Torres K.E.,Sarcoma Research Center |
Zhu Q.-S.,Sarcoma Research Center |
Bill K.,University of Texas M. D. Anderson Cancer Center |
Bill K.,Sarcoma Research Center |
And 16 more authors.
Clinical Cancer Research | Year: 2011
Purpose: MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed. Experimental Design: Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses. Human MPNST cells were studied in vitro and in vivo; Western blot (WB) and ELISA were used to evaluate MET and HGF expression, activation, and downstream signaling. Cell culture assays tested the impact of HGF-induced MET activation and anti-MET-specific siRNA inhibition on cell proliferation, migration, and invasion; in vivo gel-foam assays were used to evaluate angiogenesis. Cells stably transduced with anti-MET short hairpin RNA (shRNA) constructs were tested for growth and metastasis in severe combined immunodeficient (SCID) mice. The effect of the tyrosine kinase inhibitor XL184 (Exelixis) targeting MET/VEGFR2 (vascular endothelial growth factor receptor 2) on local and metastatic MPNST growth was examined in vivo. Results: All three markers were expressed in MPNST human samples; pMET expression was an independent prognosticator of poor patient outcome. Human MPNST cell lines expressed MET, HGF, and pMET. MET activation increased MPNST cell motility, invasion, angiogenesis, and induced matrix metalloproteinase-2 (MMP2) and VEGF expression; MET knockdown had inverse effects in vitro markedly decreased local and metastatic growth in vivo. XL184 abrogated human MPNST xenograft growth and metastasis in SCID mice. Conclusions: Informative prognosticators and novel therapies are crucially needed to improve MPNST management and outcomes. We show an important role for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context. ©2011 AACR.
Birdn J.E.,University of Texas M. D. Anderson Cancer Center |
Morse L.J.,University of Texas M. D. Anderson Cancer Center |
Feng L.,University of Texas M. D. Anderson Cancer Center |
Wang W.-L.,University of Texas M. D. Anderson Cancer Center |
And 8 more authors.
Frontiers in Oncology | Year: 2016
Purpose: To determine non-radiographic risk factors differentiating atypical lipomatous tumors (ALTs) from lipomas. Methods: All patients with deep-seated lipomatous tumors of the extremities treated from January 2000 to October 2010 were retrospectively reviewed. Factors reviewed included age, gender, tumor location, size, histology, local recurrence, dedifferentiation, and metastasis. Multivariate logistic regression models were used to evaluate the effects of patient characteristics on ALT status. Results: Ninety-four lipomas and 46 ALTs were included. Patients with an ALT were older (median: 60.5 vs. 55 years). Lipomas were evenly distributed between upper (48.9%) and lower extremities (51.1%), whereas ALTs predominately involved the lower extremities (91.3%). Median ALT size (22 cm) was greater than lipomas (10 cm), p < 0.0001. One lipoma (1.04%) recurred at 77 months and five ALTs (10.9%) recurred at an average of 39 months (19-64 months). Two ALTs originally treated with wide resection recurred with a dedifferentiated component and were treated with wide re-excision and chemotherapy. No metastases or tumor-related deaths occurred in either group at the time of last follow-up. Patients older than 60 years, tumors greater than 10 cm, or thigh location, were more likely to be diagnosed with an ALT (p < 0.05). Conclusion: Lipomatous tumors were more likely to be ALTs when the tumor was at least 10 cm in size, located in the thigh, or found in patients that were 60 years of age or older. These risk factors may be used to guide management and surveillance strategies, when lipomatous tumors do not display characteristic radiographic features. © 2016 Bird, Morse, Feng, Wang, Lin, Moon, Lazar, Satcher, Madewell and Lewis.