Conclusion
This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.
Methods
OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models.
Results
Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity.