Acute Tissue Injury Activates Satellite Cells and Promotes Sarcoma Formation via the HGF/c-MET Signaling Pathway

Abstract

Some patients with soft tissue sarcoma (STS) report a history of injury at the site of their tumor. While 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 Pax7CreER 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 (IM) 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.

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism

“…We previously showed that some tumors generated by injection of tamoxifen into Pax7 Cre-ER-T2/+ ; Kras LSL-G12D/+ ; p53 FL/FL mice resembled human rhabdomyosarcoma (RMS) [15, 16]. Because NRAS is more commonly mutated in human RMS than KRAS [17–19], we generated Pax7 Cre-ER-T2/+ ; Nras LSL-G12D/+ ; p53 FL/FL ; ROSA26 mTmG/mTmG (P7NP) mice to model mutations that more frequently occur in human RMS.…”

The Hippo signal transduction pathway in soft tissue sarcomas

“…The majority of soft tissue sarcomas arise in the limbs of older people although rhabdomyosarcoma, especially the embryonal subtype, tends to occur predominantly in young children [21]. Most soft tissue sarcomas arise sporadically but muscle injury, most likely by increasing the number of activated satellite cells, enhances the penetrance and shortens the latency of rhabdomyosarcoma phenotypes in mice [18,22]. In addition, known risk factors for the development of specific types of sarcoma in humans include exposure to radiation (e.g.…”

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

“…Because the very character of each experiment results in tumorigenesis or no tumorigenesis, any untested variable may be the key between the 2 potential results. For example, elegant work by others has recently demonstrated that the sarcomagenesis-originating potential of satellite cells in particular depends on their activation in response to injury (37,38). Our experiments did not address the application of this principle to synovial sarcomagenesis, but future work should.…”