Angiogenesis and Aggressive Cancer: The Paradox
It is widely accepted that aggressive cancers are highly angiogenic. This observation, made first in breast cancer, also appears to apply to many tumor systems.
Suggested Reference: Weidner N. Tumoral vascularity as a prognostic factor in cancer patients - the evidence continues to grow. J Pathol 1998;184:119-122.
At first glance, it appears that microvascular density is a marker of aggressive tumor behavior in the system of interest in our laboratory - uveal melanoma.
Suggested Reference: Makitie T, et al. Microvascular density in predicting survival of patients with choroidal and ciliary body melanoma. Invest Ophthalmol Vis Sci 1999;40:2471-2480.
However, high aggressive tumors are genetically deregulated and express a variety of inappropriate markers. For example, aggressive uveal melanomas and other cancer co-express vimentin and keratin intermediate filaments. Aggressive melanomas also co-express endothelial cell markers. Therefore, the parameter measured as microvascular density may reflect not only the number of vessels within a tumor, but also the number of genetically deregulated tumor cells that inappropriately express endothelial cell markers.
Suggested References:
Folberg R, et al. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 2000;156:361-381.
Hendrix MJ, et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc Natl Acad Sci USA. 2001;98:8018-8023.
Chen X, et al. Uveal melanoma cell staining for CD34 and assessment of tumor vascularity. Invest Ophthalmol Vis Sci 2002;43:2533-2539.
Question: If highly aggressive cancers are destructive of the local host microenvionment, then by what mechanisms do they permit the ingrowth of new endothelial cell-lined channels into this very cell compartment that destroys host tissues? Tumor angiogenesis may be a compartmentalized event, with angiogenic vessels contained within a stromal compartment (rather than adjacent to aggressive, locally destructructive tumor cells). Uveal melanoma does not contain a rich stroma. Therefore, when angiogenesis develops in this system, it may appear in zones of tumor that do not contain the most aggressive cells.
Suggested Reference: Maniotis AJ, et al. Control of melanoma morphogenesis, endothelial survival, and perfusion by extracellular matrix. Lab Invest 2002;81:1031-1043.