Role of the Microenvironment and Angiogenesis

The anatomical location of a tumor may be an important determinant in regulating the phenotype of its vasculature. Unfortunately, many preclinical studies neglect to account for influence of the microenvironment on tumor growth and vascularization by utilizing models in which different types of tumors are all implanted into the subcutaneous space. One may argue that, with the exception of those tumors originating from or metastasizing to skin, subcutaneously implanted tumors provide relatively little useful information regarding antiangiogenic intervention. This is perhaps true in that this model evaluates only one type of endothelial cell (dermal) and, equally important, because frequently the tumor is located in an ectopic site. Recently, Blouw and coworkers [2] utilized an elegant strategy involving HIF-1a-deficient transformed astrocytes to illustrate how HIF-1a can act as either a negative or a positive regulator of astrocytoma progression, depending on the microenvironment in which the tumor is located. Specifically, the loss of HIF-1a impaired the growth of astrocytomas in the subcutis, but not in the brain. This finding was attributed to the inability of HIF-1a-deficient cells to mobilize VEGF that, consequently, blocked their capacity to recruit new vessels in the inherently vessel-poor subcutaneous compartment (see Figure 2), whereas the same HIF-1a-deficient cells exploited the preexisting rich vascular networks of the brain. The results of this study are noteworthy in several respects. First, had the examination been conducted solely within the confines of the subcutaneous space, one may have reached the conclusion, albeit an incorrect one, that targeting HIF-1 a may be an effective approach to control the growth of glioblastomas. In addition, recently there has been an appreciable interest in the development of pharmaceuticals capable of targeting HIF-1a in tumors. If this interest is extended to the production phase, it would be very informative to determine whether agents directed against HIF-1a possess efficacy in the treatment of cancer metastases located in lung, brain, bone, or liver tissue, which are well-vascularized tissues.

Studies evaluating angiogenesis in human tumors also conclude that there is considerable heterogeneity regarding the intensity of endothelial cell proliferation among different types of tumors. Eberhard and colleagues utilized a double-labeling immunohistochemical approach to measure proliferating endothelial cells in a broad panel of human tumors. The data from this study indicate that glioblastomas and renal cell carcinomas possess the highest number of capillary beds with evidence of endothelial cell proliferation (9.6% and 9.4%, respectively), whereas lung and prostate tumors possess the fewest (2.6% and 2.0%, respectively). These results caution against accepting rapidly dividing murine tumors that grow exponentially over a period of a few weeks as the model for the more measured expansion that takes place in human malignancies.

Recent improvements in the ability to selectively isolate and propagate endothelial cells from different organs can now permit more detailed examinations into the tissue-specific factors that regulate angiogenesis. Indeed, our laboratory has applied a series of multicolor flow cytometry selection strategies that target inducible endothelial cell adhesion molecules to H-2Kb-tsA58 murine tissues in order to generate microvascular endothelial cell lines from a number of different organs [3]. Cells derived from H-2Kb-tsA58 mice all harbor a temperature-sensitive SV40 large T antigen and, thus, permit detailed molecular examinations on both activated and differentiated phenotypes of endothelial cells. Preliminary studies conducted on several endothelial cell lines reveal that each possesses distinct growth factor profiles. For example, we have noted that for uterine-derived endothelial cells, the most potent endothelial cell mitogen is epidermal growth factor (EGF). However, for endothelial cells originating from bone tissue, basic fibrob-last growth factor (bFGF) elicits the most robust increase in proliferation (unpublished data). Similarly, a recent study conducted on microvascular endothelial cells from the human intestine has determined that interleukin-8 can promote both cell division and migration. cDNA expression arrays have also been utilized to construct gene expression profiles on human endothelial cells obtained from brain, lung, and lymphatic tissue. Additional reports have provided evidence that some tissues elaborate organ-restricted endothelial cell mitogens and that, moreover, these growth factors can be detected in tumors arising from these anatomic regions.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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