Autocrine PDGFR signaling promotes mammary cancer metastasis
Autocrine PDGFR signaling promotes mammary cancer metastasis
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DOI：
10.1172/jci24652
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Gruenert, Stefan
中科院分区：
文献类型：
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作者：
Jechlinger, Martin;Sommer, Andreas;Gruenert, Stefan
转移是癌症发病的主要原因，但缺乏直接干预侵袭过程的策略。去分化的晚期肿瘤细胞分泌多种因子，这些因子是治疗干预的有吸引力的靶点。在这里，我们表明，致癌乳腺上皮细胞的转移潜力需要一个自分泌的PDGF/PDGFR环，这是建立作为TGF-β诱导的上皮间质转化（EMT），一个忠实的在体外转移相关的结果。自分泌PDGFR信号传导与致癌Ras的合作过度激活PI 3 K，并且是EMT期间生存所需的。自分泌PDGFR信号也有助于维持EMT，可能通过激活STAT 1和其他不同的途径。抑制PDGFR信号传导干扰EMT并引起小鼠和人乳腺癌细胞系的凋亡。因此，显性负性PDGFR的过度表达或已建立的癌症药物STI 571的应用干扰了小鼠的实验性转移。类似地，在小鼠乳腺肿瘤病毒-Neu（MMTV-Neu）转基因小鼠中，TGF-β增强乳腺肿瘤的转移，诱导EMT，并升高PDGFR信号传导。最后，PDGFR α和β的表达与人类乳腺癌的侵袭行为相关。因此，自分泌PDGFR信号在癌症进展过程中起着重要作用，这表明STI 571在治疗上干扰转移的新应用。
Metastasis is the major cause of cancer morbidity, but strategies for direct interference with invasion processes are lacking. Dedifferentiated, late-stage tumor cells secrete multiple factors that represent attractive targets for therapeutic intervention. Here we show that metastatic potential of oncogenic mammary epithelial cells requires an autocrine PDGF/PDGFR loop, which is established as a consequence of TGF-beta-induced epithelial-mesenchymal transition (EMT), a faithful in vitro correlate of metastasis. The cooperation of autocrine PDGFR signaling with oncogenic Ras hyperactivates PI3K and is required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways. Inhibition of PDGFR signaling interfered with EMT and caused apoptosis in murine and human mammary carcinoma cell lines. Consequently, overexpression of a dominant-negative PDGFR or application of the established cancer drug STI571 interfered with experimental metastasis in mice. Similarly, in mouse mammary tumor virus-Neu (MMTV-Neu) transgenic mice, TGF-beta enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFR alpha and -beta correlated with invasive behavior in human mammary carcinomas. Thus, autocrine PDGFR signaling plays an essential role during cancer progression, suggesting a novel application of STI571 to therapeutically interfere with metastasis.