Song Z, Powell W C, Kasahara N, van Bokhoven A, Miller G J, Roy-Burman P
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles 90033, USA.
Cancer Res. 2000 Dec 1;60(23):6730-6.
Fibroblast growth factor 8, isoform b (FGF8b), has been implicated in the oncogenesis of the prostate and mammary epithelia. We examined whether overexpression of FGF8b in a weakly tumorigenic prostate carcinoma cell line, LNCaP, could alter the growth and tumorigenic properties of these cells. LNCaP cells were infected with a lentivirus vector carrying FGF8b cDNA and the green fluorescent protein (GFP) cDNA in the same construct, and the infected cell population was sorted on the basis of GFP protein expression. It was demonstrated that, in comparison with the cells transduced with GFP-vector alone, LNCaP cells with FGF8b-GFP expression manifested an increased growth rate, higher soft agar clonogenic efficiency, enhanced in vitro invasion, and increased in vivo tumorigenesis. Most strikingly, whereas parental or vector-control LNCaP cells failed to grow at all in an in vivo tumorigenesis/diaphragm invasion assay in nude mice, the cells overexpressing FGF8b proliferated as deposits of tumor cells on the diaphragm, frequently with indications of tumor cell invasion into the diaphragm. Coculturing of primary prostatic or non-prostatic stromal cells with the infected LNCaP cells led us to observe that: (a) stromal cells, irrespective of tissue origin, strongly suppressed LNCaP cell growth; (b) FGF8b producing LNCaP cells could partially evade the stromal inhibition, perhaps from the autocrine stimulatory effect of FGF8b; and (c) production of FGF8b in the coculture had a stimulatory effect on the proliferation of the stromal cells, prostatic or non-prostatic. This stimulation was not attributable to the direct action of FGF8b on stromal cells. Instead, it appears that epithelial-stromal cell-cell contact and some unknown soluble factors secreted by LNCaP cells upon stimulation of FGF8b are required for the maximal effect. Together, these results suggest that the growth rate and biological behavior of prostatic cancer cells can be altered to a more aggressive phenotype by up-regulation of FGF8b expression. These changes in phenotype also influence the interaction of the affected cells with stromal cells. The data obtained may have direct relevance to the progression of prostate cancer, recognizing that FGF8b is naturally overexpressed in advanced disease.
成纤维细胞生长因子8b（FGF8b）与前列腺和乳腺上皮的肿瘤发生有关。我们研究了在低致瘤性前列腺癌细胞系LNCaP中过表达FGF8b是否会改变这些细胞的生长和致瘤特性。用携带FGF8b cDNA和绿色荧光蛋白（GFP）cDNA的慢病毒载体感染LNCaP细胞，且二者构建在同一载体上，然后根据GFP蛋白表达对感染的细胞群体进行分选。结果表明，与仅用GFP载体转导的细胞相比，表达FGF8b - GFP的LNCaP细胞表现出更高的生长速率、更高的软琼脂克隆形成效率、更强的体外侵袭能力以及更高的体内致瘤性。最显著的是，在裸鼠体内肿瘤发生/膈肌侵袭试验中，亲本或载体对照LNCaP细胞根本无法生长，而过表达FGF8b的细胞则在膈肌上增殖形成肿瘤细胞沉积物，且经常有肿瘤细胞侵袭膈肌的迹象。将原代前列腺或非前列腺基质细胞与感染的LNCaP细胞共培养后，我们观察到：（a）无论组织来源如何，基质细胞都强烈抑制LNCaP细胞生长；（b）产生FGF8b的LNCaP细胞可能部分逃避了基质抑制，这可能源于FGF8b的自分泌刺激作用；（c）共培养中FGF8b的产生对前列腺或非前列腺基质细胞的增殖有刺激作用。这种刺激并非归因于FGF8b对基质细胞的直接作用。相反，似乎上皮 - 基质细胞间接触以及FGF8b刺激后LNCaP细胞分泌的一些未知可溶性因子对于产生最大效应是必需的。总之，这些结果表明，通过上调FGF8b表达，前列腺癌细胞的生长速率和生物学行为可转变为更具侵袭性的表型。这些表型变化也会影响受影响细胞与基质细胞的相互作用。鉴于FGF8b在晚期疾病中自然过表达，所获得的数据可能与前列腺癌的进展直接相关。
