The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer

Abstract

Tumor-associated stroma (TAS) is not simply a supporting element for cancer cells, but plays an important role in tumor growth, invasion and metastasis. Changes on the level of stromal constituents, such as loss of Caveolin-1 and increased thymidine phosphorylase (TP) expression, have been associated with tumor aggressiveness. The mutual cooperation between stromal fibroblasts and cancer cells is another distinguishing feature, which has recently emerged. In this investigation, both the loss of Caveolin-1 and the increased TP expression in the prostatic TAS was associated with high Gleason score (p = 0.0002 and 0.003, respectively); the two proteins were acting both independently and synergistically. In addition, TP was significantly associated with high stromal Ki-67 (MIB1) proliferation index (p = 0.03). Analysis of the metabolic interactions between stromal and epithelial elements showed that, while prostatic cancer cells express principally (> 91%) lactate dehydrogenase-5 (LDH-5) (anaerobic metabolism), the tumor-associated fibroblasts/myofibroblasts (TAFs) express largely (67.8%) LDH-1 (aerobic metabolism)-the terms TAFs and TAS are used interchangeably. These two isoenzyme pathways act complementary; the LDH-5 pathway converts pyruvate to lactate, whereas the LDH-1 enzyme system utilizes the secreted metabolite lactate to produce pyruvate, essential for continuous energy supply to tumor cells. Monocarboxylate transporter-1 (MCT-1)-the main facilitator of lactate uptake in tumor cells, was expressed exclusively in prostate cancer cells and related directly to LDH-5 overexpression. These findings support and extend our previous studies on energy recycling between the aerobic stroma and the anaerobic cancer cells within the framework of Warburg effect.

PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth

“…Inhibition of the FAO metabolic pathway has shown promising results for therapy of prostate cancer (10,17), and pharmacological inhibition of FAO sensitizes human leukemic cells to apoptosis (23). In addition, proteins involved in FAO, such as carnitine palmitoyltransferase I, have been shown to have an antiapoptotic function that has been attributed to cross talk with proapoptotic proteins (11,20).…”

Does normalisation improve the diagnostic performance of apparent diffusion coefficient values for prostate cancer assessment? A blinded independent-observer evaluation

“…11 Such an explanation suggests that ADC normalisation may be particularly problematic in a presurgical setting than when applied in men with only clinical suspicion for prostate cancer, given that patients in the former group will generally have undergone more recent biopsies and harbour more aggressive disease that may incite surrounding reactive stromal changes. 12 Such factors can disrupt the ADC of benign areas and hinder the utility of benign prostate tissue as a reference measurement.…”

Phenotypic characterization of human prostatic stromal cells in primary cultures derived from human tissue samples

“…Caveolin-1 was strongly associated with the presence of fibroblasts. Although it has been demonstrated that the fibroblast expression of caveolin-1 favors directional migration and invasiveness of carcinoma cells in vitro as well as in vivo, stromal caveolin-1 remodels peri-and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency (32,33), current evidence indicates that the increased expression of caveolin-1 in prostate adenocarcinoma cells and the downregulation of the protein in prostate stroma, mediate progression to the castration-resistant phase of PCa (34). CAFs have been reported to promote epithelial-mesenchymal transition in cancer cells, thereby enhancing their aggressiveness and stem-like properties (7,(35)(36)(37)(38).…”