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.

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

“…We previously showed that TLR2/MyD88 signaling in tumor cells promotes gastric tumorigenesis in gp130 F/F mice (19,28). Consistent with these findings, it has been shown that TLR2 signaling in cancer cells plays a tumor-promoting role through the enhancement of stemness (23,24). Moreover, the epithelial cell-specific deletion of Myd88 was observed to suppress intestinal tumorigenesis in Apc Min mice (16).…”

“…Importantly, we show that MyD88 signaling in BMDCs is required for the generation of the inflammatory microenvironment in tumors even though the COX-2/PGE 2 pathway is activated. Moreover, inflammatory responses induce the expression of TLR2 and CD14 in tumor epithelial cells, which have been shown to play tumor-promoting roles through enhancement of stem cell properties (16,23,24). These results indicate that both the MyD88 signaling and the COX-2/PGE 2 pathway are required for generation of the inflammatory microenvironment, which may promote tumorigenesis through the induction of TLR2/ CD14 signaling in tumor cells.…”

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

“…Current studies suggest that recurrence is caused by the regrowth of the surviving inherently chemoresistant cancer stem cells that persisted during chemotherapy. The expansion of this chemoresistant cancer cell population, coupled with prosurvival modifications induced by the pressure of treatment, is thought to be responsible for the development of chemoresistant recurrent disease (10). Heterogeneity of ovarian tumors is not only limited to the presence of different epithelial cell subtypes with differential stemness potential, but also in the presence of different cancer cells with varying stages of mesenchymal status and migratory/invasiveness potential (9,47).…”

“…These patient samples were obtained from patients at Yale New Haven Hospital (New Haven, CT) who were diagnosed with stage III/IV serous ovarian cancer and propagated as described previously (9,10,14,(28)(29)(30)(31)(32)(33) …”

“…þ ovarian cancer cells represent the chemoresistant phenotype and, particularly, that the CD44 þ /MyD88 þ ovarian cancer stem cell (OCSC) population represents the cancer cell type that can repair and rebuild the tumor (9)(10)(11)(12)(13). This cell population, therefore, represents the therapeutically relevant subtype that should be specifically targeted to prevent recurrence and improve patient survival.…”