Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization
Section snippets
Abnormal blood vessel architecture and function in tumors
The normal microvessels consist of arterioles, capillaries, and venules, and form a well-organized, regulated, and functional architecture (Fig. 1A) (Jain, 2003). In contrast, tumor vessels are dilated, saccular, tortuous, and heterogeneous in their spatial distribution (Fig. 1A) (Jain, 1988). Normal vasculature is characterized by dichotomous branching, but tumor vasculature is unorganized and has trifurcations and branches with uneven diameters. Vessel wall structure is also abnormal in
Causes and consequences of abnormal metabolic environment in tumors
Hypoxia and acidosis are hallmarks of the abnormal metabolic environment in solid tumors (Fig. 1E) (Harris, 2002, Helmlinger et al., 1997, Tatum et al., 2006). A key function of the vasculature is to provide adequate levels of nutrients and oxygen to the parenchymal cells and to remove waste products. Tumor vessels fail to do so adequately due to their abnormal structure and function. The imbalance of vascular network development and tumor cell proliferation results in the formation of
Involvement of host stromal cells in tumor angiogenesis
It is becoming increasingly apparent that the development and pathophysiology of a tumor cannot be explained simply by the genes in the tumor cells (Weinberg, 2006). We are beginning to understand that host stromal cells profoundly influence many steps of tumor progression, such as tumor cell proliferation, invasion, angiogenesis, metastasis, and even malignant transformation (Elenbaas and Weinberg, 2001, Fukumura et al., 1998, Li et al., 2003, Liotta and Kohn, 2001, Pollard, 2004, Ruiter et
Normalization by targeting VEGF signaling
As discussed earlier, excess production of pro-angiogenic molecules and/or diminished production of anti-angiogenic molecules may cause the abnormalities in vessels and microenvironment in tumors resulting in insufficient drug delivery and therapeutic efficacy (Jain, 2005). If one can restore the balance of pro- and anti-angiogenic factors, the vasculature might revert back to a more “normal” state (Jain, 2001, Jain, 2005). Targeting angiogenic signaling such as provided by VEGF, which is
Acknowledgments
This review is based on the following previous review articles: Jain RK (2005): Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58–62; Fukumura D (2005): Role of microenvironment on gene expression, angiogenesis and microvascular functions in tumors. In Meadows GG (ed): “Integration/Interaction of Oncologic Growth.” Dordrecht: Springer Science + Business Media B.V., pp. 23–36; Fukumura D and Jain RK (in press): Tumor microenvironment abnormalities:
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