title: CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis.
abstract: Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24(+) and CD133(+) cells have increased tumor sphere-forming capacity. CD133(+) cells demonstrated a trend for increased tumor initiation while CD24(+) cells versus CD24(-) cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44(+), CD90(+), CD117(+), or ALDH(+) versus their negative counterparts. We have found that CD24(+) cells, compared with CD24(-) cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24(+) cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24(+) cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.
authors.affiliation: Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniela
authors.initials: D
authors.lastname: Burgos-Ojeda
authors.affiliation: Department of Pathology, Division of Gynecological Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Obstetrics-Gynecology, Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Karen
authors.initials: K
authors.lastname: McLean
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
authors.forename: Euisik
authors.initials: E
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Division of Gynecological Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.affiliation: Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan. Department of Obstetrics-Gynecology, Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan. ronaldbu@med.umich.edu.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D051927:CD24 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D000096926:Benzenesulfonamides
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051927:CD24 Antigen; D002945:Cisplatin; D053614:Janus Kinase 2; D051059:PTEN Phosphohydrolase; D011743:Pyrimidines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C522865:TG101209; D000096926:Benzenesulfonamides; C507926:Jak2 protein, mouse