Increasing Expression of Monocarboxylate Transporters 1 and 4 Along Progression to Invasive Cervical Carcinoma

Abstract

Solid tumor cells are known to be highly glycolytic and, to prevent apoptosis by cellular acidosis, cells increase proton efflux through pH regulators, such as monocarboxylate transporters (MCTs). However, the role of these membrane proteins in solid tumor development and survival is not fully understood. We aimed to evaluate the expression of the MCT isoforms 1, 2, and 4 in a large series of cervical lesions (neoplastic and non-neoplastic) and assess its clinical-pathologic significance. The series analyzed included 29 chronic cervicitis, 30 low-grade squamous intraepithelial lesions, 32 high-grade squamous intraepithelial lesions, 49 squamous cell carcinomas, 51 adenocarcinomas, and 30 adenosquamous carcinomas of the uterine cervix. Analysis of the expression of MCT isoforms 1, 2, and 4 was performed by immunohistochemistry with specific antibodies. Immunoreactions were evaluated both qualitatively and semiquantitatively. We found a significant increase in MCT expression from preinvasive to invasive squamous lesions and from normal glandular epithelium to adenocarcinomas. This is the first study evaluating the significance of MCT expression in lesions of the uterine cervix, including invasive carcinomas, and the results found herein led us to believe that these membrane proteins are involved in the progression to invasiveness in uterine cervix carcinoma.

CD147 Expression in Advanced Cutaneous Squamous Cell Carcinoma

“…Interestingly, MCT4 expression levels were greater than MCT1 expression levels. This pattern is consistent with what was found in cervical and colorectal carcinomas [19,20]. Despite high expression levels of these plasma proteins, there was no association found with clinicopathologic parameters.…”

“…Furthermore, the efflux of lactate decreases interstitial pH, which has been found to promote metastasis and decrease disease-free survival [20,24,25]. In addition, CD147 and MCT create environments which promote VEGF expression, further promoting tumor growth, invasion, and metastasis [19,26].…”

“…Our focus is on the MCT1 and MCT4, the proton-coupled lactate transporters. MCT1 is the most ubiquitous family member and found to be associated with colorectal, gastric, cervical, breast and ovarian cancers [15][16][17][18][19][20]. MCT4 has a low affinity for lactate and tends to be found in tissues requiring glycolysis [21].…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…With this important impact on lactate metabolism in tumor cells, MCT1, MCT2, and MCT4 have been proposed as diagnostic biomarkers or prognostic factors for cancer outcome and survival. For instance, increasing MCT1 expression is observed along with tumor aggressiveness e.g., in cervical cancer or is described as a prognostic marker in invasive breast cancer 32, 33. In prostate cancer, MCT2 has been proposed as a biomarker for disease diagnosis, because the transporter is not expressed in normal prostate tissue, an increase in expression can be observed in adjacent non‐neoplastic tissue and strong MCT2 expression is found in primary prostate tumor tissue samples 34.…”

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

“…MCTs belong to a family of 14 members, with isoforms 1-4 being lactate proton symporters that exhibit different affinities for lactate (Halestrap & Meredith 2004). As the isoforms responsible for lactate efflux, MCT1 and MCT4 are probably the most promising in the cancer context and reports on MCT1 and MCT4 upregulation in a variety of tumours are becoming more frequent (Mathupala et al 2004, Fang et al 2006, Koukourakis et al 2006, Pinheiro et al 2008a,b, 2010, 2012. Importantly, we have described association of MCTs, especially MCT1, with poor prognostic variables (Pinheiro et al 2008b, de Oliveira et al 2012, reinforcing the potential of MCT1 as a cancer therapeutic target.…”