Abstract
BackgroundTumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation. Among other microenvironment features, hypoxia and acidity play important roles in this modulation. As the metabolic reprogramming of cancer cells induces extracellular acidity, which in turn induces angiogenesis, and hypoxia induces both the metabolic reprogramming and angiogenesis, the present study aims to evaluate the immunohistochemical expression of a variety of metabolic and vascular markers as common targets of the hypoxic microenvironment in a series of cervical squamous cells carcinoma, as well as using an in vitro 3D culture model.MethodsImmunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX was assessed in a series of 28 chronic cervicitis, 34 LSIL, 29 HSIL, 38 cases of squamous cells carcinoma (SCC), as well as in in vitro 3D culture of keratinocytes expressing HPV genes. Furthermore, VEGF family members’ expression was assessed in the SCC cases. The expression profiles were associated with patients’ clinicopathological parameters.ResultsWe found an increase of MCT4 expression along progression to malignancy in cervical samples. Also, MCT4 was associated with CD147 and CAIX expression. VEGF-A expression was more frequently found in cases without MCT1 expression. Both MCT4 and CD147 were more frequently expressed in younger patients at diagnosis while no associations were found between VEGF family and clinicopathological parameters. Finally, we show evidence for the upregulation of MCT4, as well as CD147 and CAIX, after HPV transfection.ConclusionsThe results herein presented point at MCT4 as a promising therapeutic target in squamous cells carcinoma of the uterine cervix. Importantly, we show a possible association between lactate transport and angiogenesis, which should be further explored.
Highlights
Tumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation
CD147 followed a pattern of expression similar to MCT1, without statistical significance, while glucose transporter 1 (GLUT1) was significantly increased in malignant lesions when compared with non-malignant lesions (p = 0.025)
In the other hand, it was described that HPV16 E7 oncoprotein expression stimulates glutaminolysis, decreasing glucose consumption and lactate production [43]. We found that both MCT4 and CD147 were stimulated in E7 expressing cells, while carbonic anhydrase IX (CAIX) was stimulated by E6 and E7, alone or in combination, which is in accordance with the stimulation of the Warburg effect, as a result of HPV-dependent Hypoxia inducible factor 1 alpha (HIF-1α) stabilization [41,42]
Summary
Tumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation. It is widely known that cancer cells rely on the conversion of glucose into lactate, even in the presence of oxygen, for energy and anabolic intermediates production, a phenomenon known as the Warburg effect [2] In this context, MCTs, especially MCT1 and MCT4, are crucial for the cellular export of the high amounts of lactate resultant from the high glycolytic activity. MCTs, especially MCT1 and MCT4, are crucial for the cellular export of the high amounts of lactate resultant from the high glycolytic activity They are important contributors for intracellular pH maintenance, by partially exporting the protons resultant from the metabolic activity, avoiding intracellular acidification and, cell death. Both MCT1 and MCT4 require CD147 as an ancillary protein for correct plasma membrane location and activity [3]
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