Tumor-Stroma Interactions Reprogram Metabolism in Human Anaplastic Thyroid Cancer Cells

FOZZATTI, LAURA; ALAMINO, VANINA; GIUSIANO, LUCILA; STEMPIN, CINTHIA; DONADIO, ANA CAROLINA; PELLIZAS, CLAUDIA GABRIELA

Victoria, Canadá

Congreso; 87th Annual Meeting of the American Thyroid Association; 2017

American Thyroid Association

Thyroid cancer is the most common endocrine malignancy, with rising incidence. Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. Characterized by its undifferentiated cells, it spreads quickly to distant organs and does not respond well to therapy. It is well known that genetic abnormalities in oncogenes and/or tumor suppressor genes promote tumorigenesis. Emerging evidences, however, have shown that tumor stroma has a crucial influence on cancer development and progression as well. Dysregulated metabolism within the tumor stroma is critical to the process of tumorigenesis, however studies analyzing the role of multicompartment metabolism in ATC are lacking. To investigate whether the interaction of ATC cells-fibroblasts (main component of tumor stroma) reprograms their cellular metabolism, we used an in vitro ATC cell (8505c and KTC-2 cells)-fibroblast (MRC-5 cells) transwell co-culture system and measured a variety of metabolic parameters by flow cytometry, RT-qPCR, ELISA and Western blot analysis. We showed that during co-cultures, fibroblasts increased reactive oxygen species (ROS) production, the transcript and secretion of the inflammatory cytokine IL6, the mRNA expression of two glycolytic enzymes: lactate dehydrogenase A (LDHA) and enolase 1 (ENO1) and the mRNA and protein levels of glucose transporter 1 (GLUT1). Conversely, co-cultured ATC cells showed reduction in GLUT1, ENO1 and LDHA expression. High ROS levels induce oxidative stress that may trigger the activation of hypoxia-inducible factor 1α (HIF-1α), leading to inflammation and glycolysis. Therefore, we analyzed its mRNA expression in the co-cultures. Interestingly, we registered an increase of mRNA levels of HIF-1α in fibroblasts co-cultured with thyroid cells. Accordingly, we observed a significant rise of this transcription factor in the tumor thyroid cells co-cultured with fibroblasts. Our findings provide in vitro evidences of a reprogrammed metabolism by stromal-thyroid tumor cells interactions, suggesting their participation in ATC development and progression. An improved understanding of the molecular basis of tumor-stroma communications may enable identification and targeting of tumor-supportive mechanisms.