title: Participation of the Fas/FasL signaling pathway and the lung microenvironment in the development of osteosarcoma lung metastases.
abstract: The lungs are the most common site for the metastatic spread of osteosarcoma. Success in using chemotherapy to improve overall survival has reached a plateau. Understanding the biologic properties that permit osteosarcoma cells to grow in the lungs may allow the identification of novel therapeutic approaches-the goal being to alter the tumor cells' expression of cell surface proteins so that there is no longer compatibility with the metastatic niche. We have demonstrated that the Fas Ligand positive (FasL(+)) lung microenvironment eliminates Fas(+) osteosarcoma cells that metastasize to the lungs. Indeed, osteosarcoma lung metastases from patients are Fas(-), similar to what we found in several different mouse models. The Fas(+) cells are cleared from the lungs through apoptosis induced by the Fas signaling pathway following interaction of Fas on the tumor cell surface with the lung FasL. Blocking the Fas signaling pathway interferes with this process, allowing the Fas(+) cells to grow in the lungs. Our investigations show that Fas expression in osteosarcoma cells is regulated epigenetically by the micro-RNA miR-20a, encoded by the miR-17-92 cluster. Our studies support the feasibility of finding agents that can re-induce Fas expression as a novel therapeutic approach to treat osteosarcoma patients with lung metastases. We have identified two such agents, the histone deacetylase inhibitor entinostat and the chemotherapeutic agent gemcitabine (GCB). Aerosol GCB and oral entinostat induce the upregulation of Fas and the regression of established osteosarcoma lung metastases. Aerosol GCB was not effective in the FasL-deficient gld mouse confirming that the lung microenvironment was central to the success of this therapy. Our studies establish the critical role of the lung microenvironment in the metastatic process of osteosarcoma to the lungs and suggest an alternative focus for therapy, that is, incorporating the lung microenvironment as part of the treatment strategy against established osteosarcoma disease in the lungs.
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Children's Cancer Hospital, 1515 Holcombe - MOD1.002, Houston, TX, 77030, USA.
authors.forename: Gangxiong
authors.initials: G
authors.lastname: Huang
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Nishimoto
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D044127:Epigenesis, Genetic; D053222:Fas Ligand Protein / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D011725:Pyridines / Q000494:pharmacology; D062085:RNA, Long Noncoding; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects*; D019014:fas Receptor / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C568997:MIR17HG, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D011725:Pyridines; D062085:RNA, Long Noncoding; D019014:fas Receptor; D003841:Deoxycytidine; C118739:entinostat; D000093542:Gemcitabine