title: Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment.
abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44-/MyD88- EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Craveiro
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang-Hartwich
authors.forename: Jennie C
authors.initials: JC
authors.lastname: Holmberg
authors.forename: Won Duk
authors.initials: WD
authors.lastname: Joo
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Sumi
authors.forename: John
authors.initials: J
authors.lastname: Pizzonia
authors.forename: Brian
authors.initials: B
authors.lastname: Griffin
authors.forename: Sabrina K
authors.initials: SK
authors.lastname: Gill
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.forename: Thomas
authors.initials: T
authors.lastname: Rutherford
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D012008:Recurrence; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017239:Paclitaxel
keywords: EMT; ovarian cancer stem cells; recurrence; slug