The thyroid status modulates the development of murine T lymphoma line EL-4 growing in vivo as a solid tumor in syngeneic mice

STERLE H.; VALLI E; CAYROL F; COLOMBO L.; CREMASCHI G.A.; BARREIRO ARCOS M.L.

Dresden

Congreso; 8th Congress for NeuroImmunoModulation (ISNIM) and the German Endocrine-Brain-Immune network (GEBIN); 2011

We showed that thyroid hormones (THs) are capable of regulating the proliferation of T cells. The results on the involvement of THs in tumor development are controversial. We developed murine model of hyper- and hypothyroidism in C57BL/ Hep mice by oral administration of T4 or of the anti-thyroid agent PTU, respectively. In vitro THs were able to increase EL-4 cell proliferation, syngeneic with C57BL/Hep mice. To study the modulation of THs on tumor progression, EL-4 cells were s.c. inoculated in eu-, hypo- and hyperthyroid animals, giving rise to solid tumors at 13  ± 2 days. Hyperthyroid mice displayed a higher rate of tumor growth, increased tumor volume and reduced survival than euthyroid animals. By contrast, hypothyroid mice showed a lower tumor growth rate than controls, however, developed more metastases in the kidney than eu- o hyperthyroid animals. Analysis by RT Real-Time PCR for the expression of cell cycle regulatory proteins in solid tumors, indicate an increased expression of cyclins A2, D1, D3 and E1 and a decrease in the levels of expression p21 y p27 in hyperthyroid animals. In contrast, hypothyroid animals showed no significant differences in genomic expression of cyclins, but increased the expression of p27. Messenger RNA expression of Rb was not modulated by thyroid status of animals. The genomic expression of metalloproteinases 2 and 9 in solid tumors are found increased in hyperthyroid animals, while hypothyroid showed no significant differences compared to controls. On the other hand, we tested the modulation of thyroid status on the functionality of the immune system. Hyperthyroidism increases the in vitro proliferative response (quantified by the incorporation of [3H]TdR) of T and B cells against mitogenic stimuli, whereas hypothyroidism decreases it. Also observed a higher and lower NK cell activity in hyper-and hypothyroid animals, respectively, than controls, measured through the lysis of radiolabeled YAC-1 cells. These results suggest that THs modulate tumor growth through the regulation of proteins involved in the progression and/or arrest the cell cycle, the expression of metalloproteinases that could contribute to angiogenesis and the regulation of immune cell function that could limit the generation of metastases.