Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice.
Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice.
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发表时间：
1997-03
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通讯作者：
K. Lamszus;Liang Jin;A. Fuchs;E. Shi;S. Chowdhury;Yan Yao;P. Polverini;J. Laterra;I. Goldberg-I.
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作者：
K. Lamszus;Liang Jin;A. Fuchs;E. Shi;S. Chowdhury;Yan Yao;P. Polverini;J. Laterra;I. Goldberg-I.
分散因子（SF）（也称为肝细胞生长因子）是一种纤溶酶原相关生长因子，可诱导肿瘤细胞运动、侵袭和血管生成。它的受体是一种由原癌基因c-met编码的酪氨酸激酶。人乳腺癌细胞在体内表达SF和c-met;但人乳腺癌细胞系在体外不产生SF。为了确定SF是否可以调节人乳腺癌在天然乳腺环境中的体内生长，我们研究了SF转染的（SF+）与对照（SF-）MDAMB 231人乳腺癌细胞克隆在无胸腺裸鼠乳腺脂肪垫中的原位生长。SF+克隆表达SF mRNA并产生非常高滴度的SF蛋白，而SF-克隆不表达SF mRNA或产生可检测的SF蛋白。与两个SF-克隆（32和34）相比，两个SF+克隆（21和29）显示出显著增加的肿瘤生长速率，在杀死时间达到3至4倍大的原发性肿瘤体积和重量（p <0.001），以及更高的腋窝淋巴结转移率（p < 0.02）。与此相反，在体外增殖率，二维集落形成，软琼脂集落形成不大于SF+比SF-克隆。我们进行了进一步的研究，以调查体内和体外生长结果之间的差异。来自SF+克隆（21 + 29）肿瘤的肿瘤提取物具有比SF-克隆（32 + 34）肿瘤高50倍的SF含量，证实了SF+肿瘤中的体内高水平SF表达。肿瘤切片的增殖细胞核抗原免疫染色显示，SF+与SF-肿瘤中的循环细胞比例仅适度增加（分别为70%与60%）。SF+和SF-肿瘤的末端脱氧转移酶标记指数同样低（约1%），表明细胞凋亡不是SF-肿瘤生长缓慢的原因。然而，SF+肿瘤具有比SF-肿瘤显著更高的肿瘤微血管密度（p < 0.001）。此外，与SF-克隆相比，SF+克隆的细胞条件培养基和原发性肿瘤提取物中的微血管内皮细胞的趋化活性滴度高得多。如使用大鼠角膜测定所证明的，SF+肿瘤提取物中的血管生成活性比SF-提取物中的血管生成活性更高。SF+肿瘤提取物中趋化性和血管生成活性的增加不能通过血管生成介质、血管内皮生长因子或抗血管生成糖蛋白、血小板反应蛋白-1的含量的继发性改变来解释;并且这些活性使用抗SF单克隆抗体来中和。这些研究结果表明，SF促进原位生长的人乳腺癌，至少在一定程度上，通过刺激肿瘤血管生成。
Scatter factor (SF) (also known as hepatocyte growth factor) is a plasminogen-related growth factor that induces tumor cell motility, invasion, and angiogenesis. Its receptor is a tyrosine kinase encoded by c-met, a protooncogene. Human breast cancer cells express SF and c-met in vivo; but human breast cancer cell lines do not produce SF in vitro. To determine whether SF can modulate the in vivo growth of human breast cancers within a natural mammary environment, we studied the orthotopic growth of SF-transfected (SF+) versus control (SF-) clones of MDAMB231 human mammary carcinoma cells in the mammary fat pads of athymic nude mice. SF+ clones expressed SF mRNA and produced very high titers of SF protein, whereas SF- clones did not express SF mRNA or produce detectable SF protein. Two SF+ clones (21 and 29) showed significantly increased tumor growth rates, reaching 3- to 4-fold larger primary tumor volumes and weights by time of killing (p < 0.001), as well as higher rates of axillary lymph node metastasis (p < 0.02), as compared with two SF- clones (32 and 34). In contrast, in vitro proliferation rates, two-dimensional colony formation, and soft agar colony formation were no greater in SF+ than in SF- clones. We performed further studies to investigate the discrepancy between the in vivo and in vitro growth results. Tumor extracts from SF+ clone (21 + 29) tumors had 50-fold higher SF content than did SF- clone (32 + 34) tumors, confirming high-level SF expression in vivo in SF+ tumors. Immunostaining of tumor sections for proliferating cell nuclear antigen revealed only a modest increase in the proportion of cycling cells in SF+ versus SF- tumors (70% versus 60%, respectively). The terminal deoxytransferase-labeling index was equally low (approximately 1%) in SF+ and SF- tumors, suggesting that apoptosis was not responsible for the slower growth of SF- tumors. However, SF+ tumors had significantly higher tumor microvessel densities than SF- tumors (p < 0.001). Moreover, there were much higher titers of chemotactic activity for microvascular endothelial cells in cell-conditioned media and primary tumor extracts from SF+ clones as compared with SF- clones. As demonstrated using the rat cornea assay, there was more angiogenic activity in SF+ tumor extracts than in SF- extracts. The increased chemotactic and angiogenic activities in SF+ tumor extracts were not explained by secondary alterations in the content of the angiogenic mediator, vascular endothelial growth factor, or the antiangiogenic glycoprotein, thrombospondin-1; and those activities were neutralized using an anti-SF monoclonal antibody. These findings suggest that SF promotes the orthotopic growth of human breast cancers, at least in part, by stimulating tumor angiogenesis.