Roger Clemens

Few struggle with the war against cancer more than the half-million families affected by cancer deaths annually than Dr. Judah Folkman, whose 1971 landmark publication launched one of the most significant research battles against cancerous tumors. Tumor growth requires endothelial cell proliferation and its own network of blood vessels, a process known as angiogenesis. The concept of controlling tumor growth through anti-angiogenic therapy has dominated cancer research strategies in major medical centers for three decades.

Approved for clinical use in the United States are angiogenesis inhibitors for treatment of metastatic cancer of the colon or rectum, advanced pancreatic and lung cancer, and neovascular (wet) age-related macular degeneration. This approach of clinical therapy with the co-administration of anti-neoplastics such as 5-fluorouracil, have markedly increased patient survival with minimal side effects.

Angiogenesis is not particularly evident in the mature adult, except for the female reproductive system, which undergoes cyclic changes associated with intense growth of new blood vessels. Significant angiogenic changes also occur in the mammary gland, mostly following childbirth, and in the placenta during pregnancy. These angiogenic dynamics are intricately controlled by many factors, among them promoters like vascular endothelial growth factor (VEGF), placental growth factor (PlGF), transforming growth factor (TGF)-β1, and fibroblast growth factors (FGF), which are balanced by a myriad of endogenous anti-angiogenic factors. Angiotensin and endostatin are just two of the 27 endogenous angiogenesis inhibitors that have been identified. Approximately 60% of the nearly 200 different types of human cancers express VEGF. Thus, anticancer activity is often focused on the inhibition of synthesis, receptor blockage, and interruption of expression of VEGF, FGF, and TGF isoforms.

Emerging evidence suggests that some dietary components may exert pharmacological functions and modulate angiogenesis and proliferation of tumor cells. Aged garlic extract has been shown to inhibit growth of HT29, SW480, and SW620 colorectal cancer cells and their angiogenesis (Matsuura et al., 2006). The c9,t11 form of conjugated linoleic acid (CLA) inhibited angiogenesis, induced apoptosis of adipocytes, and decreased serum VEGF in mice (Masso-Welch et al., 2004). The oral administration of green tea polyphenols to mice reduced the incidence , multiplicity, and growth of UVB-induced tumors by enhancing the expression of select matrix metalloproteinases and VEGF, while inhibiting the expression of proliferating cell nuclear antigen (Mantena et al., 2005). Pharmacological doses of dietary soy polyphenols inhibited the proliferation and angiogenesis of prostate cancer in mice and the growth of LNCaP human prostate cancer cells while increasing apoptosis and reducing the vascular density in the tumor bed (Zhou et al., 1999). The chemopreventive observations of two pools of selenium metabolites, namely hydrogen selenide and methylselenol, may be related to the inhibition of tumor-associated angiogenesis and apoptosis (Jian et al., 2004).

Angiogenesis has a critical role in arthritis, atherosclerosis, and age-related macular degeneration, recurrent squamous cell carcinoma, and perhaps even obesity. The clinical literature suggests the treatment of these conditions and the concomitant administration of food-derived compounds at pharmacological or supraphysiological doses can significantly raise endostatin and lower VEGF levels in joint fluids and plaques while decreasing the progression of disease.

Preliminary findings such as these, and results from phase III clinical studies may demonstrate that the clinical utility of the inhibition of angiogenic factors is not limited to cancer. These kinds of research may enhance our understanding of the biological mechanisms of vascularization and cell proliferation and how those mechanisms are modulated by dietary components.

by Roger Clemens, Dr.P.H.,
Contributing Editor Director, Analytical Research, Professor, Molecular Pharmacology & Toxicology, USC School of Pharmacy,
Los Angeles, Calif. 
[email protected]

by Peter Pressman, M.D.,
Contributing Editor Attending Staff, Internal Medicine, Cedars-Sinai Medical Center,
Los Angeles, Calif.
[email protected]

References

Folkman, J. 1971. Tumor angiogenesis: Therapeutic implications. New Eng. J. Med. 285: 1182-1186.

Jian, C., et al.2004. Methyl selenium-induced vascular endothelial apoptosis is executed by caspases and principally medicated by P38 MAPK pathway. Nutr Cancer 49: 174-183.

Mantena, S.K., et al. 2005. Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. J. Nutr. 135: 2871-2877.

Masso-Welch, P.A., et al. 2004. Isomers of conjugated linoleic acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature. J. Nutr. 134: 299-307.

Matsuura, N., et al. 2006. Aged garlic extract inhibits angiogenesis and proliferation of colorectal carcinoma cells. J. Nutr. 136: 842S-846S.

Zhou, J-R., et al. 1999. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J. Nutr. 129: 1628-1635.