Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

Abstract

T-cell lymphomas (TCL) are a heterogeneous group of aggressive clinical lymphoproliferative disorders with considerable clinical, morphological, immunophenotypic, and genetic variation, including ~10-15% of all lymphoid neoplasms. Several evidences indicate an important role of the non-neoplastic microenvironment in promoting both tumor growth and dissemination in T cell malignancies. Thus, dysregulation of integrin expression and activity is associated with TCL survival and proliferation. We found that thyroid hormones acting via the integrin αvβ3 receptor are crucial factors in tumor microenvironment (TME) affecting the pathophysiology of TCL cells. Specifically, TH-activated αvβ3 integrin signaling promoted TCL proliferation and induced and an angiogenic program via the up-regulation of the vascular endothelial growth factor (VEGF). This was observed both on different TCL cell lines representing the different subtypes of human hematological malignancy, and in preclinical models of TCL tumors xenotransplanted in immunodeficient mice as well. Moreover, development of solid tumors by inoculation of murine TCLs in syngeneic hyperthyroid mice, showed increased tumor growth along with increased expression of cell cycle regulators. The genomic or pharmacological inhibition of integrin αvβ3 decreased VEGF production, induced TCL cell death and decreased in vivo tumor growth and angiogenesis. Here, we review the non-genomic actions of THs on TCL regulation and their contribution to TCL development and evolution. These actions not only provide novel new insights on the endocrine modulation of TCL, but also provide a potential molecular target for its treatment.

Keywords: T-cell lymphoma; VEGF; angiogenesis; integrin αvβ3; proliferation; thyroid hormones.

Figure 1

Regulation of antitumor immune cells by circulating levels of THs. In hyperthyroid conditions (blue arrows) increased number and activity of NK and cytotoxic CD8+ lymphocytes, while decreased number of myeloid-derived suppressor cells, were found in the spleens of TCL tumor-bearing mice. However, hypothyroid tumor-bearing animals displayed higher numbers of T regulatory lymphocytes (Treg) in tumor-draining lymph nodes and lower number and activity of splenic NK and CD8+ lymphocytes than control, indicating that the hypothyroid status favors the dissemination of TCL cells.

Figure 2

Non-genomic action of THs initiated at the surface receptor of TCL cells on the integrin αvβ3. THs induce signaling pathways triggered after binding to integrin αvβ3 include the activation of NF-κB, thus leading to the production of angiogenic factors such as VEGF and to cell proliferation, cell survival and angiogenesis. Figure adapted from Cremaschi et al. (122) with permission from Elsevier.