Van Mater David, Añó Leonor, Blum Jordan M, Webster Micah T, Huang WeiQiao, Williams Nerissa, Ma Yan, Cardona Diana M, Fan Chen-Ming, Kirsch David G
Department of Pediatrics, Division of Hematology-Oncology, Duke University Medical Center, Durham, North Carolina.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
Cancer Res. 2015 Feb 1;75(3):605-14. doi: 10.1158/0008-5472.CAN-14-2527. Epub 2014 Dec 12.
Some patients with soft-tissue sarcoma (STS) report a history of injury at the site of their tumor. Although this phenomenon is widely reported, there are relatively few experimental systems that have directly assessed the role of injury in sarcoma formation. We recently described a mouse model of STS whereby p53 is deleted and oncogenic Kras is activated in muscle satellite cells via a Pax7(CreER) driver following intraperitoneal injection with tamoxifen. Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7-expressing cells remain quiescent despite mutation of p53 and Kras. The fate of these muscle progenitors is dramatically altered by tissue injury, which leads to faster kinetics of sarcoma formation. In adult muscle, quiescent satellite cells will transition into an active state in response to hepatocyte growth factor (HGF). We show that modulating satellite cell quiescence via intramuscular injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET. Unexpectedly, the tumor-promoting effect of tissue injury also requires c-Met. These results reveal a mechanism by which HGF/c-MET signaling promotes tumor formation after tissue injury in a mouse model of primary STS, and they may explain why some patients develop a STS at the site of injury.
一些软组织肉瘤（STS）患者报告其肿瘤部位有受伤史。尽管这一现象被广泛报道，但直接评估损伤在肉瘤形成中作用的实验系统相对较少。我们最近描述了一种STS小鼠模型，在腹腔注射他莫昔芬后，通过Pax7（CreER）驱动在肌肉卫星细胞中删除p53并激活致癌性Kras。在此，我们报告在全身注射他莫昔芬后，尽管p53和Kras发生了突变，但绝大多数表达Pax7的细胞仍保持静止。这些肌肉祖细胞的命运因组织损伤而发生显著改变，这导致肉瘤形成的动力学加快。在成年肌肉中，静止的卫星细胞会响应肝细胞生长因子（HGF）而转变为活跃状态。我们表明，通过肌肉注射HGF调节卫星细胞的静止状态会增加注射部位肉瘤形成的发生率，这依赖于其同源受体c-MET。出乎意料的是，组织损伤的促肿瘤作用也需要c-Met。这些结果揭示了一种机制，通过该机制HGF/c-MET信号在原发性STS小鼠模型中促进组织损伤后的肿瘤形成，并且它们可能解释了为什么一些患者在受伤部位会发生STS。
