title: TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence.
abstract: Primary ovarian cancer is responsive to treatment, but chemoresistant recurrent disease ensues in majority of patients. Recent compelling evidence demonstrates that a specific population of cancer cells, the cancer stem cells, initiates and sustains tumors. It is therefore possible that this cell population is also responsible for recurrence. We have shown previously that CD44+/MyD88+ epithelial ovarian cancer stem cells (CD44+/MyD88+ EOC stem cells) are responsible for tumor initiation. In this study, we demonstrate that this population drives tumor repair following surgery- and chemotherapy-induced tumor injury. Using in vivo and in vitro models, we also demonstrate that during the process of tumor repair, CD44+/MyD88+ EOC stem cells undergo self-renewal as evidenced by upregulation of stemness-associated genes. More importantly, we show that a pro-inflammatory microenvironment created by the TLR2-MyD88-NFκB pathway supports EOC stem cell-driven repair and self-renewal. Overall, our findings point to a specific cancer cell population, the CD44+/MyD88+ EOC stem cells and a specific pro-inflammatory pathway, the TLR2-MyD88-NFκB pathway, as two of the required players promoting tumor repair, which is associated with enhanced cancer stem cell load. Identification of these key players is the first step in elucidating the steps necessary to prevent recurrence in EOC patients.
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA.
authors: Ilana
authors: I
authors: Chefetz
authors: Ayesha B
authors: AB
authors: Alvero
authors: Jennie C
authors: JC
authors: Holmberg
authors: Noah
authors: N
authors: Lebowitz
authors: Vinicius
authors: V
authors: Craveiro
authors: Yang
authors: Y
authors: Yang-Hartwich
authors: Gang
authors: G
authors: Yin
authors: Lisa
authors: L
authors: Squillace
authors: Marta
authors: M
authors: Gurrea Soteras
authors: Paulomi
authors: P
authors: Aldo
authors: Gil
authors: G
authors: Mor
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D019008:Drug Resistance, Neoplasm; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2
keywords: TLR2; ovarian cancer stem cells; recurrence; self-renewal; tumor repair