title: Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2.
abstract: Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. We found that only ALDH(+)CD133(+) cells could generate all four ALDH(+/-)CD133(+/-) cell populations and identified a clear branched differentiation hierarchy. We also observed a single putative stochastic event. Within the hierarchy of cells, bone morphologenetic protein 2 (BMP2) is preferentially expressed in ALDH(-)CD133(-) cells. BMP2 promotes ALDH(+)CD133(+) cell expansion while suppressing the proliferation of ALDH(-)CD133(-) cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer.
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Ingram
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Lan
authors.initials: L
authors.lastname: Coffman
authors.affiliation: Department of Cell and Molecular Biology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Mangala
authors.initials: M
authors.lastname: Iyengar
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Shoumei
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Pathology University of Michigan, Ann Arbor, MI 48109;
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Euisik
authors.initials: E
authors.lastname: Yoon
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; Department of Cell and Molecular Biology, University of Michigan, Ann Arbor, MI 48109; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109 ronaldbu@med.umich.edu.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D044085:Microfluidics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; C525718:BMP2 protein, human; D014408:Biomarkers, Tumor; D055396:Bone Morphogenetic Protein 2; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D000444:Aldehyde Dehydrogenase
keywords: BMP2; cancer stem cells; differentiation capacity; hierarchical; ovarian cancer