title: Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.
abstract: The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Lan G
authors.initials: LG
authors.lastname: Coffman
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: McLean
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Allen
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.|Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Marina Pasca
authors.initials: MP
authors.lastname: di Magliano
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D020690:GTPase-Activating Proteins; D053823:Hedgehog Proteins / Q000378:metabolism*; D006649:Histocompatibility Antigens; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D020690:GTPase-Activating Proteins; D053823:Hedgehog Proteins; C056907:Hh1 protein, mouse; D006649:Histocompatibility Antigens
keywords: BMP4; Hedgehog; mesenchymal stem cell; ovarian cancer; tumor microenvironment