Monocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acid-resistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness.

Tumour cells are known to be highly glycolytic, thus producing high amounts of lactic acid. Monocarboxylate transporters (MCTs), by promoting the efflux of the accumulating acids, constitute one of the most important mechanisms in the maintenance of tumour intracellular pH.Since data concerning MCT expression in colorectal carcinomas (CRC) are scarce and controversial, the present study aimed to assess the expressions of MCT1, 2, and 4 in a well characterized series of CRC and assess their role in CRC carcinogenesis. CRC samples (126 cases) were analyzed for MCT1, MCT2, and MCT4 immunoexpression and findings correlated with clinico-pathological parameters. Expression of all MCT isoforms in tumour cells was significantly increased when compared to adjacent normal epithelium. Remarkably, there was a significant gain of membrane expression for MCT1 and MCT4 and loss of plasma membrane expression for MCT2 in tumour cells. Plasma membrane expression of MCT1 was directly related to the presence of vascular invasion. This is the larger study on MCT expression in CRC and evaluates for the first time its clinico-pathological significance. The increased expression of these transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.

Buruli ulcer (BU) is a devastating, necrotizing, tropical skin disease caused by infections with Mycobacterium ulcerans. In contrast to other mycobacterioses, BU has been associated with minimal or absent inflammation. However, here we show that in the mouse M. ulcerans induces persistent inflammatory responses with virulence-dependent patterns. Mycolactone-positive, cytotoxic strains are virulent for mice and multiply progressively, inducing both early and persistent acute inflammatory responses. The cytotoxicity of these strains leads to progressive destruction of the inflammatory infiltrates by postapoptotic secondary necrosis, generating necrotic acellular areas with extracellular bacilli released by the lysis of infected phagocytes. The necrotic areas, always surrounded by acute inflammatory infiltrates, expand through the progressive invasion of healthy tissues around the initial necrotic lesions by bacteria and by newly recruited acute inflammatory cells. Our observations show that the lack of inflammatory infiltrates in the extensive areas of necrosis seen in advanced infections results from the destruction of continuously produced inflammatory infiltrates and not from M. ulcerans-induced local or systemic immunosuppression. Whether this is the mechanism behind the predominance of minimal or absent inflammatory responses in BU biopsies remains to be elucidated.Pathogenic mycobacteria are intracellular parasites that are responsible for several clinically important infections in humans and animals. The most frequent mycobacterial infections in humans are caused by Mycobacterium tuberculosis and M. leprae. However, a unique group of mycobacterioses has been emerging and comprises infections caused by M. marinum, M. hemophilum, and M. ulcerans (12). These are slow-growing mycobacteria with some genetic relatedness (71) and common peculiar characteristics. These mycobacteria have optimal growth temperatures of 28 to 33°C and infect primarily the cooler parts of the body, mainly the skin. They have cytotoxic activity (17,56,57) and, as a consequence, produce necrotizing lesions (3,7,12,72).Buruli ulcer (BU), caused by M. ulcerans, has become the third most prevalent mycobacteriosis throughout the world, after tuberculosis and leprosy, with higher incidence in the tropical regions of western and central Africa (11,74). BU is a devastating skin disease characterized by different clinical forms, including nonulcerative subcutaneous nodules, papules, edema, and plaques, that can eventually progress to ulcerative forms and often to extensive necrotic lesions (11, 74). Osteomyelitis has been described as a complication of M. ulcerans infection, particularly in some African regions (11,39).Genetic analyses showed that M. marinum and M. ulcerans are very closely related to M. tuberculosis (71), a mycobacterium that also exhibits some cytotoxicity (14,19,37,43), which contributes to the necrotic lesions seen in tuberculosis (43). Recently, genes in the extRD1 region have been implicated in the cytotoxic activity of M...

Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein.

The LAMS study failed to reproduce the performance figures obtained with VIA and VILI (as stand-alone tests) in some other settings, where the prevalence of cervical disease was higher. However, a combined use of VIA or VILI with the Pap test or HCII allowed specific detection of cervical abnormalities.

Background:Malignant gliomas are the most prevalent type of primary brain tumours but the therapeutic armamentarium for these tumours is limited. Platelet-derived growth factor (PDGF) signalling has been shown to be a key regulator of glioma development. Clinical trials evaluating the efficacy of anti-PDGFRA therapies on gliomas are ongoing. In this study, we intended to analyse the expression of PDGFA and its receptor PDGFRA, as well as the underlying genetic (mutations and amplification) mechanisms driving their expression in a large series of human gliomas.Methods:PDGFA and PDGFRA expression was evaluated by immunohistochemistry in a series of 160 gliomas of distinct World Health Organization (WHO) malignancy grade. PDGFRA-activating gene mutations (exons 12, 18 and 23) were assessed in a subset of 86 cases by PCR—single-strand conformational polymorphism (PCR-SSCP), followed by direct sequencing. PDGFRA gene amplification analysis was performed in 57 cases by quantitative real-time PCR (QPCR) and further validated in a subset of cases by chromogenic in situ hybridisation (CISH) and microarray-based comparative genomic hybridisation (aCGH).Results:PDGFA and PDGFRA expression was found in 81.2% (130 out of 160) and 29.6% (48 out of 160) of gliomas, respectively. Its expression was significantly correlated with histological type of the tumours; however, no significant association between the expression of the ligand and its receptor was observed. The absence of PDGFA expression was significantly associated with the age of patients and with poor prognosis. Although PDGFRA gene-activating mutations were not found, PDGFRA gene amplification was observed in 21.1% (12 out of 57) of gliomas. No association was found between the presence of PDGFRA gene amplification and expression, excepting for grade II diffuse astrocytomas.Conclusion:The concurrent expression of PDGFA and PDGFRA in different subtypes of gliomas, reinforce the recognised significance of this signalling pathway in gliomas. PDGFRA gene amplification rather than gene mutation may be the underlying genetic mechanism driving PDGFRA overexpression in a portion of gliomas. Taken together, our results could provide in the future a molecular basis for PDGFRA-targeted therapies in gliomas.

Characteristic cytokine patterns have been described in different cancer patients and they are related to their diagnosis, prognosis, prediction of treatment responses and survival. A panel of cytokines was evaluated in the plasma of non-small cell lung cancer (NSCLC) patients and healthy controls to investigate their profile and relationship with clinical characteristics and overall survival. The case-controlled cross-sectional study design recruited 77 patients with confirmed diagnosis of NSCLC (cases) and 91 healthy subjects (controls) aimed to examine peripheral pro-inflammatory and anti-inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF and IFN-γ) by Cytometry Beads Arrays (CBA Flex) in. The cytokine IL-6 showed a statistically significant difference among groups with increased expression in the case group (p < 0.001). The correlation between the cytokines expression with patient’s clinical characteristics variables revealed the cytokine IL-6 was found to be associated with gender, showing higher levels in male (p = 0.036), whereas IL-17A levels were associated with TNM stage, being higher in III–IV stages (p = 0.044). We observed worse overall survival for individuals with high levels of IL-6 when compared to those with low levels of this cytokine in 6, 12 and 24 months. Further studies of IL-6 levels in independent cohort could clarify the real role of IL-6 as an independent marker of prognostic of NSCLC.

In the last decade, new molecular techniques were introduced into pathology laboratories. Cytology also benefited from the innovations emerging from this new era. Molecular cytopathology (MCP) can be defined as molecular studies applied on all types of cytological specimens, namely gynaecology cytology, exfoliative non- gynaecology cytology and fine needle aspirates. The development of many new ancillary techniques has paralleled the emergence of clinical cytology as a major diagnostic specialty. Clinical applications of these techniques have been growing in the last decade. The widespread acceptance of liquid-based systems in gynaecological cytology emphasises the relation between cells and molecules. The increased use of morphology and molecular biology in human papillomavirus-induced lesions for example, showed the potential to optimise, in one single brushed sample, diagnosis and research. Cytology samples from serous effusions, the pulmonary tree, urine, and aspirations, among others, are now likely to be studied by different molecular techniques for diagnosis, prognosis, or even assessment of therapeutic targets. In this review, the main published results concerning the application of molecular techniques in different fields of cytopathology are highlighted, and their applications discussed.