Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression

Abstract

BackgroundCancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism.MethodsRole of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression.ResultsTransformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression.ConclusionsOur data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to stressful environments.

Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer

“…Group 1, patients with no unfavorable genotypes; Group 2, those with one unfavorable genotype; Group 3, those with two unfavorable genotypes; Group 4, those with three unfavorable genotypes (Gerlinger et al 2012;Lee et al 2012) and poor prognosis of patients (Gerlinger et al 2012;Halestrap 2013;Miranda-Goncalves et al 2013;PertegaGomes et al 2011;Zhu et al 2014). Besides MCT molecules in tumor cells, recent studies have demonstrated that MCTs expressed on tumor and stroma cells mediate a lactate shuttle, which prevent lactate accumulation in tumor microenvironment and promote the survival, proliferation and progression of cancer cells (Sanita et al 2014;Vegran et al 2011). Therefore, the MCTs may be useful biomarkers for prognosis prediction and a potential therapeutic target for cancer therapy.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…An other study showed that prostate can cer cells can redi rect the me tab o lism of ad ja cent fi brob lasts to wards a gly colytic phe no type. The sub se quent re lease of lac tate by fi brob lasts in turn pro moted prostate tu mor growth [81].…”

Caveolae and signalling in cancer

“…Prostate carcinoma cells induce glycolysis in fibroblasts and this glycolysis and lactate extrusion drives OXPHOS in carcinoma cells 167,174 . In ovarian cancer, adipocytes transfer free fatty acids (FFAs) via fatty acid-binding protein 4 (FABP4) to carcinoma cells 175 .…”