Anaplastic thyroid cancer metabolism: implication of in vitro tumor and stromal cells interactions

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

Rio de Janeiro

Congreso; XVI Congreso Latinoamericano de Tiroides; 2017

Sociedad Latinoamericana de Tiroides(LATS)

Introduction: 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 anddoes not respond well to therapy. It is well known that genetic abnormalities in oncogenes and/or tumor suppressor genespromote tumorigenesis. Emerging evidences, however, have shown that tumor stroma has a crucial influence on cancer developmentand 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. Objective: To investigate whether theinteraction of ATC cells-fibroblasts (main component of tumor stroma) reprograms their cellular metabolism. Methods: Weused an in vitro ATC cell (8505c cells)-fibroblast (MRC-5 cells) transwell co-culture system and measured a variety of metabolicparameters by flow cytometry, RT-qPCR, ELISA and Western blot analysis, as depicted in the next section. Statistical analysiswas performed using Student?s t test. Results: 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 and the mRNA and protein levels of glucose transporter 1 (GLUT1).Conversely, co-cultured ATC cells showed only reduction in GLUT1 and LDHA expression. High ROS levels induce oxidativestress 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 and registered an increase in fibroblasts co-cultured with thyroid cells.In contrast, we did not observe significant changes of this transcription factor in the thyroid cells co-cultured with fibroblasts.Conclusions and discussion: Our findings provide in vitro evidences of a reprogrammed metabolism by stromal-thyroid tumorcells interactions, suggesting their participation in ATC development and progression. The understanding of these eventsmay have profound clinical repercussions by the implementation of new biomarkers for tumor detection and novel therapeuticstrategies to allow the manipulation of the deregulated tumor metabolism and hence reduce or eradicate the tumor.