The role for transforming growth factor-beta (TGF-beta) in human cancer.

Uncontrolled cellular proliferation is a hallmark of cancer. Thus, a relevant and important question is how cancer cells have escaped from normal growth regulatory mechanisms to become malignant and, further, what events favor progression and metastasis. Growth regulatory proteins of the transforming growth factor-beta family (TGF-beta) are one of the few classes of endogenous inhibitors of cell growth. Contrary to the first notion that these proteins may be downregulated in cancer cells to promote their growth, generally it has been otherwise found that there is a marked increase in the expression of TGF-beta mRNA and protein in human cancers (in vivo), including those of the pancreas, colon, stomach, lung, endometrium, prostate, breast, brain, and bone. Furthermore, in many of these cancers high expression correlates with more advanced stages of malignancy and decreased survival. The increased expression of TGF-beta is usually accompanied by a loss in the growth inhibitory response to TGF-beta. For example, certain tumor cells in culture (i.e., colon carcinoma and glioblastoma multiforme) demonstrate a progressive loss of the growth inhibitory response to TGF-beta that varies directly with the malignant stage of the original tumor, and the most aggressive forms actually switch to being autocrine and/or paracrine growth stimulated by TGF-beta. The study of the molecular events associated with the escape of tumor cells from growth regulation by TGF-beta has provided insight into mechanisms underlying carcinogenesis. The mechanisms for upregulation of TGF-beta are unknown. However, once malignant cells lose their growth inhibitory response to TGF-beta and produce massive amounts of these proteins, the increased expression of TGF-beta provides a selective advantage for tumor cell survival as TGF-betas are also angiogenic and have potent immunosuppressive effects, including specifically inhibiting tumoricidal natural and lymphocyte-activated killer cells. In light of the significant role for TGF-betas in regulating cell growth, it is not surprising that in more recent years studies have shown that specific genetic alterations involved in the signaling pathway for TGF-beta-mediated growth inhibition have occurred in many human cancers. Specific defects in TGF-beta receptors, TGF-beta-related-signal transduction/gene activation, and TGF-beta-regulated cell cycle proteins, have all been implicated in the oncogenesis of many human cancers. In this context, components of the TGF-beta growth response pathway are considered to be tumor suppressor genes, as absence (or malfunction) of one or more receptors or signaling proteins would have the potential to cause loss of growth regulation. More recently, the posttranslational reduction of levels of the cyclin-dependent kinase inhibitor (CKI), p27kip1, which mediates TGF-beta growth inhibition, provides an additional means for cancer cells to escape negative growth regulation by TGF-beta. This review provides background information on TGF-beta and updates the status of our knowledge of the role for TGF-beta in specific human malignancies. Understanding the molecular events involved in TGF-beta function in normal cells and its lack of function in tumor cells should identify novel therapeutic targets in human cancers.