Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer

Abstract

Inflammatory cytokines, components of cancer stem cells (CSCs) niche, could affect the characteristics of CSCs such as self-renewal and metastasis. Interleukin-17 (IL-17) is a new pro-inflammatory cytokine mainly produced by T-helper (Th17) cells and macrophages. The effects of IL-17 on the characteristics of CSCs remain to be explored. Here we first demonstrated a role of IL-17 in promoting the self-renewal of ovarian CD133(+) cancer stem-like cells (CSLCs). We detected IL-17-producing cells (CD4(+) cells and CD68(+) macrophages) in the niche of CD133(+)CSLCs. Meanwhile, there was IL-17 receptor expression on CD133(+)CSLCs derived from A2780 cell line and primary ovarian cancer tissues. By recombinant human IL-17 stimulation and IL-17 transfection, the growth and sphere formation capacities of ovarian CD133(+)CSLCs were significantly enhanced in a dose-dependent manner. Moreover, ovarian CD133(+)CSLCs transfected with IL-17 showed greater tumorigenesis capacity in nude mice. These data suggest that IL-17 promoted the self-renewal of ovarian CD133(+)CSLCs. Further investigation through gene profiling revealed that the stimulation function of IL-17 on self-renewal of ovarian CD133(+)CSLCs might be mediated by the nuclear factor (NF)-κB and p38 mitogen-activated protein kinases (MAPK) signaling pathway. NF-κB and p38 MAPK were activated by IL-17. More importantly, IL-17-promoted self-renewal was inhibited by specific inhibitors of NF-κB and p38 MAPK. Taken together, our data indicate that IL-17 contributed to ovarian cancer malignancy through promoting the self-renewal of CD133(+)CSLCs and that IL-17 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.

IL-17A exacerbates cisplatin-based resistance of OVCA via upregulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signaling

“…Interestingly, it should be mentioned our data in vitro indicate that relatively low concentration of rhIL-17A (we used 1ng/ml rather than 25ng/ml or 50ng/ml reported in other studies concerning the effects of rhIL-17A on tumor biological behaviors [13,17]) could decrease the sensitivity of OVCA to DDP. The lack of actual measurement renders it difficult to ascertain the amount of IL-17A in cancer lesions in clinical settings.…”

“…Accumulating evidences manifested that IL-17A is an identified pro-inflammatory cytokine which might play a key role in OVCA progression, by accelerating tumor migration, invasion and angiogenesis [16,17]. It is well known that tumor cell proliferation plays critical role in tumor development.…”

“…As of today, IL-17A direct role in the proliferation of the tumor cells has not been made very clear. Xiang T. et al reported that A2780-derived ovarian CD133-positive CSLCs and counterpart CD133-negative expressed IL-17R, and rhIL-17 could significantly increase the number of spheres of the former, however, did not have any effect on the proliferation of the latter [17]. Eric Tartour group reported there was no direct effect of IL-17A on proliferation of cervical tumor cell lines in vitro [39].…”

“…In addition, it had been reported that IL-17A could be detected in a variety of human tumors frequently [7], including gastric adenocarcinoma [8], non-small-cell lung carcinoma (NSCLC) [9], hepatocellular carcinoma (HCC) [10,11], colorectal carcinoma [12], cervical cancer [13], and ovarian cancer (OVCA) [14,15]. More recent studies have demonstrated that IL-17A might play a key role in OVCA progression by accelerating tumor migration, invasion and angiogenesis [16,17]. However, the relevance of IL-17A with drug-resistance of OVCA has been poorly elaborated.…”

Detection of TSH, FT3, FT4, and TRAb in ovarian cancer with highly sensitive electrochemical immunoassay

“…Consequently, most patients have been diagnosed with advanced stages. 2 The 5-year survival rate of the patients diagnosed at stages III and IV of ovarian cancer will dramatically reduce when comparing with that of the patients diagnosed at stages I and II. The mortality rate of ovarian cancer is the highest in gynecologic oncology and displayed the trend to happen in younger age 3 .…”