β4 Integrin signaling induces expansion of prostate tumor progenitors
β4 Integrin signaling induces expansion of prostate tumor progenitors
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DOI：
10.1172/jci60720
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Giancotti, Filippo G.
中科院分区：
文献类型：
--
作者：
Yoshioka, Toshiaki;Otero, Javier;Giancotti, Filippo G.
调节前列腺肿瘤祖细胞扩增的背景信号定义不清。我们发现，相当一部分晚期前列腺癌和去势抵抗性转移瘤表达高水平的β 4整合素，其结合层粘连蛋白-5。在前列腺癌小鼠模型（PB-TAg小鼠）中，靶向缺失β 4的信号传导结构域可抑制前列腺肿瘤的生长和进展，以响应p53和Rb功能的丧失。此外，在组织重组实验中，它抑制Pten丢失驱动的前列腺肿瘤发生。我们将这一缺陷追溯到信号缺陷β 4在体外无法维持推定的癌症干细胞的自我更新和体内转运扩增细胞的增殖。机制研究表明，突变体β 4不能促进前列腺肿瘤祖细胞和人类癌细胞系中ErbB 2和c-Met的反式激活。ErbB 2和c-Met的药理学抑制降低了前列腺肿瘤祖细胞在体外进行自我更新的能力。最后，我们发现，β 4通常与c-Met和ErbB 2在人前列腺癌中共表达，并且这些受体酪氨酸激酶的联合药理学抑制在小鼠异种移植模型中发挥抗肿瘤活性。这些发现表明β 4整合素通过放大肿瘤祖细胞中的ErbB 2和c-Met信号传导促进前列腺肿瘤发生。
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the beta 4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of beta 4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective beta 4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant beta 4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that beta 4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the beta 4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.