Glucose transporter isoform 1 (GLUT1) expression in melanoma enhances formation and growth of hepatic metastases
GLUT1 is the key rate-limiting factor in glucose transport into cancer cells. We aimed to analyze whether GLUT1 expression in cancer cells and a high capacity for glucose uptake, respectively, affect hepatic metastasis. 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 microarray 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 by stable transfection with shRNA. GLUT1 suppression inhibited anaerobic glycolysis, proliferation and migration of B16 cells. Moreover, GLUT1 suppression induced apoptosis in low glucose but not in high glucose conditions. 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 smaller and less invasive metastasis than mock-transfected controls. Furthermore, TUNEL staining reveled more apoptotic cells in metastases derived from GLUT1 suppressed B16 cells compared to metastases from control cells.
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. GLUT1, which is almost selectively expressed in malignant cells but not in healthy liver or other non-malignant tissues, appears as attractive therapeutic target for hepatic metastasis.