[The role of expression of monocarboxylates of the first and fourth types (MCT1, MCT4) by tumor and stromal cells of prostate cancer in determining the prognosis and the efficiency of definitive treatment].

AIM: A search for new methods for diagnosing clinically significant prostate cancer is of importance due to the insufficient accuracy of modern methods in detecting aggressive tumors. One of the promising opportunities for the early diagnosis of clinically significant prostate cancer is the assessment of the glycolytic profile of the tumor by determining the expression of monocarboxylates (MCT) types 1 and 4 in tumor cells, as well as in adjacent stromal cells. MATERIALS AND METHODS: An analysis of patients of who underwent radical prostatectomy at the Institute of Urology and Reproductive Health of Sechenov University from 2015 to 2017 was carried out. The patients with histologically confirmed prostate adenocarcinoma were included in the study. Among them, the presence or absence of biochemical recurrence during the first year was studied. An immunohistochemical (IHC) study of postoperative specimen was performed to determine the expression of MCT1 and MCT4 by tumor and stromal cells. The correlation between the intensity of their expression and the risk of biochemical recurrence and the tumor characteristics was evaluated. RESULTS: High membrane expression of MCT1 directly correlated with high stromal expression of MCT4 (r=0.314, p<0.003). A significant direct correlation was found between the predominance of stromal expression of MCT4 over membrane expression and biochemical recurrence (r=0.403, p<0.001), as well as a high ISUP group (4 and 5) (r=0.294, p=0.005). CONCLUSIONS: Determination of the level of expression of type 1 and 4 monocarboxylate transporters in adenocarcinoma cells and tumor stromal cells can become an effective tool for risk stratification, and may also predict the biological behaviors of the prostate cancer and the efficiency of definitive treatment.

Maternal obesity-associated disruption of polarized lactate transporter MCT4 expression in human placenta.

Maternal obesity is associated with an increased risk of adverse pregnancy outcomes including stillbirth, and their etiology is thought to be related to placental and fetal hypoxia. In this study, we sought to investigate the levels of lactate in maternal and umbilical cord blood, a well characterized biomarker for hypoxia, and expression of plasma membrane lactate transporter MCT1 and MCT4 in the placental syncytiotrophoblast (STB), which are responsible for lactate uptake and extrusion, respectively, from pregnant women with a diagnosis of obesity following a Cesarean delivery at term. With use of approaches including immunofluorescence staining, Western blot, RT-qPCR and ELISA, our results revealed that in controls the expression of MCT1 was equally observed between basal (fetal-facing, BM) and microvillous (maternal-facing, MVM) membrane of the STB, whereas MCT4 was predominantly expressed in the MVM but barely detected in the BM. However, obese patients demonstrated significant decreased MCT4 abundance in the MVM coupled with concurrent elevated expression in the BM. We also found a linear trend toward decreasing MCT4 expression ratio of MVM to BM with increasing maternal pre-pregnancy BMI. Furthermore, our data showed that the lactate ratios of fetal cord arterial to maternal blood were remarkably reduced in obese samples compared to their normal counterparts. Collectively, these results suggest that the loss of polarization of lactate transporter MCT4 expression in placental STB leading to disruption of unidirectional lactate transport from the fetal to the maternal compartment may constitute part of mechanisms linking maternal obesity and pathogenesis of stillbirth.

Coexpression of MCT1 and MCT4 in ALK-positive Anaplastic Large Cell Lymphoma: Diagnostic and Therapeutic Implications.

In solid tumors, glycolytic cancer or stromal cells export lactates through monocarboxylate transporter (MCT) 4, while oxidative cancer or stromal cells take up lactates as metabolic fuels or signaling molecules through MCT1. CD147 acts as a chaperone of MCT1 or MCT4. Unlike solid tumors, malignant lymphomas have a peculiar tumor microenvironment. To investigate the metabolic phenotype of malignant lymphoma associated with lactate transport, we analyzed immunohistochemical expressions of MCT1, MCT4, and CD147 in 247 cases of various malignant lymphomas. Surprisingly, both MCT1 and MCT4 were diffusely expressed on tumor cell membranes in all cases (11/11, 100%) of anaplastic lymphoma kinase (ALK) (+) anaplastic large cell lymphoma (ALCL). In contrast, only MCT1 was diffusely expressed in tumor cells of ALK(-) ALCL, as well as in B-cell, natural killer/T-cell, T-cell, and classic Hodgkin lymphomas. In these lymphomas, MCT4 expression was mostly localized to adjacent stromal cells. The pattern of diffuse membranous MCT1 and partial MCT4 expressions in tumor cells was observed in 1 case each of peripheral T-cell lymphoma (1/15, 6.7%) and multiple myeloma (1/34, 2.9%). CD147 was diffusely expressed in all types of lymphoma tumor and/or stromal cells. In conclusion, ALK(+) ALCL has a unique metabolism showing high coexpression of MCT1 and MCT4 in tumor cells. Because only ALK(+) ALCL overexpresses MCT4, immunostaining for MCT4 together with ALK is very useful for differential diagnosis from ALK(-) ALCL or peripheral T-cell lymphoma. Moreover, dual targeting against MCT1 and MCT4 would be an appropriate therapeutic approach for ALK(+) ALCL.

Identification of the HT-29 cell line as a model for investigating MCT1 transporters in sigmoid colon adenocarcinoma.

MCT1 transporters play a crucial role in the symbiotic relationship between humans and their colonic microbiome by facilitating the transport of bacteria-derived short chain fatty acids. Expression of colonic MCT1 transporters, localized in surface epithelial cells, is regulated by luminal butyrate levels. However, MCT1 also transports lactate and can be used by cancer cells to facilitate anaerobic glycolysis. Using immunolocalization techniques, this study investigated whether changes in MCT1 during cancer varied between different colonic regions. Whilst MCT1 abundance did not significantly change in transverse colon adenocarcinoma (P = 0.363, N = 6, paired T-Test), there was an increase in MCT1 in sigmoid colon adenocarcinoma (P = 0.010, N = 21, paired T-test). Using RT-PCR and western blotting, three human intestinal cell lines were tested for their suitability as a MCT1 cancer cell model. Experiments with Caco-2 cells confirmed that they modelled normal cells, with MCT1 only expressed after exposure to butyrate. In contrast, MCT1 was expressed in the absence of butyrate in both HCT-8 and HT-29 cell lines, with consistently high levels of MCT1 protein being present in HT-29 cells. Furthermore, butyrate treatment of HT-29 cells significantly decreased both MCT1 protein abundance (P < 0.001, N = 4, unpaired T-test) and glycosylation of its' chaperone protein, CD147 (P < 0.001, N = 4, unpaired T-test). These data suggest that (i) MCT1 transporter abundance increases in sigmoid colon adenocarcinoma, and (ii) HT-29 cells are an appropriate cell model with which to investigate MCT1 function in this disease.

SLC1A1, SLC16A9, and CNTN3 Are Potential Biomarkers for the Occurrence of Colorectal Cancer.

BACKGROUND: This study is aimed at identifying unknown clinically relevant genes involved in colorectal cancer using bioinformatics analysis. METHODS: Original microarray datasets GSE107499 (ulcerative colitis), GSE8671 (colorectal adenoma), and GSE32323 (colorectal cancer) were downloaded from the Gene Expression Omnibus. Common differentially expressed genes were filtered from the three datasets above. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, followed by construction of a protein-protein interaction network to identify hub genes. Kaplan-Meier survival analysis and TIMER database analysis were used to screen the genes related to the prognosis and tumour-infiltrating immune cells of colorectal cancer. Receiver operating characteristic curves were used to assess whether the genes could be used as markers for the diagnosis of ulcerative colitis, colorectal adenoma, and colorectal cancer. RESULTS: A total of 237 differentially expressed genes common to the three datasets were identified, of which 60 were upregulated, 125 were downregulated, and 52 genes that were inconsistently up- and downregulated. Common differentially expressed genes were mainly enriched in the cellular component of extracellular exosome and integral component of membrane categories. Eight hub genes, i.e., CXCL3, CXCL8, CEACAM7, CNTN3, SLC1A1, SLC16A9, SLC4A4, and TIMP1, were related to the prognosis and tumour-infiltrating immune cells of colorectal cancer, and these genes have diagnostic value for ulcerative colitis, colorectal adenoma, and colorectal cancer. CONCLUSION: Three novel genes, CNTN3, SLC1A1, and SLC16A9 were shown to have diagnostic value with respect to the occurrence of colorectal cancer and should be verified in future studies.

lncRNA SLC16A1-AS1 as a novel prognostic biomarker in non-small cell lung cancer.

Long non-coding RNAs (lncRNAs) have proved to act as crucial biomarkers in tumors. Novel biomarkers in non-small cell lung cancer (NSCLC) need to be investigated badly. To identify the differentially expressed lncRNAs between NSCLC tissue and adjacent tissue, microarray analysis was performed. lncRNA SLC16A1-AS1 was significantly less expressed in NSCLC tissue than that in adjacent tissue. Gain-of-function experiments was performed to determine the biological functions of SLC16A1-AS. In situhybridization and survival analysis were applied in lung cancer tissue samples to determine the prognostic role of SLC16A1-AS1. It was showed that SLC16A1-AS1 was remarkably downregulated in NSCLC tissues and cell lines. Functionally, SLC16A1-AS1 overexpression could inhibit the viability and proliferation of lung cancer cell, block the cell cycle and promote cell apoptosis in vitro which may result from reduced phosphorylation of rat sarcoma (RAS)/ proto-oncogene serine/threonine-protein kinase (RAF)/ mitogen-activated protein kinase kinase (MEK)/ extracellular regulated protein kinases (ERK) pathway caused by elevated expression of SLC16A1-AS1. Clinical sample analysis showed that SLC16A1-AS1 had a favorable impact on the overall survival and progression-free survival of patients with NSCLC. Our results suggested that SLC16A1-AS1 may act as a potential biomarker for patients with NSCLC.

Clinical effects of CD33 and MPC-1 on the prognosis of multiple myeloma treated with bortezomib.

In the present study, the effects of immunophenotyping on the prognoses of patients with MM treated with bortezomib as induction therapy were investigated. A total of 118 patients with MM were examined, and the prognostic significance of the immunophenotyping and other factors were investigated. Immature and plasmablastic cell types and high-risk cytogenesis were more frequently observed in patients with CD33+ and MPC-1-. CD33+ and MPC-1- have potential as prognostic factors and correlated with lower progression-free survival and overall survival in a Kaplan-Meier analysis. Moreover, the present results demonstrated that at the relapse of disease, the percentage of CD33 increased (median 48.7%) and MPC-1 decreased (median 14.1%), respectively, therefore, both of these antigens may be associated with the refractory disease status. The present study showed that the expression of CD33 and MPC-1 in neoplastic plasma cells from patients with MM was associated with patient prognosis independent of other prognostic factors.

Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level.

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of Gq/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.

Helicobacter pylori Infection Is Associated with Decreased Expression of SLC5A8, a Cancer Suppressor Gene, in Young Children.

Background:Helicobacter pylori infects half of the world's population and causes gastric cancer in a subset of infected adults. Previous blood microarray findings showed that apparently healthy children, persistently infected with H. pylori have differential gene expression compared to age-matched, non-infected children. SLC5A8, a cancer suppressor gene with decreased expression among infected children, was chosen for further study based on bioinformatics analysis. Methods: A pilot study was conducted using specific qRT-PCR amplification of SLC5A8 in blood samples from H. pylori infected and non-infected children, followed by a larger, blinded, case-control study. We then analyzed gastric tissue from H. pylori infected and non-infected children undergoing endoscopy for clinical purposes. Results: Demographics, clinical findings, and family history were similar between groups. SLC5A8 expression was decreased in infected vs. non-infected children in blood, 0.12 (IQR: 0-0.89) vs. 1.86 (IQR: 0-8.94, P = 0.002), and in gastric tissue, 0.08 (IQR: 0.04-0.15) vs. 1.88 (IQR: 0.55-2.56; P = 0.001). Children who were both stool positive and seropositive for H. pylori had the lowest SLC5A8 expression levels. Conclusions:H. pylori infection is associated with suppression of SCL5A8, a cancer suppressor gene, in both blood and tissue samples from young children. Key Points: Young children, persistently infected with Helicobacter pylori show decreased expression of SLC5A8 mRNA in both blood and tissue samples as compared to non-infected children.

Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as l-lactate. We previously reported that α-cyano-4-hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control-treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity.

Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/ß-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling.

The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/ß-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Furthermore, activation of the canonical Wnt/ß-catenin pathway in RBE4 cells via nuclear ß-catenin signaling with LiCl does not alter brain endothelialMct1mRNA but increases the amount of MCT1 transporter protein. Plasma membrane biotinylation studies and confocal microscopic examination of mCherry-tagged MCT1 indicate that increased transporter results from reduced MCT1 trafficking from the plasma membrane via the endosomal/lysosomal pathway and is facilitated by decreased MCT1 ubiquitination following LiCl treatment. Inhibition of the Notch pathway by the γ-secretase inhibitorN-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester negated the up-regulation of MCT1 by LiCl, demonstrating a cross-talk between the canonical Wnt/ß-catenin and Notch pathways. Our results are important because they show, for the first time, the regulation of MCT1 in cerebrovascular endothelial cells by the multifunctional canonical Wnt/ß-catenin and Notch signaling pathways.

Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer.

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment.

Multicompartment metabolism in papillary thyroid cancer.

OBJECTIVES/HYPOTHESIS: In many cancers, varying regions within the tumor are often phenotypically heterogeneous, including their metabolic phenotype. Further, tumor regions can be metabolically compartmentalized, with metabolites transferred between compartments. When present, this metabolic coupling can promote aggressive behavior. Tumor metabolism in papillary thyroid cancer (PTC) is poorly characterized. STUDY DESIGN: Immunohistochemical staining of tissue samples. METHODS: Papillary thyroid cancer specimens from 46 patients with (n = 19) and without advanced disease (n = 27) were compared to noncancerous thyroid tissue (NCT) and benign thyroid specimens (n = 6 follicular adenoma [FA] and n = 5 nodular goiter [NG]). Advanced disease was defined as the presence of lateral neck lymphadenopathy. Immunohistochemistry was performed for translocase of outer mitochondrial membrane 20 (TOMM20), a marker of oxidative phosphorylation, and monocarboxylate transporter 4 (MCT4), a marker of glycolysis. RESULTS: Papillary thyroid cancer and FA thyrocytes had high staining for TOMM20 compared to NCT and nodular goiter (NG) (P < 0.01). High MCT4 staining in fibroblasts was more common in PTC with advanced disease than in any other tissue type studied (P < 0.01). High MCT4 staining was found in all 19 cases of PTC with advanced disease, in 11 of 19 samples with low-stage disease, in one of five samples of FA, in one of 34 NCT, and in 0 of six NG samples. Low fibroblast MCT4 staining in PTC correlated with the absence of clinical adenopathy (P = 0.028); the absence of extrathyroidal extension (P = 0.004); low American Thyroid Association risk (P = 0.001); low AGES (age, grade, extent, size) score (P = 0.004); and low age, metastasis, extent of disease, size risk (P = 0.002). CONCLUSION: This study suggests that multiple metabolic compartments exist in PTC, and low fibroblast MCT4 may be a biomarker of indolent disease. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:2410-2418, 2016.

Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors.

Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.

MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats.

Wolff-Chaikoff effect is characterized by the blockade of thyroid hormone synthesis and secretion due to iodine overload. However, the regulation of monocarboxylate transporter 8 during Wolff-Chaikoff effect and its possible role in the rapid reduction of T4 secretion by the thyroid gland remains unclear. Patients with monocarboxylate transporter 8 gene loss-of-function mutations and monocarboxylate transporter 8 knockout mice were shown to have decreased serum T4 levels, indicating that monocarboxylate transporter 8 could be involved in the secretion of thyroid hormones from the thyroid gland. Herein, we aimed to evaluate the regulation of monocarboxylate transporter 8 during the Wolff-Chaikoff effect and the escape from iodine overload, besides the importance of iodine organification for this regulation. Monocarboxylate transporter 8 mRNA and protein levels significantly decreased after 1 day of NaI administration to rats, together with decreased serum T4; while no alteration was observed in LAT2 expression. Moreover, both monocarboxylate transporter 8 expression and serum T4 was restored after 6 days of NaI. The inhibition of thyroperoxidase activity by methimazole prevented the inhibitory effect of NaI on thyroid monocarboxylate transporter 8 expression, suggesting that an active thyroperoxidase is necessary for MCT8 downregulation by iodine overload, similarly to other thyroid markers, such as sodium iodide symporter. Therefore, we conclude that thyroid monocarboxylate transporter 8 expression is downregulated during iodine overload and that the normalization of its expression parallels the escape phenomenon. These data suggest a possible role for monocarboxylate transporter 8 in the changes of thyroid hormones secretion during the Wolff-Chaikoff effect and escape.

Overexpression of reactive oxygen species scavenger enzymes is associated with a good prognosis in triple-negative breast cancer.

OBJECTIVE: The aim of this study was to investigate the expression of redox proteins in triple-negative breast cancer (TNBC), a breast cancer type which harbors an aggressive phenotype, and to demonstrate the relationships between the expression of reactive oxygen species (ROS) markers and clinical outcome. METHODS: From 2000 to 2005, we analyzed tissue samples from 135 cases of TNBC obtained from curative surgeries at the Severance Hospital, Seoul, South Korea. Immunochemical staining for redox proteins was performed. RESULTS: The median patient age was 48 (range 27-76) years. TNM staging was as follows: T1 (n = 52, 38.5%), T2 (n = 81, 60%), T3 (n = 2, 1.5%), N0 (n = 88, 65.2%), N1 (n = 35, 25.9%), N2 (n = 8, 5.9%) and N3 (n = 4, 3.0%). Median follow-up was 59 (range 12-99) months. The high-expression catalase group tended to have a lower N stage (p = 0.016), lower tumor recurrence (p = 0.02) as well as longer overall survival rates (p = 0.05). After adjusting for patient age as well as tumor and nodal stage, we found that primary breast cancers with high catalase expression levels did not have an improved clinical outcome. A high MTC4 expression in the stroma was strongly associated with increased manganese superoxide dismutase expression (p = 0.015) and a significantly longer overall survival (p = 0.032). CONCLUSION: Considering the lack of targeted molecules as well as molecular heterogeneity of TNBC, ROS markers may provide clues to clinical outcome in TNBC.

Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.

Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression.

Lactate transporters in the context of prostate cancer metabolism: what do we know?

Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The crucial role of lactate efflux and exchange within the tumour microenvironment drew attention to monocarboxylate transporters (MCTs). MCTs have been recognized as promising targets in cancer therapy, and their expression was described in a large variety of tumours; however, studies showing how these isoforms contribute to the acquisition of the malignant phenotype are scarce and still unclear regarding prostate cancer. In this review, we focus on the role for MCTs in cell metabolism, supporting the development and progression of prostate cancer, and discuss the exploitation of the metabolic nature of prostate cancer for therapeutic and diagnostic purposes.

Characterization of monocarboxylate transporter activity in hepatocellular carcinoma.

AIM: To assess the immunoexpression of hypoxia-related markers in samples from cirrhosis and primary and metastatic hepatocellular carcinoma (HCC). METHODS: From a total of 5836 autopsies performed at the Pathology Department - University of Sao Paulo School of Medicine Hospital - from 2003 to 2009, 188 presented primary liver tumors. Immunohistochemical reactivity for monocarboxylate transporters (MCTs)-1, 2 and 4, CD147 and glucose transporter-1 (GLUT1) was assessed in necropsies from 80 cases of HCC. Data were stored and analyzed using the IBM SPSS statistical software (version 19, IBM Company, Armonk, NY). All comparisons were examined for statistical significance using Pearson's χ (2) test and Fisher's exact test (when n < 5). The threshold for significant P values was established as P < 0.05. RESULTS: Plasma membrane expression of MCT4 and overall expression of GLUT1 showed progressively higher expression from non-neoplastic to primary HCC and to metastases. In contrast, overall expression of MCT2 was progressively decreased from non-neoplastic to primary HCC and to metastases. MCT1 (overall and plasma membrane expression), MCT2 and CD147 plasma membrane expression were associated with absence of cirrhosis, while plasma membrane expression of CD147 was also associated with absence of HBV infection. MCT2 overall expression was associated with lower liver weight, absence of metastasis and absence of abdominal dissemination. Additionally, MCT4 plasma membrane positivity was strongly associated with Ki-67 expression. CONCLUSION: MCT4 and GLUT1 appear to play a role in HCC progression, while MCT2 is lost during progression and associated with better prognosis.

A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer.

BACKGROUND: In a malignant tumour, cancer cells are embedded in stromal cells, namely cancer-associated fibroblasts (CAFs). These CAFs are now accepted as important players in cancer dynamics, being involved in tumour growth and progression. Although there are various reports on the interaction between tumour and stromal cells, the clinico-pathological significance of this cross-talk is still largely unknown. In this study, we aimed to characterise the expression of key metabolic proteins involved in glucose transport, pyruvate/lactate shuttle system, glycolytic metabolism and fatty acid oxidation in CAFs and tumour cells in different stages of malignant transformation. We further aimed to contextualise the clinico-pathological significance of these protein expression profiles with reference to known prognostic indicators, including biochemical recurrence in pT stage. METHODS: Prostate tissues were obtained from 480 patients with a median age of 64 years following radical prostatectomy with no previous hormonal therapy. Tissues were analysed for the expression of several key metabolism-related proteins in glands and surrounding fibroblasts by immunohistochemistry. Reliable markers of prognosis such as pT stage and biochemical recurrence were assessed for each case. RESULTS: We observed that prostate cancer cells did not rely mainly on glycolytic metabolism, while there was a high expression of MCT4 and CAIX - in CAFs. This corroborates the hypothesis of the "Reverse Warburg effect" in prostate cancer, in which fibroblasts are under oxidative stress and express CAIX, an established hypoxia marker. We found that alterations in the expression of metabolism-related proteins were already evident in the early stages of malignant transformation, suggesting the continuing alteration of CAFs from an early stage. Additionally, and for the first time, we show that cases showing high MCT4 expression in CAFs with concomitant strong MCT1 expression in prostate cancer (PCa) cells are associated with poor clinical outcome, namely pT3 stage of the tumour. CONCLUSIONS: In summary, this work demonstrates for the first time the clinico-pathological significance of the lactate shuttle in prostate cancer. It also suggests that other alterations in CAFs may be useful prognostic factors, and further supports the use of MCT1/MCT4 as targets for PCa therapy.