Thyroid hormone promotes differentiation of colon cancer stem cells

Tumor formation and maintenance depend on a small fraction of cancer stem cells (CSCs) that can self-renew and generate a wide variety of differentiated cells. CSCs are resistant to chemotherapy and radiation, and can represent a reservoir of cancer cells that often cause relapse after treatment. Evidence suggests that CSCs also give rise to metastases. Thyroid hormone (TH) controls a variety of biological processes including the development and functioning of most adult tissues. Recent years has seen the emergence of an intimate link between TH and multiple steps of tumorigenesis. Thyroid hormone controls the balance between the proliferation and differentiation of CSCs, and may thus be a druggable anti-cancer agent. Here, we review current understanding of the effects of TH on colorectal CSCs, including the cross regulatory loops between TH and regulators of CSC stemness. Targeting TH in the tumor microenvironment may improve treatment strategies

Deiodinases and Cancer

: Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interplay between deiodinases and cancer and how this family of enzymes is relevant in cancer progression. We also discuss whether deiodinase expression could represent a diagnostic tool with which to define tumor staging in cancer treatment or even a therapeutic tool against cancer

The androgen-thyroid hormone crosstalk in prostate cancer and the clinical implications

: There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements (AREs) in the promoter regions of TH-related genes, such as deiodinases and thyroid hormone receptor isoforms have been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of Prostate Cancer (PCa) and hyperthyroidism. This article aims to review the role of androgen-thyroid hormone crosstalk in PCa and its implication in the clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve the clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer

Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts

Thyroid hormones (THs) are key determinants of cellular metabolism and regulate a variety of pathways that are involved in the metabolism of carbohydrates, lipids and proteins in several target tissues. Notably, hyperthyroidism induces a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, increased lipolysis and gluconeogenesis followed by weight loss, whereas hypothyroidism induces a hypo-metabolic state characterized by reduced energy expenditure, increased cholesterol levels, reduced lipolysis and gluconeogenesis followed by weight gain. Thyroid hormone is also a key regulator of mitochondria respiration and biogenesis. Besides mirroring systemic TH concentrations, the intracellular availability of TH is potently regulated in target cells by a mechanism of activation/inactivation catalyzed by three seleno-proteins: type 1 and type 2 iodothyronine deiodinase (D1 and D2) that convert the biologically inactive precursor thyroxine T4 into T3, and type 3 iodothyronine deiodinase (D3) that inactivates TH action. Thus, the pleiotropic effects of TH can fluctuate among tissues and strictly depend on the cell-autonomous action of the deiodinases. Here we review the mechanisms of TH action that mediate metabolic regulation. This review traces the critical impact of peripheral regulation of TH by the deiodinases on the pathways that regulate energy metabolism and the balance among energy intake, expenditure and storage in specific target tissues

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

: Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

: The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms

Report on the Challenges of Air Transportation Experienced by People with Disabilities

Boarding an airplane is difficult for persons with mobility impairments and increases the risk of injury to both passengers and employees. Airplane seats are uncomfortable and lack the necessary support for many individuals with disabilities. Additionally, airplane restrooms can be inaccessible to wheelchair users. Potential solutions for these issues include the use of detachable plane seats or personal wheelchairs on board and an airplane redesign to provide additional restroom space. The number of service and emotional support animals being brought on airplanes have also increased substantially over the past few years. Passengers that travel with their service animals must contend with having to follow different rules for different airlines carriers and not having sufficient space for animals to be safe and comfortable

Dual dichotomies--when thyroid dysfunction and thyroid hormones get into the skin.

Guest Editorial Dual Dichotomiessâ When Thyroid Dysfunction and Thyroid Hormones Ge tinto the Skin Monica Dentice1 and Giuseppe Monfrecola 2 his issue of Thyroid features three brief reports illustrating related but rare complications of thyroid disease: cutaneous and subcutaneous invasion by thyroid cancer metastasis. Santarpia et al. (1) describe several patients with skin metastasis from medullary thyroid carcinomas (MTC). They suggest that dissemination of this tumor be included in the differential diagnosis of cutaneous eruptions and nodules, especially when they are located in the upper part of the body in patients with a history of MTC. In another paper, Lou et al. report a patient with what appeared to be slin contamination after radioactive iodine therapy. Further investigation showed that the aberrant papillary carcinoma. Finally. Harish et al. (3) present a 60-year-old woman with an ulcerating cutaneous lesion of the neck due to contiguous extension of a non-hodgkinâs lymphoma of the thyroid. They were unable to ï-nd other published examples of this complication in thyroid lymphoma. Because of their rarity, few clinicians would even list metastasis of thyroid tumors to be one of the skin manifestations