Krasagakis K, Garbe C, Schrier P I, Orfanos C E
Department of Dermatology, Univ. Medical Center Benjamin Franklin, Free University of Berlin, Germany.
Anticancer Res. 1994 Nov-Dec;14(6B):2565-71.
It has been considered that the growth of human melanoma cells is positively and negatively regulated by transforming growth factors. To investigate further the role of transforming growth factor beta (TGF-beta) in melanoma biology, we analysed paracrine and autocrine growth regulatory properties of TGF-beta in normal human melanocytes and malignant melanoma cell lines in vitro. Exogenously added TGF-beta 1 potently inhibited normal melanocyte proliferation and DNA-synthesis in all cultures examined; in contrast, TGF-beta 1 inhibited only moderately or not at all the growth of cultured melanoma cells. Melanoma cell lines established from metastatic lesions were found to be less sensitive to TGF-beta 1 than those derived from primary melanomas. TGF-beta 1 resistance correlated with high levels of active TGF-beta secreted by metastatic cell lines. Inactivation of endogenously produced TGF-beta by neutralizing anti-TGF-beta antibody resulted in the stimulation of cell proliferation of a TGF-beta-sensitive primary melanoma cell line but not of a resistant metastatic one. These findings suggest that TGF-beta may function as a paracrine and autocrine growth inhibiting factor in the growth regulation of human melanocytic cells. The gradual loss of response of melanocytic cells to TGF-beta during malignant progression suggests that escape of melanoma cells from growth regulation by TGF-beta could be involved in melanoma oncogenesis.
人们认为，转化生长因子对人类黑色素瘤细胞的生长具有正向和负向调节作用。为了进一步研究转化生长因子β（TGF-β）在黑色素瘤生物学中的作用，我们在体外分析了TGF-β在正常人黑素细胞和恶性黑色素瘤细胞系中的旁分泌和自分泌生长调节特性。在所有检测的培养物中，外源性添加的TGF-β1能有效抑制正常黑素细胞的增殖和DNA合成；相比之下，TGF-β1对培养的黑色素瘤细胞生长的抑制作用仅为中度或根本没有抑制作用。发现从转移性病变建立的黑色素瘤细胞系对TGF-β1的敏感性低于源自原发性黑色素瘤的细胞系。TGF-β1抗性与转移性细胞系分泌的高水平活性TGF-β相关。用中和性抗TGF-β抗体灭活内源性产生的TGF-β会刺激对TGF-β敏感的原发性黑色素瘤细胞系的细胞增殖，但不会刺激抗性转移性细胞系的细胞增殖。这些发现表明，TGF-β可能在人类黑素细胞的生长调节中作为旁分泌和自分泌生长抑制因子发挥作用。黑素细胞在恶性进展过程中对TGF-β的反应逐渐丧失，这表明黑色素瘤细胞逃避TGF-β的生长调节可能与黑色素瘤的肿瘤发生有关。
