Humphrey P A, Zhu X, Zarnegar R, Swanson P E, Ratliff T L, Vollmer R T, Day M L
Department of Pathology, Washington University Medical Center, St. Louis, Missouri 63110, USA.
Am J Pathol. 1995 Aug;147(2):386-96.
Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
肝细胞生长因子（散射因子）及其受体，即c-met原癌基因产物（c-MET），已被证实与胚胎发育、组织重塑及肿瘤进展有关。然而，对于这些分子在前列腺细胞和组织中的表达及功能意义却知之甚少。在本研究中，我们评估了肝细胞生长因子（HGF）和c-MET在前列腺组织及细胞系中的表达，并确定了纯化的重组HGF对前列腺癌细胞系细胞增殖和散射的影响。通过Northern印迹分析评估，原代培养的人前列腺基质肌成纤维细胞表达HGF，但三种人前列腺癌细胞系（LNCaP、DU 145和PC-3）不表达。通过逆转录聚合酶链反应在前列腺根治术标本的良性和恶性组织中也检测到了HGF。通过Northern印迹在两种雄激素不敏感的人前列腺癌细胞系（DU 145和PC-3）中鉴定出c-MET转录本，但雄激素敏感的LNCaP细胞系中未检测到。通过去势使正常大鼠前列腺雄激素缺乏的实验进一步证明了雄激素反应性与c-MET的关联，通过Northern印迹和免疫组织化学测定，雄激素缺乏导致c-MET表达显著上调。通过免疫组织化学分析在相当比例（128例中的58例或45%）的前列腺癌中检测到c-MET蛋白，与原发性肿瘤（108例中的43例；P < 0.005）相比，在人前列腺癌转移灶中更常见（20例患者中的15例）。此外，在Dunning R-3327大鼠前列腺癌细胞系中，c-MET表达在具有最高转移能力的雄激素不敏感亚系中最高。纯化的重组人HGF在DU 145癌细胞系中诱导剂量依赖性细胞增殖和散射。这些数据表明，HGF在前列腺中可能作为旁分泌生长因子发挥作用，由基质细胞合成，生物学靶细胞为上皮细胞。HGF受体c-MET的表达受雄激素剥夺上调，且c-MET似乎在雄激素不敏感的转移细胞上优先表达，提示c-MET表达与前列腺癌进展可能存在关联。
