Gold L I
New York University School of Medicine, Department of Pathology, The Stanley Kaplan Comprehensive Cancer Center, NY 10016, USA.
Crit Rev Oncog. 1999;10(4):303-60.
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.
细胞增殖失控是癌症的一个标志。因此，一个相关且重要的问题是癌细胞如何从正常的生长调节机制中逃脱而变得恶性，进而，哪些事件有利于肿瘤进展和转移。转化生长因子-β家族（TGF-β）的生长调节蛋白是少数几类内源性细胞生长抑制剂之一。与最初认为这些蛋白在癌细胞中可能下调以促进其生长的观点相反，一般发现，在人类癌症（体内）中，包括胰腺癌、结肠癌、胃癌、肺癌、子宫内膜癌、前列腺癌、乳腺癌、脑癌和骨癌，TGF-β mRNA和蛋白的表达显著增加。此外，在许多这些癌症中，高表达与更晚期的恶性程度和生存率降低相关。TGF-β表达的增加通常伴随着对TGF-β生长抑制反应的丧失。例如，培养中的某些肿瘤细胞（即结肠癌细胞和多形性胶质母细胞瘤）对TGF-β的生长抑制反应逐渐丧失，这种丧失与原发肿瘤的恶性程度直接相关，最具侵袭性的形式实际上转变为受TGF-β自分泌和/或旁分泌生长刺激。对与肿瘤细胞从TGF-β介导的生长调节中逃脱相关的分子事件的研究，为致癌机制提供了深入了解。TGF-β上调的机制尚不清楚。然而，一旦恶性细胞对TGF-β失去生长抑制反应并产生大量这些蛋白，TGF-β表达的增加为肿瘤细胞存活提供了选择性优势，因为TGF-β也是促血管生成的，并且具有强大的免疫抑制作用，包括特异性抑制杀肿瘤的自然杀伤细胞和淋巴细胞激活的杀伤细胞。鉴于TGF-β在调节细胞生长中的重要作用，近年来的研究表明许多人类癌症中发生了与TGF-β介导的生长抑制信号通路相关的特定基因改变，这并不奇怪。TGF-β受体、TGF-β相关信号转导/基因激活以及TGF-β调节的细胞周期蛋白的特定缺陷，都与许多人类癌症的肿瘤发生有关。在这种情况下，TGF-β生长反应通路的成分被认为是肿瘤抑制基因，因为一种或多种受体或信号蛋白的缺失（或功能障碍）有可能导致生长调节的丧失。最近，介导TGF-β生长抑制的细胞周期蛋白依赖性激酶抑制剂（CKI）p27kip1水平的翻译后降低，为癌细胞逃脱TGF-β介导的负生长调节提供了另一种方式。本综述提供了关于TGF-β的背景信息，并更新了我们对TGF-β在特定人类恶性肿瘤中作用的认识。了解正常细胞中TGF-β功能所涉及的分子事件及其在肿瘤细胞中的功能缺失，应该能够确定人类癌症中的新治疗靶点。
