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Salado C.,Innoprot SL | Olaso E.,University of the Basque Country | Gallot N.,Pharmakine Ltd. | Valcarcel M.,Pharmakine Ltd. | And 3 more authors.
Journal of Translational Medicine

Background: Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis.Methods: Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18thhour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied.Results: Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells.Conclusions: These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver. © 2011 Salado et al; licensee BioMed Central Ltd. Source

Rodriguez-Cuesta J.,University of Navarra | Rodriguez-Cuesta J.,University of the Basque Country | Rodriguez-Cuesta J.,Biosciences Co operative Research Center Bio | Hernando F.L.,University of the Basque Country | And 5 more authors.
Clinical and Experimental Metastasis

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 × 104 C. 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. © 2009 Springer Science+Business Media B.V. Source

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