy in human gastrointestinal malignancies
Authors: J Heidemann
Journal: Gut (2006)

Angiogenesis is a crucial process involved in numerous physiological and pathophysiological settings.During the past three decades, the field of tumour associated angiogenesis has been the focus of a plethora of basic research projects and clinical studies.Tumour associated neovessels satisfying the increased demand of oxygen and nutrients in malignant tumours are now emerging as specific targets for novel antineoplastic agents.This article discusses the present data on antiangiogenic treatment of human gastrointestinal malignancies, including gastric, pancreatic, and colorectal adenocarcinoma, and outlines potential future perspectives, such as development of surrogate markers of angiogenesis. PROCESS OF TUMOUR ANGIOGENESIS cAngiogenesis, the formation of new vessels from existing capillary beds, represents a central mechanism involved in many physiological and pathophysiological conditions, including embryonal development, wound healing, and chronic inflammation. 1In malignant tumours, angiogenesis represents a prerequisite for tumour growth, as the high metabolism of tumour cells requires large amounts of oxygen and nutrients.Without angiogenesis, the growth of malignant tumours is limited to 1-2 mm in diameter, which corresponds to the maximum distance oxygen can diffuse. 2 3Tumour vascularisation represents a conditio sine qua non for exponential tumour growth.Studies have indicated that the mitotic index of tumour cells decreases with increasing distance from the supplying microvessel. 1 3 4 Primary tumours as well as their metastases are dependent on tumour associated microvessels to establish an independent blood supply. 3 5Enhanced vascularity allows tumours not only to expand in size but also facilitates haematogenous spreading by a higher probability of tumour angioinvasion.Once deposited in a distant organ, tumour metastases are dependent on building their own microvasculature. 6For this reason, disruption of angiogenesis pathways provides a therapeutic perspective in the treatment of primary malignant human tumours as well as their metastases.The concept that metastases are solely dependent on newly formed blood vessels in order to grow is opposed by observations made by Vermeulen and colleagues. 7According to their findings, approximately one third of hepatic colon cancer metastases studied (n = 28) do not induce new vessels but rather use and preserve the existing abundant vascularisation of the liver parenchyma.This pattern, called ''replacement pattern'', differs from the so-called ''desmoplastic'' and ''pushing''-type of metastasis.In all three patterns of metastasis, overall vessel density was not significantly different.However, a much lower endothelial cell proliferation was encountered in the replacement-type of metastasis.These findings suggest that not counting vessels, but rather evaluating endothelial cell (EC) proliferation, might be the appropriate way for assessing angiogenesis, depending on the type of metastasis. 8he concept of human tumours being capable of secreting angiogenic factors was first introduced by Dr Judah Folkman in the 1970s, who is widely regarded as a pioneer of angiogenesis research. 9Human microvascular angiogenesis is tightly controlled by a plethora of biochemical variables, including soluble factors (for example, cytokines, growth factors, enzymes modifying the extracellular matrix), as well as hypoxia and acidity (fig 1).Tumour angiogenesis is a mechanism by which the tumour responds to hypoxia and resistance to hypoxia may be attributed to overexpression of enzymes such as haemoxygenase-1 10 and carbonic anhydrase. 11Angiogenic factors are produced by a multitude of physiological cell populations, 12 including smooth muscle cells and pericytes, 13 endothelial cells, 14-16 and tumour cells, as well as epithelial cells from colorectal carcinoma. 17ascular endothelial growth factor (VEGF) and many other angiogenic factors are endogenous ligands of receptors present on the EC surface, leading to initiation of intracellular signal transduction and gene transcription, eventually resulting in EC proliferation, active locomotion c Activation of oncogenes or loss of tumour suppressor genes is often associated with expression of angiogenic factors by tumour cells.