Abstract
BackgroundOvarian cancer, an inflammation-associated cancer, is the fifth leading cause of cancer deaths in women. The malignancy produces a large amount of tumor necrosis factor (TNF) which promotes a proinflammatory tumor microenvironment. In addition, the epidermal growth factor receptor (EGFR) is frequently overexpressed in high-grade ovarian cancer, which likely aggravates cancer progression. Since ovarian cancer progression is closely associated with chemokine networks driven by inflammation or EGFR activation, we investigated the chemokine signatures elicited by EGF and TNF in ovarian cancer cells to determine their individual profiles and if there was in fact some kind of synergy between their actions on the chemokine network.MethodsWe used a PCR array for the chemokine network to examine the signature of chemokines and their receptors elicited by EGF and TNF in four ovarian cancer cell lines (OVCAR-3, SKOV-3, CaOV-3 and TOV-21G).ResultsThe chemokine network revealed that ovarian cancer cells commonly expressed high levels of proinflammatory chemokines such as CCL20, CXCL1-3 and CXCL8 in response to EGF or TNF. However, the responsiveness to EGF or TNF displayed a cell line specific pattern. Although OVCAR-3 and SKOV-3 cells were responsive to either EGF or TNF, their TNF responsiveness was dominant. On the other hand, CaOV-3 and TOV-21G cells were responsive to EGF but less to TNF, probably due to the high levels of non-canonical nuclear factor (NF)-κB components such as IKKα and p52 in these cell lines compared to OVCAR-3 and SKOV-3 cells. Among chemokine receptors, only CXCR5 was responsive to EGF or TNF in CaOV-3 cells. Finally, CCL20 and CXCL8 responded synergistically in response to EGF and TNF in OVCAR-3 and SKOV-3 cells.ConclusionOur results indicate that CCL20, CXCL1-3 and CXCL8 are the primary chemokines induced by EGF or TNF and are elicited in these ovarian cancer cells via NF-κB, Akt and Erk signaling pathways. Of interest, there was a syngergistic response in terms of CCL20 and CXCL8 levels, when OVCAR-3 and SKOV-3 cells were exposed to EGF plus TNF. Targeting these proinflammatory chemokines may be a promising therapeutic strategy for ovarian cancer with abundant TNF and EGFR activation patterns.
Highlights
Ovarian cancer, an inflammation-associated cancer, is the fifth leading cause of cancer deaths in women
Control CCL2 and CXCL16 cytokines were expressed at low levels, they were both highly elevated following the addition of EGF or tumor necrosis factor (TNF)
CXCR4 was responsive to EGF or TNF, the expression levels post addition of either factor, were still low (Figure 1B)
Summary
An inflammation-associated cancer, is the fifth leading cause of cancer deaths in women. The epidermal growth factor receptor (EGFR) is frequently overexpressed in high-grade ovarian cancer, which likely aggravates cancer progression. Ovarian cancer cells highly express highly tumor necrosis factor (TNF), indicating the importance of TNF as a regulator of the proinflammatory tumor [10]. Those cells with a high endogenous expression of TNF expressed higher levels of CXCR4 than cells with a low TNF expression level [11]. The phosphatidylinositol 3-kinase (PI3K) which acts as a main downstream signaling pathway for EGF is frequently activated, leading to increased cell survival. EGF enhances the expression of CXCR4 as well as migration of ovarian cancer cells [17]
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