Structured Abstract Objective MPNSTs are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of NF1, or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, neurofibromatosis type 1 (NF1)-associated, and radiation (RT)-associated malignant peripheral nerve sheath tumor (MPNST) are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. Methods Patients (n = 317) were identified through our institutional tumor registry. Clinicopathologic features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathologic features were used to identify adverse predictors of recurrence and survival outcomes. Results Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6% for the high-grade MPNST cohort, respectively. Five-year DSS was lower in NF1-associated and RT-associated compared to sporadic MPNST (48.7%, 40.9%, and 63.0%, respectively; p = 0.140). RT-associated MPNST had worse LRFS than sporadic and NF1-associated subtypes (p = 0.047). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. Conclusion RT-associated MPNSTs demonstrate poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared to sporadic tumors.
Background Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The aim of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. Methods A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA and outcome. Results At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63%. Clinical variables associated with improved DSS included age < 61 years, tumor size < 10 cm, margin-negative resection and sporadic-tumor status. At the protein level, loss of cyclin D1 (p=0.06), pEGFR (p=0.023), pIGF-1R (p=0.022), and PTEN (p<0.001) and overexpression of AXL (p=0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS) while RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. Discussion Cyclin D1, AXL and PTEN are associated with cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and could also explain the aggressive phenotype seen in RA-UPS when compared to the sporadic lesions.
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.
Intracellular and intercellular polarity requires that specific proteins be sorted to discreet locations within and between cells. One mechanism for sorting proteins is through RNA localization. In Saccharomyces cerevisiae, ASH1 mRNA localizes to the distal tip of the bud, resulting in the asymmetric sorting of the transcriptional repressor Ash1p. ASH1 mRNA localization requires four cis-acting localization elements and the trans-acting factors Myo4p, She3p, and She2p. Myo4p is a type V myosin motor that functions to directly transport ASH1 mRNA to the bud. She2p is an RNA-binding protein that directly interacts with the ASH1 mRNA cis-acting elements. Currently, the role for She3p in ASH1 mRNA localization is as an adaptor protein, since it can simultaneously associate with Myo4p and She2p. Here, we present data for two novel mutants of She3p, S348E and the double mutant S343E S361E, that are defective for ASH1 mRNA localization, and yet both of these mutants retain the ability to associate with Myo4p and She2p. These observations suggest that She3p possesses a novel activity required for ASH1 mRNA localization, and our data imply that this function is related to the ability of She3p to associate with ASH1 mRNA. Interestingly, we determined that She3p is phosphorylated, and global mass spectrometry approaches have determined that Ser 343, 348, and 361 are sites of phosphorylation, suggesting that the novel function for She3p could be negatively regulated by phosphorylation. The present study reveals that the current accepted model for ASH1 mRNA localization does not fully account for the function of She3p in ASH1 mRNA localization.RNA localization is a process to spatially and temporally restrict intracellular and intercellular protein expression. This mechanism for protein sorting is utilized by a number of eukaryotic organisms including mammals, Drosophila melanogaster, Xenopus spp., and Saccharomyces cerevisiae (4,15,25,37,44). RNA localization can be achieved through at least three distinct mechanisms: cytoplasmic diffusion followed by entrapment of the RNA at the site of localization, generalized degradation/localized protection, and directed transport using motor proteins and cytoskeletal elements (60). S. cerevisiae utilizes directed transport to localize at least 30 mRNAs to the bud tip (2,3,57,61). Localization of ASH1 mRNA to the bud tip in yeast results in the asymmetric sorting of Ash1p to the daughter cell nucleus (10,43,62). Ash1p is a transcriptional repressor that prevents expression of the HO endonuclease in the daughter cell, restricting mating-type switching exclusively to the mother cell (6,36,45,58).ASH1 mRNA localization is dependent on She2p, She3p, and Myo4p (43, 62). She2p is an RNA-binding protein that associates with the four ASH1 mRNA cis-acting localization elements: E1, E2A, E2B, and E3 (7,11,26,41,48). She2p also directly associates with the C terminus of She3p (7,11,26,41,48). The N terminus of She3p has the ability to associate with the type V myosin, Myo4p (7,19,47). Furthermore...
BackgroundAXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined.MethodsImmunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo.ResultsIn this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo.ConclusionsOur results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.
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