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Judah Folkman (1974) estimated that as many as 350 billion mitoses occur in the human body every day. With each cell division comes the chance that the resulting cells will be malignant. Indeed, autopsies have shown that every person over 50 years old has microscopic tumors in their thyroid glands, although less than 1 in 1000 persons have thyroid cancer (Folkman and Kalluri 2004). Folkman suggested that cells capable of forming tumors develop at a certain frequency, but that they most never form observable tumors. The reason is that a solid tumor, like any other rapidly dividing tissue, needs oxygen and nutrients to survive. Without a blood supply, potential tumors either die or remain as dormant “microtumors”; stable cell populations wherein dying cells are replaced by new cells. Thus, one important area in which knowledge of development can contribute to cancer therapies is the inhibition of angiogenesis (blood vessel formation).
The critical point at which a node of cancerous cells becomes a rapidly growing tumor occurs when the node becomes vascularized. A microtumor can expand to 16,000 times its original volume in the two weeks following vascularization (Folkman 1974; Ausprunk and Folkman 1977). To achieve vascularization, the microtumor secretes substances called tumor angiogenesis factors, which often include the same factors that engender blood vessel growth in the embryo—VEGF, Fgf2, placenta-like growth factor, and others. Tumor angiogenesis factors stimulate mitosis in endothelial cells and direct their differentiation into blood vessels in the direction of the tumor.
Tumor angiogenesis can be demonstrated by implanting a piece of tumor tissue within the layers of a rabbit or mouse cornea. The cornea itself is not vascularized, but it is surrounded by a vascular border, or limbus. The tumor tissue induces blood vessels to form and grow toward the tumor (Figure 1; Muthukkaruppan and Auerbach 1979). Once the blood vessels enter the tumor, the tumor cells undergo explosive growth, eventually bursting the eye. Other adult solid tissues do not induce blood vessels to form. It might therefore be possible to block tumor development by blocking angiogenesis. Numerous chemicals are being tested as natural and artificial angiogenesis inhibitors. These compounds act by preventing endothelial cells from responding to the angiogenetic signal of the tumor.
In one set of clinical trials, an antibody against VEGF was found to be successful against colon cancer, but not against mammary carcinoma. This is probably because colon cancer is more dependent on VEGF-induced angiogenesis than are mammary tumors (Whisenant and Bergsland 2005). Antibodies against a placental form of VEGF were able to inhibit the growth of tumors without affecting healthy blood vessels (Fischer et al. 2007). Blocking the VEGF receptor VEGFR3 prevents the angiogenic sprouting needed for new blood vessels (Tammela et al. 2008), and prevents tumors from getting blood-born nutrients and oxygen. Interestingly, thalidomide, the teratogen responsible for birth defects in the 1960s, is on this list. Thalidomide has been found to be a potent anti-angiogenesis factor that can reduce the growth of cancers in rats and mice* (D’Amato et al. 1994; Dredge et al. 2002; see also Website Topic 18.3 Thalidomide as a teratogen).
Unfortunately, cancers can become able to circumvent the angiogenesis inhibitors (Bellou et al. 2013; Giuliano and Pagès 2013). Early in treatment, the growth of the primary tumor is slowed or prevented, but this cessation is often followed by development of formation of new blood vessels and the subsequent growth of the tumor. This circumvention can occur in several ways, and these have each been linked to the hypoxic (low oxygen) conditions that arise around the tumor cells. Remember that developing organs often develop before they receive blood supply. That is to say, they develop in hypoxic environments, and they have evolved strategies for dealing with this—and the tumor cells use these strategies. The oxygen-deficient condition triggers the expression of pro-angiogenesis factors in the tumor cells or in tumor-associated macrophages. These factors (such as epithelial growth factor, FGFs, angiogenins, HIF-1α, and CXCL cytokines) are normal cell responses to hypoxia. These pro-angiogenic factors recruit cells to form new blood vessels. The tumor cells may also downregulate normal anti-angiogenesis factors such as soluble VEGF. Thus, by causing hypoxia, anti-angiogenesis therapies can aid the selection of hypoxia-tolerant tumor cells and activate alternative pathways to blood vessel formation. Moreover, hypoxia may also enhance the invasive properties of the tumor cells, themselves, thereby increasing the possibility of metastases.
Just as in embryonic development, hypoxia induces the formation of blood vessels, and when one system is blocked, other systems can be brought in to compensate. Anti-angiogenesis is an excellent way of preventing tumor growth; but in order to prevent angiogenesis, we have to learn more about how it normally can occur. Most of the therapies, for instance, have been against the VEGF receptors. Newer therapies are blocking other angiogenic paracrine pathways, either singly or in combination.
*Another interesting agent for reducing angiogenesis is green tea. The consumption of green tea has been associated with lower incidences of human cancer and the inhibition of tumor cell growth in laboratory animals. Cao and Cao (1999) have shown that green tea, as well as one of its components, epigallocatechin-3-gallate (EGCG), prevents Fgf2- and VEGF-induced angiogenesis. EGCG may also inhibit the receptor tyrosine kinase pathway, repress the activity of certain transcription factors, and cause apoptosis in malignant cells (Jung et al. 2001; Yang et al. 2009; Gu et al. 2013).
Ausprunk, D. H. and J. Folkman. 1977. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14: 53–65.
Bellou, S., Pentheroudakis, G., Murphy, C., and Fotsis, T. 2013. Anti-angiogenesis in cancer therapy: Hercules and hydra. Cancer Lett. doi:pii: S0304-3835(13)00384-4. 10.1016/j.canlet.2013.05.015.
Cao, Y. and Cao, R. 1999. Angiogenesis inhibited by drinking tea. Nature 398: 381.
D’Amato, R. J., Loughnan, M. S., Flynn, E., and Folkman, J. 1994. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. USA 91: 4082–4085.
Dredge, K. and 7 others. 2002. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Brit. J. Cancer 87: 1166–1172.
Fischer, C. and 19 others. 2007. Anti-PIGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131: 463–475.
Folkman, J. 1974. Tumor angiogenesis. Adv. Cancer Res. 19: 331–358.
Folkman, J. and Kalluri R.. 2004. Cancer without disease. Nature 427: 787.
Giuliano S., Pagès G. 2013.Mechanisms of resistance to anti-angiogenesis therapies. Biochimie. 2013 Jun;95(6):1110-9.
Gu, J. W, Makey, K. L., Tucker, K. B., Chinchar, E., Mao, X., Pei, I., Thomas, E. Y., Miele, L. 2013. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression. Vascular Cell 5(1):9. doi: 10.1186/2045-824X-5-9.
Jung Y. D., Kim M. S., Shin B. A., Chay K. O., Ahn B. W., Liu W., Bucana C. D., Gallick G. E., Ellis L. M. 2001. EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. Brit. J. Cancer. 84: 844–850.
Muthukkaruppan, V. R. and Auerbach, R. 1979. Angiogenesis in the mouse cornea. Science 205: 1416–1418.
Tammela, T. and 20 others. 2008. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454: 656–660.
Whisenant, J. and Bergsland, E. 2005. Anti-angiogenic strategies in gastrointestinal malignancies. Curr. Treat. Options Oncol. 6: 411–421.
Yang, C. S., Wang, X., Lu, G., Picinich, S.C. 2009. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nature Rev. Cancer. 9: 429–39.
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