(This is part two of three articles with excerpts from
“Tumor Angiogenesis as a Target for Dietary Cancer Prevention”
by Dr. William Li.)
The Dormant-to-Tumor Phase of Cancer
Cancer cells are common in a healthy adult but small tumor growth remains limited.(37-39) Tumors can grow to about the size of a pin head before maxing out. They can’t get enough oxygen and nutrients (by osmosis) from nearby blood vessels. The rate of tumor cancer cell growth, therefore, is limited to the rate of cells dying.(40)
These tumors are common, but limited, during aging. Lack of new blood vessels (anti-angiogenesis) is regarded as one of the body’s mechanisms that prevent these cancer cells from converting to a malignant cancer.
To expand, tumors recruit new blood vessels from surrounding vessels, an event known as ‘the switch’.(41) New blood vessel growth is encouraged by the production of angiogenic growth factors by mutated cancer cells.
Angiogenesis is clearly evident during this further growth. Distinct stages are observed from mild and aggressive fibromas to fibrosarcoma (secreting bFGF not secreted by normal cells or by mild fibromas).
It is also significant that inflammatory cells may amplify the angiogenic switch!
The onset of angiogenesis precedes an exponential phase of tumor growth. Once new blood vessels reach the explant, tumors can expand 16,000-fold in size in 2 weeks.(42)
Targeting Tumor Angiogenesis for Cancer Prevention
The concept of “anti-angiogenesis” was first proposed in 1971 by Judah Folkman. He suggested that preventing new blood vessel growth at an early stage of cancer development could prevent tumor growth.(4) Since then, many studies show angiogenesis inhibition (anti-angiogenesis) may be an effective strategy to restrict cancer growth in a wide variety of cancers.(5, 43)
Selective targeting of angiogenic blood vessels is possible because normal blood vessel endothelial cells have a very slow doubling time.(44-46) In contrast, tumor blood vessel cells can double in a few weeks. Thus, anti-angiogenic molecules are geared to inhibiting tumor blood vessel growth – but do not affect normal blood vessels!
Specific targets have been identified for tumor angiogenesis with drugs. However, it has been suggested that a synergy of different nutrients with the different active extracts may be a better broad prevention for supplementation to foods. To date, more than 300 anti-angiogenesis molecules have been identified as potential drug candidates, including many natural ones.
Early Intervention and Cancer Prevention
Advanced cancers contain well-established, extensive vascular networks that may respond minimally to angiogenesis inhibitors. This is why intervention for cancer prevention or early-stage cancer has been proposed as the scenario of the greatest clinical benefit using angiogenesis inhibitors.(50)
Anti-angiogenesis offers an opportunity to interrupt an early tumor growth.(51-52) Suppression of blood-vessel growth prevents early tumors from progressing to the malignant phenotypes.
Animal studies have demonstrated that early administration of angiogenesis inhibitors is highly effective. In one study, treated tumors were reduced by 90%, compared to control animals. In another study tumor growth was suppressed in the TNP-470-treated group by 82%, compared to saline-treated controls.(40,53)
“Cancer chemoprevention” is defined as the use of pharmacological, natural or dietary agents to inhibit the development of invasive cancer. It does this by blocking DNA damage or by arresting the progression of premalignant cells after damage has already occurred.(54)
- C. Y. Li, S. Shan, Q. Huang et al., “Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models,” Journal of the National Cancer Institute, vol. 92, no. 2, pp. 143–147, 2000.
- J. Holash, P. C. Maisonpierre, D. Compton et al., “Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF,” Science, vol. 284, no. 5422, pp. 1994–1998, 1999. V
- J. Folkman, “Incipient angiogenesis,” Journal of the National Cancer Institute, vol. 92, no. 2, pp. 94–95, 2000.
- L. Holmgren, M. S. O’Reilly, and J. Folkman, “Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression,” Nature Medicine, vol. 1, no. 2, pp. 149–153, 1995.
- W. W. Li, “Tumor angiogenesis: molecular pathology, therapeutic targeting, and imaging,” Academic Radiology, vol. 7, no. 10, pp. 800–811, 2000.
- M. A. Gimbrone Jr., S. B. Leapman, R. S. Cotran, and J. Folkman, “Tumor dormancy in vivo by prevention of neovascularization,” Journal of Experimental Medicine, vol. 136, no. 2, pp. 261–276, 1972.
- J. Folkman, “Antiangiogenesis agents,” in Cancer Principles & Practice of Oncology, V. T. DeVita, S. Hellman, and S. A. Rosenberg, Eds., pp. 509–519, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 6th edition, 2001.
- R. L. Engerman, D. Pfaffenbach, and M. D. Davis, “Cell turnover of capillaries,” Laboratory Investigation, vol. 17, no. 6, pp. 738–743, 1967.
- B. Hobson and J. Denekamp, “Endothelial proliferation in tumours and normal tissues: continuous labelling studies,” British Journal of Cancer, vol. 49, no. 4, pp. 405–413, 1984.
- I. F. Tannock, “Population kinetics of carcinoma cells, capillary endothelial cells, and fibroblasts in a transplanted mouse mammary tumor,” Cancer Research, vol. 30, no. 10, pp. 2470–2476, 1970.
- S. A. Hill, G. M. Tozer, G. R. Pettit, and D. J. Chaplin, “Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503,” Anticancer Research, vol. 22, no. 3, pp. 1453–1458, 2002.
- H. Goto, S. Yano, H. Zhang et al., “Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice,” Cancer Research, vol. 62, no. 13, pp. 3711–3715, 2002.
- D. W. Siemann, E. Mercer, S. Lepler, and A. M. Rojiani, “Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy,” International Journal of Cancer, vol. 99, no. 1, pp. 1–6, 2002.
- W. W. Li, V. W. Li, R. Casey, et al., “Clinical trials of angiogenesis based therapies: overview and new guiding principles,” in Angiogenesis Models, Modulators and Clinical Application, M. Maragoudakis, Ed., pp. 475–492, Plenum Press, New York, NY, USA, 1998.
- N. B. Teo, B. S. Shoker, L. Martin, J. P. Sloane, and C. Holcombe, “Angiogenesis in pre-invasive cancers,” Anticancer Research, vol. 22, no. 4, pp. 2061–2072, 2002.
- P. Vajkoczy, M. Farhadi, A. Gaumann et al., “Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2,” Journal of Clinical Investigation, vol. 109, no. 6, pp. 777–785, 2002.
- S. Shusterman, S. A. Grupp, R. Barr, D. Carpentieri, H. Zhao, and J. M. Maris, “The angiogenesis inhibitor TNP-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease,” Clinical Cancer Research, vol. 7, no. 4, pp. 977–984, 2001.
- Chemoprevention Working Group, “Prevention of cancer in the next millennium: report of the Chemoprevention Working Group to the American Association for Cancer Research,” Cancer Research, vol. 59, no. 19, pp. 4743–4758, 1999. View at Google Scholar • View at Scopus