Normal cells within tissues are also responsive to antiproliferative signals that serve to maintain cellular quiescence and tissue homeostasis. These antigrowth signals are soluble factors or inhibitors embedded in the extracellular matrix. Signals are transmitted to the nucleus via intracellular signaling circuits that are in a balance with the positive growth signals. One of the most prominent negative growth signals in many cell types is TGF-P).26
Most antigrowth signals act on the tumor suppressor proteins, such as Rb. TGF-P acts to prevent the phosphorylation that inactivates Rb, thus blocks advance through G1.26 When hypophosphorylated, Rb sequesters and inhibits E2F transcription factors that control the expression of genes required for progression from G1 to S. Other tumor suppressor proteins include p53 (or TP53), which in the wild-type state suppresses tumor growth by initiating DNA repair and inducing death of irreparable cells. Generally, p53 is maintained at a low concentration, although it can be induced by physical or chemical DNA damage.9 When p53 is mutated or suppressed by Mdm2, an oncogenic protein, proliferation of cells with DNA damage results.23 Studies have shown that function of the p53 pathway is lost in most if not all of human cancers.26 However, many other tumor suppressor genes have been defined and may be definitive for certain types of cancers, such as APC (adenomatous polyposis coli) in colorectal cancer24 or BRCA in breast cancer.35 For example, during human colon carcinogenesis, inactivation of APC/p-catenin pathway blocks the differentiation of the enterocytes in the colonic crypts, resulting in aberrant crypt foci.26
Antigrowth signals block proliferation by either forcing cells into quiescence or G0, which is a reversible state upon activation by pro-growth signals, or by inducing differentiation, which, depending on cell type, is a permanent acquisition of specific phenotypic traits characteristic of the mature cell type. As cells move toward the differentiated state, the rate of proliferation slows, so that fully differentiated cells do not proliferate, or at least do so at a very slow rate. Cancer cells are poorly differentiated yet retain the potential to differentiate into more mature cells. Thus, induction of differentiation (or redifferentiation) is a cancer prevention and treatment strategy, although its effectiveness is lower for relatively slow-growing cancers like breast or prostate than for faster ones such as leukemia. Several nuclear acting nutrients, including vitamins D and A, have been the most comprehensively studied as differentiation-promoting agents, although a number of other compounds have been shown to induce cellular markers of differentiation in vitro, including a variety of flavonoids, the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and resveratrol.36
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