Abstract
Candida albicans infections are very frequent in cancer patients, whose immune system is often compromised, but whether this fungal pathogen affects cancer progression is unknown. C. albicans infection involves endogenous production of inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-18 (IL-18). Increased levels of these cytokines have already been correlated with metastasis of most common cancer types. In this study, a well-established model of IL-18-dependent hepatic melanoma metastasis was used to study whether C. albicans can alter the ability of murine B16 melanoma (B16M) cells to colonize the liver. First, we determined the ability of intrasplenically (IS) injected B16M cells to metastasize into the liver of mice challenged with 5 × 104C. albicans cells by three different routes (intravenous, IV; intrasplenic, IS; or intraperitoneal, IP) 12 h prior to injection of B16M cells. We demonstrated that C. albicans significantly increased metastasis of B16M cells with all three fungal injection routes. Pro-metastatic effects occurred when hepatic colonization with B16M cells place after the peak of TNF-α and IL-18 levels had been reached in the hepatic blood of fungal challenged mice. In a second set of experiments, mice were fungal challenged 4 days after injection of B16M cells. In these mice, C. albicans also potentiated the growth of established micro-metastases. Significantly, the fungal challenge had pro-metastatic effects without the C. albicans being able to reach the liver, suggesting that soluble factors can promote metastasis in remote sites. Mouse treatment with antifungal ketoconazol abrogated hepatic TNF-α stimulation by C. albicans and prevented the enhancement of hepatic metastasis in fungal challenged-mice. Therefore, the pro-inflammatory microenvironment generated by the host’s systemic response to C. albicans stimulates circulating cancer cells to metastasize in the liver.
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Acknowledgments
This work was supported by grants from the Carlos III National Institute of Health (FIS program, no. PI031727), from the CICYT (no. SAF2006-09341) and from Basque Country University to consolidated research groups (no. UPV13641/2003 and GIU06/07) to Fernando Vidal-Vanaclocha and to Fernando L. Hernando (no. UE03/A04 and UE08/14). We acknowledge Dr. David Gubb for critical reading of the manuscript.
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Guillermo Martínez-de-Tejada and Fernando Vidal-Vanaclocha share senior authorship.
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Rodríguez-Cuesta, J., Hernando, F.L., Mendoza, L. et al. Candida albicans enhances experimental hepatic melanoma metastasis. Clin Exp Metastasis 27, 35–42 (2010). https://doi.org/10.1007/s10585-009-9300-9
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DOI: https://doi.org/10.1007/s10585-009-9300-9