207 Poster Session 2 - Connective Tissue Oncology Society

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Scientific Posters – Poster Session 2modulate cellular senescence, DNA repair, angiogenesis,epithelial-mesenchymal transition and metastasis.Conclusion: A prognostic miRNA signature consisting ofsix miRNAs has been successfully developed and validatedfor UPS. This signature could help identify patients at"High" risk for distant metastasis, who might benefit frommore aggressive systemic therapies or novel treatmentapproaches. Further, examination of the biological roles ofthese miRNAs in sarcoma could lead to the identificationof novel therapeutic targets which can impact on survivalfor future patients with UPS.Poster #148SOFT TISSUE SARCOMAS AND BONEMETASTASIS: PATHWAY PROTEINS INVOLVEDIN THE METASTASIS MICROENVIRONMENTAmalia Conti 2 ; Antonella Chiechi 2 ; Chiara Novello 1 ;Giovanna Magagnoli 1 ; Maria Serena Benassi 1 ; Piero Picci 1 ;Lance Liotta 2 ; Viriginia Espina 21Experiment Oncology Laboratory, Rizzoli OrthopaedicInstitute, Bologna, Italy; 2 Center for Applied Proteomicand Molecular Medicine, George Mason University,Manassas, VA, USAObjective: Soft-tissue sarcomas (STS) are a heterogeneousgroup of tumors that frequently have distant metastases.Although pathophysiology of bone metastases is wellknown, treatment still has a limited success. There istherefore a great need to develop new strategies employingmolecular targeted inhibitors. Proteomic molecular profilingcan identify pathways or specific proteins useful forpatient stratification and consequent treatment.The aim of this study was to investigate expression of keyproteins belonging to multiple signal transduction pathwaysand define their role in insurgence of STS and theirbone metastases in order to identify prognostic biomarkersand potential targets for molecular targeted therapies.Methods: 34 fresh frozen bone metastasis samples frompatients diagnosed with primary STS, 10 primary STSspecimens, 10 paired adjacent normal tissues, and as controlnon tumoral normal bone samples were completelyhomogenized using CryoPrepTM and Adaptative FocusAcousticTM (AFATM) technology by Covaris, with verygood protein extraction efficiency. Expression of 48 proteinsinvolved in bone metabolism, matrix breakdown, hormoneresponse, growth-proliferation, stress-inflammation andadhesive-cytoskeletal pathways was quantified by Reversephase protein arrays (RPMA).Results: By Mann Whitney analysis we first comparedprimary STS, paired normal tissues and bone metastaseswith normal bone. Differential expression (p < 0.05) wasfound for proteins involved in bone metabolism (DKK1,WNT5a/B), matrix degradation (MMP11, MMP14), proliferation(PI3K, AKT, mTOR, mTOR S2448, 4EBP S37/46) andadhesive-cytoskeletal pathways (Fibronectin, Syndecan 1,FAK Y576/577, Shc Y317). When comparing only pairedsamples, proteins involved in adhesion pathways showeddifferent activation intensity. Spearman’s rho correlationindex between primary tumor and metastasis showedsignificant values for TNF alpha (ρs= 0.7143; p=0.0288)and TNFR1 (ρs= 0.7381; p=0.0229).Conclusion: These preliminary results reveal an activationstate of pathways that are involved in STS metastatizationto bone. A validation of these preliminary results is ongoingby using immunohistochemistry analysis on a largerseries of samples. Our comprehensive approach could leadto identification of proteins involved in tumor-microenvironmentcross talk as targets for new molecular targetedtherapies.Poster #149PATIENT-DERIVED XENOGRAFT MODELS FORSOFT TISSUE SARCOMASFrank Traub, MD, PhD 1 ; Jana Rolff 2 ; Dimosthenis Andreou 1 ;Maya Niethard 1 ; Carmen Tiedke 1 ; Anne Richter 1 ;Iduna Fichtner 2 ; Per-Ulf Tunn 11Tumororthopädie, HELIOS Klinikum Berlin Buch,Berlin, Germany; 2 Experimental Pharmacology,Max-Delbrück-Center for Molecular Medicine,Berlin, GermanyObjective: Well-characterized animal models are neededto improve the therapeutic outcome of soft tissue sarcomapatients. Xenograft sarcoma models are frequently used,but commonly derived from cell lines rather than fromprimary human sarcoma tissue. The objective of the presentstudy was to establish xenograft models of primaryhuman soft tissue sarcomas in immunodeficient mice. Inthese models novel therapeutic options will be evaluatedand predictive biomarkers can be defined.Methods: Tissue from ten primary human soft tissue sarcomaswas directly transferred from our surgical theatre tothe laboratory. The tumour samples were taken from representativeareas of the original tumour. The samples weredivided into two adjacent parts, one for further histologicalanalysis (conventional light and immunohistochemistry)and the other for the in vivo experiment. A fragment fromeach tumor tissue was transplanted subcutaneously intoseveral (3-5) mice.Results: Five out of 10 derived sarcoma xenografts could besuccessfully established leading to solid tumors. Histologi-242
Scientific Posters – Poster Session 2cal and immunohistochemical staining showed a similarhistological morphology of the xenografts compared withthe original tumour. Necrosis was found ranging from 15to 25%. The specimens showed a marginal inflammation.Conclusion: Patient-derived sarcoma xenografts allowdetailed investigation of therapy-related markers and theirdynamic regulation in a well-standardised and clinicallyrelated way.Poster #150THE EXPRESSION OF THROMBOMODULINMESSENGER RNA IN 62 SOFT TISSUE SARCOMAPATIENTSKunihiro Asanuma; Akihiko Matsumine; Takao Matsubara;Tomoki Nakamura; Atsumasa Uchida; Akihiro SudoOrthopedic Surgery, Mie University, Tsu, Japan0.05). OS were significantly worse for patients with highTM expression group compared with low TM expressiongroup in high grade group (Fig2: P〈0.05).Conclusion: This is the first study of the comparison betweenTM mRNA level and clinicopathological parametersof STS patients. In this study, TM expression is not relatedto histological malignancy. However, high TM expressionis related to metastasis and OS. Anticoagulation factorslike TM may play an important role on tumor metastasisof sarcoma cells. The measurement of TM expression insarcoma tissues may contribute to the prediction of notonly tumor metastasis but OS for sarcoma patient. Theseneed further study.Objective: Thrombomodulin (TM) is well-known as athrombin receptor that inhibits the procoagulant activitiesof thrombin. TM modulates tumor cell growth, celldifferentiation and metastasis. TM is demonstrated to bean independent prognostic indicator for overall survival(OS) in carcinoma. The purpose of this study is to elucidatethe correlation between TM mRNA expression level andclinicopathological parameters and to predict the prognosisof soft tissue sarcoma (STS) patients.Methods: This study was performed on tumor tissuesamples of 62 patients with histologically verified STS.The median age of patients was 52.9 years. The medianfollow-up time of patients was 88 months. These patientswere diagnosed with the following subtypes: Alveolar softpart sarcoma (2 patients); Clear cell sarcoma (3 patients);Leiomyosarcoma (1 patient); Liposarcoma (8 patients);Malignant granular cell tumor (1 patient); Malignantfibrous histiocytoma (21 patients); Malignant peripheralnerve sheath tumor (9 patients); Rhabdomyosarcoma (3patients); Synovial sarcoma (10 patients); ExtraskeletalEwing's sarcoma (1 patient); Extraskeltal Myxoid Chondrosarcoma(1 patient); unknown (2 patient). cDNA weresynthesized and TM mRNA expression levels was quantifiedusing a endogenous gene (GAPDH). The relation ofTM expression levels with clinicopathological parameterswas evaluated by non-parametric Mann–Whitney tests. Forsurvival analyses, the OS of STS was used as follow-up endpoint. The association between TM expression levels andprognosis was evaluated by Kaplan–Meier analyses.Results: There is no difference in TM expression levelbetween histological low and high grade STS. TM expressionlevel was significantly higher in the metastatic patentsthan no-metastatic patients in high grade group (Fig1: P〈243
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207 Poster Session 2 - Connective Tissue Oncology Society

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