Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
Much of the cellular heterogeneity within tumors is found in their stromal compartments. Prominent among the stromal constituents are the cells forming the tumor-associated vasculature. Mechanisms of development, differentiation, and homeostasis of endothelial cells composing the arteries, veins, and capillaries were already well understood in 2000. So too was the concept of the “angiogenic switch,” which activates quiescent endothelial cells, causing them to enter into a cell-biological program that allows them to construct new blood vessels (see above). Over the last decade, a network of interconnected signaling pathways involving ligands of signal-transducing receptors displayed by endothelial cells (e.g., Notch, Neuropilin, Robo, and Eph-A/B) has been added to the already-prominent VEGF, angiopoietin, and FGF signals. These newly characterized pathways have been functionally implicated in developmental and tumor-associated angiogenesis and illustrate the complex regulation of endothelial cell phenotypes.
Other avenues of research are revealing distinctive gene expression profiles of tumor-associated endothelial cells and identifying cell-surface markers displayed on the lumenal surfaces of normal versus tumor endothelial cells. Differences in signaling, in transcriptome profiles, and in vascular «ZIP codes» will likely prove to be important for understanding the conversion of normal endothelial cells into tumor-associated endothelial cells. Such knowledge may lead, in turn, to opportunities to develop novel therapies that exploit these differences in order to selectively target tumor-associated endothelial cells.
Closely related to the endothelial cells of the general circulation are those forming lymphatic vessels. Their role in the tumor-associated stroma, specifically in supporting tumor growth, is poorly understood. Indeed, because of high interstitial pressure within solid tumors, intratumoral lymphatic vessels are typically collapsed and nonfunctional; in contrast, however, there are often functional, actively growing («lymphangiogenic») lymphatic vessels at the peripheries of tumors and in the adjacent normal tissues that cancer cells invade. These associated lymphatics likely serve as channels for the seeding of metastases in the draining lymph nodes that are commonly observed in a number of cancer types.