GLUT-1 expression is largely unrelated to both hypoxia and the Warburg phenotype in squamous cell carcinomas of the vulva

Abstract

BackgroundStrongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy.MethodsWe have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, αSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS).ResultsExpression of GLUT-1 in invasive carcinomas was predominantly located in the outer layers of the tumor cell aggregates close to the vascularized tumor stroma, and only to a lesser extent colocalized with CA IX, which was repeatedly found at larger diffusion distances away from microvessels. CA IX expression was lower in invasive carcinomas compared to dysplasias and non-neoplastic tissue and higher in recurrent vs. primary tumors. Ki67-positive proliferating cells were partially colocalized with GLUT-1. However, HK-2 and PK-2 - proteins centrally involved in the Warburg phenotype - did not show such a correlation.ConclusionsConsistent with prior studies, the pattern of GLUT-1 clearly indicated that a large part of its expression is presumably unrelated to hypoxia. However, there was also no association with HK-2 and PK-M2, suggesting that the functional background of this expression is also independent of aerobic glycolysis. CA IX may be worth consideration as a marker of biological hypoxia, as should its pathophysiological consequences in SCC-V.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-760) contains supplementary material, which is available to authorized users.

Metabolic reprogramming: the emerging concept and associated therapeutic strategies

“…In striking contrast to normal cells, cancer cells preferentially uptake and convert glucose into lactate even in the presence of sufficient oxygen [ 29 ]. This seemingly “inefficient” metabolic characteristic relies largely on aberrant upregulation of GLUT1, a glucose transporters abundantly expressed in cancer cells [ 30 , 31 ], although one contradictory study reported that GLUT1 is not necessarily involved in the Warburg effect depending on the degree of tumor invasiveness [ 32 ]. Inefficient ATP synthesis becomes an obstacle for cancer cells only when their energy resources are scarce.…”

ERO1α is a novel endogenous marker of hypoxia in human cancer cell lines

“…Additionally, pimonidazole, administered exogenously and successively stained, is also considered a useful marker for the identification of low-oxygen environments [9]. Some studies, however, indicate that the expression of CA9 and GLUT-1 varies in different cancer cell lines [10, 11]. Additionally, immunohistochemistry for these markers in relation to pimonidazole staining has yielded conflicting results [12, 13].…”

Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer

“…Our group previously showed that high expression of VEGF, GLUT-1, p53, markers of angiogenesis [ 16 ], tumour metabolism [ 17 ] and tumour proliferation [ 18 , 19 ], and low expression of ER, are predictors of response to epirubicin. Among these, the role of GLUT-1 is still controversial, in fact it is unknown whether GLUT-1 is associated to hypoxia in breast cancer cells or it is a hypoxia-independent feature of transformed cells which display altered metabolism, as in other cancers [ 20 ]. Therefore, the discrepancy between the expression of hypoxia-markers and the rate of response to anthracyclines/DFS/OS that we found in this study could be explained by the fact that GLUT-1 is perhaps expressed in breast cells irrespective of the degree of hypoxia, or independently from it.…”

“…Therefore, the discrepancy between the expression of hypoxia-markers and the rate of response to anthracyclines/DFS/OS that we found in this study could be explained by the fact that GLUT-1 is perhaps expressed in breast cells irrespective of the degree of hypoxia, or independently from it. A recent report demonstrated a requirement for GLUT-1 in mammary tumourigenesis [ 20 , 21 ] as a consequence of the fact that early malignant transformation requires glucose. The metabolic alterations typically found in tumour cells, more than the response to hypoxia, could explain our results.…”