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

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

Beneficial effect of fluoxetine and dertraline on chronic stress-induced tumor crowth and cell dissemination in a mouse model of lymphoma : crucial role of antitumor immunity

Abstract: Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response

Del laboratorio a la clínica : importancia de la regulación de la inmunidad ejercida por el estado tiroideo

Resumen: Una fina y compleja red de mecanismos autorregulados le permite al sistema inmune reaccionar ante el desafío antigénico para activar una respuesta de defensa contra agentes patógenos o extraños y volver luego a un modo de espera o vigilancia. Esta red de autorregulación mantiene la homeostasis y evita las dañinas respuestas autoinmunes. A pesar de su autonomía se ha demostrado que los sistemas inmune y neuroendócrino interactúan entre sí a través de una red bidireccional de la que participan los receptores para ligando s comunes y sus vías intracelulares de señalización. Las hormonas y neurotransmisores pueden afectar la función inmune y, a su vez, los factores inmunitarios como las citoquinas pueden ejercer cambios neuroendocrinos (Melmed, 2001; Wrona, 2006). Además, las células inmunes pueden producir hormonas y neurotransmisores, mientras que las citoquinas, principales factores solubles liberados por las células inmunes, pueden funcionar como hormonas y moduladores de ciertas respuestas del sistema nervioso central (Haddad, 2008). Las consecuencias de la disfunción entre estos componentes neuroendocrinos y la inmunidad son evidentes durante situaciones de estrés, lesiones físicas, infecciones y otras condiciones fisiopatológicas

Thyroid hormones and their membrane receptors as therapeutic targets for T cell lymphomas

Abstract: Thyroid hormones (THs) are important regulators of metabolism, differentiation and cell proliferation.They can modify the physiology of human and murine T cell lymphomas (TCL). These effects involvegenomic mechanisms, mediated by specific nuclear receptors (TR), as well as nongenomic mechanisms,that lead to the activation of different signaling pathways through the activation of a membrane recep-tor, the integrin v3. Therefore, THs are able to induce the survival and growth of TCL. Specifically, thesignaling induced by THs through the integrin v3 activates proliferative and angiogenic programs,mediated by the regulation of the vascular endothelial growth factor (VEGF). The genomic or pharmaco-logic inhibition of integrin v3 reduces the production of VEGF and induces cell death both in vitro andin xenograft models of human TCL.Here we review the mechanisms involved in the modulation of the physiology of TCL induced by THs,the analysis of the interaction between genomic and nongenomic actions of THs and their contribution toT cell lymphomagenesis. These actions of THs suggest a novel mechanism for the endocrine modulationof the physiopathology of TCL and they provide a potential molecular target for its treatment

Hypothyroidism-associated immunosuppression involves induction of galectin1-producing regulatory T cells

Abstract: Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamicpituitary-thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barely understood. Here we investigated the mechanisms underlying hypothyroid-related immunosuppression by examining the regulatory role of components of the HPT axis. We first analyzed lymphocyte activity in mice overexpressing the TRH gene (Tg-Trh). T cells from TgTrh showed increased proliferation than wild type (WT) euthyroid mice in response to polyclonal activation. The release of Th1 proinflammatory cytokines was also increased in TgTrh, and TSH levels correlated with T cell proliferation. To gain further mechanistic insights into hypothyroidism-related immunosuppression, we evaluated T cell subpopulations in lymphoid tissues of hypothyroid and control mice. No differences were observed in CD3/CD19 or CD4/CD8 ratios between these strains. However, the frequency of regulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg-Trh mice. Accordingly, in vitro Tregs differentiation was more pronounced in naïve T cells isolated from hypothyroid mice. Since Tregs overexpress galectin-1 (Gal-1) and mice lacking this lectin (Lgals1-/-) show reduced Treg function, we investigated the involvement of this immunoregulatory lectin in the control of Tregs in settings of hypothyroidism. Increased T lymphocyte reactivity and reduced frequency of Tregs were found in hypothyroid Lgals1-/- mice when compared to hypothyroid WT animals. This effect was rescued by addition of recombinant Gal-1. Finally, increased expression of Gal-1 was found in Tregs purified from hypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase in the frequency and activity of Gal-1-expressing Tregs underlies immunosuppression associated with hypothyroid conditions, with critical implications in immunopathology, metabolic disorders, and cancer

Study of the antitumour effects and the modulation of immune response by histamine in breast cancer

Abstract: Background: The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker. Methods: Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg kg−1): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10). Results: Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg kg−1) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice. Conclusions: Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer

Inhibition of Integrin aVb3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Abstract: Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the aVb3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an aVb3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin aVb3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin aVb3 inhibitors as part of CTCL regimens based on bexarotene administration

The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies

Abstract: In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8+ T cells, and higher percentage of CD19+ B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas