Citrus Fruits shown to be Antiangiogenic and Reduce Risk for some Cancers
Summary: Citrus fruits contain high levels of flavanoids, which have been shown to inhibit the growth and spread of tumors. Two flavanoids abundant in citrus fruits, nobiletin and ascorbic acid (vitamin C), are antiangiogenic. Some observational studies that follow the dietary habits and health of large populations have found reduced incidences of certain cancers, including lung cancer and colorectal cancer, among people who consume large amounts of citrus on a regular basis. The evidence shows that, in addition to promoting immune and cardiovascular health, citrus fruits have chemopreventive potential and should be part of a healthy diet.
Citrus fruits are abundant in antioxidants called flavanoids—bioactive compounds that possess a number of beneficial health effects, such as boosting the immune system and promoting cardiovascular health. Certain flavanoids found in citrus have also been shown to have cancer-fighting properties. These include inhibiting the proliferation of cancer cells and suppressing the growth of tumor blood vessels (angiogenesis).
One flavanoid, nobiletin, found in high concentrations in tangerines and some species of oranges, has been shown in animal studies to suppress tumor growth and the spread of cancer throughout the body (metastasis). Since cancer metastasis can be a result of angiogenesis, Japanese researchers conducted a study to find out whether nobiletin is antiangiogenic.  Using standard laboratory tests to measure angiogenesis, called assays, they discovered that nobiletin directly inhibits angiogenesis by interfering with a key protein involved in the process, called matrix metalloproteinase-2 (MMP-2). MMP-2 and related proteins help blood vessels sprout and grow toward cancerous tumors. This new blood supply nourishes the tumor, allowing it to grow and spread.
The researchers found that nobiletin suppressed both the proliferation of endothelial cells, the cells that line the inner walls of blood vessels, and the development of actual blood vessels in embryos growing in chicken eggs. The study did not assess whether nobiletin suppresses angiogenesis initiated by tumors. Nobiletin also suppresses inflammation—another key process in cancer development that is closely linked to angiogenesis—although it is not believed that inflammation played a role in this study. Another antioxidant found in citrus fruits, ascorbic acid, commonly known as vitamin C, is also antiangiogenic. In a separate study also conducted in Japan, ascorbic acid demonstrated similar antiangiogenic activity as nobiletin in the same types of assays, although the angiogenesis inhibiting mechanism was a bit different. 
Observational studies have shown that people who regularly consume citrus fruits have lower incidences of certain cancers than the general population. In the Nurses Health Study (NHS), a large, prospective observational study, women who consumed at least three servings of citrus fruit per day had significantly lower rates of colorectal adenomas, a type benign polyp, than those who consumed less than one serving per day.  Although only about 15% of adenomas progress to full-blown colorectal cancer, these polyps are the primary precursor for colorectal cancer in those who develop the disease. Consumption of both fruits and vegetables rich in vitamin C (ascorbic acid) was also associated with a reduced incidence of polyps. A second observational study conducted in Europe found a significantly reduced incidence of a type of lung cancer most common in smokers, called squamous cell carcinoma, among those who consumed the highest daily amounts of citrus fruits. 
These results indicate that some varieties of citrus fruits, particularly tangerines and oranges, have antiangiogenic and anti-tumor activity, which could contribute to a lower risk of certain cancers among people who consume citrus fruit on a daily basis. While future studies will need to better define the anti-cancer and antiangiogenic properties of individual species of fruit, citrus fruit is an important part of an overall healthy diet with substantial chemopreventive potential.
By Roderick Smith, M.S.
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