Authors: Alexandra Giatromanolaki, Michael I. Koukourakis, Anastasios Koutsopoulos, Savvas Mendrinos and Efthimios Sivridis

Alexandra Giatromanolaki

Corresponding author: agiatrom@med.duth.gr
Department of Pathology; Democritus University of Thrace Medical School; University General Hospital of Alexandroupolis; Alexandroupolis, Greece

Michael I. Koukourakis

Department of Radiotherapy/Oncology; Democritus University of Thrace Medical School; University General Hospital of Alexandroupolis; Alexandroupolis, Greece

Anastasios Koutsopoulos

Department of Pathology; Democritus University of Thrace Medical School; University General Hospital of Alexandroupolis; Alexandroupolis, Greece

Savvas Mendrinos

Division of Pathology Integrated Medical Professionals; Garden City; New York, NY USA

Efthimios Sivridis

Department of Pathology; Democritus University of Thrace Medical School; University General Hospital of Alexandroupolis; Alexandroupolis, Greece

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 K_i-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.

Received: May 6, 2012; Accepted: August 8, 2012; Published Online: August 16, 2012

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