Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer

Abstract

BackgroundMonocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown. The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma.MethodsProstate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n = 171), adjacent non-neoplastic tissues (n = 135), PIN lesions (n = 40) and normal prostatic tissue (n = 14). Protein expression was correlated with patients' clinicopathologic characteristics.ResultsIn the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence.ConclusionsOur data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer.

Targeting lactate metabolism for cancer therapeutics

“…For example, elevated levels of MCT1 have been detected in breast, colorectal, gastric, and cervical cancer as well as in neuroblastoma and glioma (63)(64)(65)(66)(67)(68). In contrast, MCT4 expression is highly elevated in renal cell carcinoma as well as in cervical and prostate cancer (65,69,70). Importantly, the elevated expression of MCT1 and MCT4 in cancer provides a therapeutic window for disabling these transporters with smallmolecule inhibitors and/or by targeting their cochaperone CD147, for example using CD147-specific antibody therapeutics.…”

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

“…22). The expression of MCT4 has been associated with highly glycolytic cells (17,23,24), and elevated expression of MCT4 in tumors is clinically relevant, as it has been associated with poor patient prognosis in multiple types of cancer (25)(26)(27), including prostate cancer (28,29). Furthermore, elevated MCT4 expression may be important in cancer-stroma interactions facilitating prostate cancer progression (30).…”

Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

“…Aberrant expression of CD147 has been observed in various epithelial malignancies (17,18), including hepatocellular carcinoma, lung cancer, breast cancer, and carcinomas of the pancreas, prostate, and bladder. Importantly, the levels of CD147 overexpression have been implicated in poor patient prognosis for many tumor types (17,(19)(20)(21)(22). Thus, CD147 is a potential therapeutic target in cancer.…”