Ovarian cancer stem cells induce the M2 polarization of macrophages through the PPARγ and NF-κB pathways

Abstract

Abstract.Increasing evidence suggests an association between cancer stem cells and the tumor microenvironment. Ovarian cancer stem cell (OCSC) factors can influence the tumor microenvironment and prognosis. However, the effects of OCSCs on macrophage M1/M2 polarization are not yet completely understood. In the present study, we evaluated the effects of OCSCs on macrophage M1/M2 polarization. In addition, we investigated whether the activation of the peroxisome proliferator-activated receptor γ (PPARγ)/nuclear factor-κB (NF-κB) pathway is involved in these effects, thus modulating the M1/M2 differentiation of monocytes into macrophages. The expression levels of markers of the M1 state, such as tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD86, as well as those of markers of M2 activation, such as mannose receptor (MR), interleukin (IL)-10 and arginase-1 (Arg-1), were measured by RT-qPCR. We found that the OCSCs promoted the M2 polarization of Raw264.7 macrophages by upregulating the expression of MR, IL-10 and Arg-1, while the expression levels of M1 macrophages markers, including TNF-α, iNOS and CD86 were suppressed. In addition, treatment with OCSCs activated PPARγ and suppressed NF-κB in the Raw264.7 cells. Furthermore, the PPARγ, antagonist GW9662, attenuated the promoting effects of OCSCs on the M2 polarization of macrophages. To the best of our knowledge, the findings of the present study, provide the first evidence that OCSCs promote the M2 polarization of macrophages through the PPARγ/ NF-κB pathway.

New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy

“…It seems that active CSCs should be able to promote the M1-to-M2 conversion, induce formation of new vasculature via VEGF release, and build CSC-protective niches via tissue-repair pathways [2]. OCSCs may promote the M2 polarization of macrophages through the PPAR γ /NF- κ B pathway [115]. Chemoresistant CSCs may promote M2 macrophage differentiation through interferon-regulatory factor-5- (IRF5-) and macrophage-colony stimulating factor- (M-CSF-) dependent mechanisms [116].…”

Epithelial ovarian cancer inherent resistance: May the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role?

“…In addition, tumor-associated macrophages (TAM) seem to be crucial in the “immunoescaping” of EOC cells: according to recent data (Deng et al, 2015), M2 macrophages produce a selective cytokine pattern which address toward the immunosuppression respect to the M1 counterpart. Not surprisingly, it was recently evidenced that ovarian cancer drug-resistant cells promote the M2 polarization of macrophages through the proliferator-activated receptor γ (PPARγ)/nuclear factor-κB (NF-κB) pathway (Deng et al, 2015).…”

“…Not surprisingly, it was recently evidenced that ovarian cancer drug-resistant cells promote the M2 polarization of macrophages through the proliferator-activated receptor γ (PPARγ)/nuclear factor-κB (NF-κB) pathway (Deng et al, 2015). From the clinical point of view, patients affected by EOC usually undergo satisfactory response to the initial surgical cytoreduction and chemotherapy, although most of them have drug-resistant recurrence later in time, that is conceivably due to the ability of ovarian cancer drug-resistant cells to escape first-line chemotherapy (Laganà et al, 2015).…”

MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway

“…In addition, recent studies have shown that ovarian cancer stem cells induce M2 polarization of macrophages by activating PPARγ and NF-κB [28]. We found that PPARγ is a potential regulatory element for MFHAS1 gene in DECODE database of SABiosciences (Qiagen), so we hypothesized that the PPARγ in CRC microenviroment induced the express of MFHAS1 in TAMs.…”