Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Research article

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

Patrizia Sanità1, Mattia Capulli1, Anna Teti1, Giuseppe Paradiso Galatioto2, Carlo Vicentini2, Paola Chiarugi3, Mauro Bologna2 and Adriano Angelucci1*

Author Affiliations

1 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy

2 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy

3 Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”, University of Florence, 50134 Florence Italy

For all author emails, please log on.

BMC Cancer 2014, 14:154  doi:10.1186/1471-2407-14-154

Published: 5 March 2014

Abstract

Background

Cancer 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.

Methods

Role 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.

Results

Transformed 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.

Conclusions

Our 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.

Keywords:
Aerobic glycolysis; Monocarboxylate transporters; Cancer associated fibroblasts; Warburg effect; Tumor stroma