Glucose transporter isoform 1 (GLUT1) expression determines tumorigenicity of melanoma cells and their potential to form hepatic metastasis

The liver is the site of metastasis from virtually any primary malignant tumor and high portal glucose levels may be one of the factors supporting tumor growth in the liver. The facilitative glucose transporter isoform 1 (GLUT1) is the key rate-limiting factor in glucose transport into cancer cells, and we have previously shown that GLUT1 is a tumor-promotor in hepatocellular carcinoma, while its expression is at the detection limit in normal hepatocytes.

The aim of this study was to analyze whether GLUT1 expression and a high capacity for glucose uptake, respectively, are general pro-cancerogenic factors in the liver. For that, we used malignant melanoma as a model-tumor, which is known to preferentially metastasize to the liver.

Methods and Results: Similar as observed in HCC, GLUT1 expression was enhanced in melanoma cell lines compared to primary melanocytes, as well as in melanoma compared to naevi. Furthermore, immunohistochemical analysis of a tissue micro array consisting of 140 human melanoma tissues showed that GLUT1 expression was significantly enhanced in metastasis compared to primary tumors. GLUT1 expression in primary tumors correlated with tumor staging, and most importantly, with progression- and overall-survival, which are known to be determined by metastasis in this tumor. To determine the role of GLUT1 in melanoma metastasis, GLUT1 expression was suppressed in the murine melanoma cell line B16 (i) by stable transfection with shRNA and (ii) by using the selective GLUT1-Inhibitor WZB117. GLUT1 suppression caused decreased anaerobic glycolysis and lactate secretion, and inhibited proliferation and migration of B16 cells. Moreover, GLUT1 suppression lowered apoptosis resistance of melanoma cells. Next, B16 cell clones with and without GLUT1 suppression were subjected to an established model of hepatic metastasis, in which tumor cells were injected into the spleen of syngeneic mice, from where they metastasize into the liver via the portal circulation. GLUT1 suppressed cells formed significantly less metastases than mock-transfected controls. Furthermore, hepatic metastases derived from GLUT1 suppressed B16 cells revealed less immune-cell infiltration and more apoptosis as assessed by CD3-immunohistochemistry and TUNEL staining.

Conclusions: Our data promote the hypothesis that high glucose levels in the portal circulation and the liver, and the capacity to utilize those, respectively, promote hepatic metastasis. Our data indicate enhanced apoptosis resistance of tumor cells and known immunomodulatory effects of lactate as potential underlying mechanisms of this phenomenon. GLUT1, which is almost selectively expressed in malignant cells but not in healthy liver or other non-malignant tissues, appears as an attractive therapeutic target for hepatic metastasis.