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Type 2 diabetes in neuroendocrine tumors: are biguanides and statins part of the solution?

Background: Biguanides and statins have been reported to exert beneficial effects on various cancer types. However, their precise effects and underlying molecular mechanisms are still poorly understood.

Materials and Methods: We analyzed the relation between metabolic-syndrome, i.e., presence of type-2 diabetes (T2DM), hyperlipidemia and their treatment, with histological, epidemiological, and prognosis variables in two patient cohorts with neuroendocrine-tumors [NETs: lung-carcinoids (LCs; n=81) and gastro-entero-pancreatic (GEP-NET; n=100)]. Additionally, we investigated the antitumoral effects of different biguanides and statins by evaluating proliferation/migration/secretion/gene-expression and involved molecular pathways using BON1/QGP1-cell cultures.

Results: In T2DM patients, pleura invasion was higher (LCs group; p<0.05) and tumor diameter tended to be increased (GEP-NET group). mRNA levels of somatostatin and ghrelin systems were different in tumor tissue of T2DM patients with and without metformin. Biguanides (metformin/buformin/phenformin) decreased proliferation rate in BON1/QGP1-cells (24-72h). However, the effects of statins on proliferation-rate were dependent of the statin-type, cell-type, and time. Specifically, only simvastatin/atorvastatin decreased proliferation in BON1-cells (48/72h and 72h, respectively), while all statins decreased proliferation rate in QGP1-cells (48/72h). Remarkably, metformin and simvastatin decreased migration capacity in BON1-cells and biguanides decreased serotonin secretion in BON1-cells. Phenformin increased apoptosis in BON1/QGP1-cells, and simvastatin in QGP1-cells. These antitumor effects likely involved altered expression of key genes related to cancer aggressiveness (i.e. GLUT4, INSR). Altogether, our results reveal a clear inhibitory effect of biguanides and statins on NET-cell aggressiveness.

Conclusion: Given the demonstrated clinical safety of these drugs, our results invite to further explore their potential therapeutic role for the treatment of NET patients.

Precis: Clinical/molecular changes in patients with T2DM and NETs reversed in metformin treated patients. Biguanides/statins altered aggressiveness features (proliferation, apoptosis, etc.) in NET cells.

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