TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence

Ilana Chefetz, Ayesha B. Alvero, Jennie C. Holmberg, Noah Lebowitz, Vinicius Craveiro, Yang Yang-Hartwich, Gang Yin, Lisa Squillace, Marta Gurrea Soteras, Paulomi Aldo, Gil Mor

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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+ EO C 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+ EO C stem cells undergo self-renewal as evidenced by upregulation of stemnessassociated genes. More importantly, we show that a pro-inflammatory microenvironment created by the TLR2-MyD88- NFκB pathway supports EO C stem cell-driven repair and self-renewal. Overall, our findings point to a specific cancer cell population, the CD44+/MyD88+ EO C 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 EO C patients.

Original languageEnglish (US)
Pages (from-to)511-521
Number of pages11
JournalCell Cycle
Volume12
Issue number3
DOIs
StatePublished - Feb 1 2013

Bibliographical note

Funding Information:
This study was supported in part by grants from NCI/NIH RO1CA127913, RO1CA118678, the Sands Family Foundation and the Discovery to Cure Research Program. I.C. is a Life Science Research Foundation Postdoctoral fellow. M.G. is a fellow from Fundacion Alfonso Martin Escudero.

Keywords

  • Ovarian cancer stem cells
  • Recurrence
  • Self-renewal
  • TLR2
  • Tumor repair

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