In Nature Medicine, Glenn Merlino and colleagues report that defects in several different pathways need to converge to form rhabdomyosarcoma (RMS) tumors, as mice with disruptions in the Cdkn2a locus and activation of the c-Met signaling pathway develop RMS.
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet little is known about the molecular events that are associated with tumorigenesis and progression. Lack of a mouse model of this cancer has been a significant obstacle to this research. In the November issue of Nature Medicine, Glenn Merlino and colleagues report that defects in several different pathways need to converge to form these tumours, as mice with disruptions in the Cdkn2a locus and activation of the c-Met signalling pathway develop RMS.
The c-MET oncogene encodes a receptor tyrosine kinase that binds to hepatocyte growth factor/scatter factor (HGF/SF). Activation of this signalling pathway regulates cell proliferation, motility, survival, extracellular-matrix degradation and angiogenesis, and has been associated with various human cancers — including RMS. Sarcoma development has also been associated with the CDKN2A locus, which encodes two tumour-suppressor transcipts, INK4A and ARF. These gene products regulate cell-cycle progression, apoptosis and senescence.
To investigate a possible interaction between the c-MET and INK4A/ARF signalling pathways in sarcoma development, Sharp et al. overexpressed an Hgf/Sf transgene in Ink4a/Arf-null mice. They found that by four months after birth, nearly all of the mice had developed multifocal sarcomatous malignanices in trunk or limb skeletal muscle. Overexpression of Hgf/Sf in Ink4a/Arf+/- mice caused RMS by 8.8 months. These tumours had many features in common with human embryonal RMS. The defects in these two signalling pathways had a synergistic effect, as less than 10% of mice that overexpressed Hgf/Sf, or those that carried only a homozygous or heterozygous deletion in Ink4a/Arf, developed RMS-like tumours.
To determine the nature of the synergy by which c-Met activation and Ink4a/Arf inactivation promote RMS, Sharp et al. studied skeletal muscle cells from mutant mice. They found that myogenesis was suppressed, as differentiation — but not proliferation — of Ink4a/Arf-null myoblasts was blocked after Hgf/Sf exposure. The authors suggest that constitutive activation of c-Met in the absence of Ink4a/Arf creates an expanded a premalignant population of myogenic precursors that are incapable of undergoing cell-cycle arrest or apoptosis. Therapeutics designed to target both of these pathways might be useful in treating this childhood cancer.
Kristine Novak
References
Sharp, R. et al. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nature Med. 7 Oct 2002 (doi:10.1038/nm787). | Article | PubMed |
Trusolino, L. & Comoglio, P.M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev. Cancer2, 289–300 (2002) | Article | PubMed |
