Thyroid Hormones and Cancer: A Comprehensive Review of Preclinical and Clinical Studies

Abstract

Thyroid hormones take major part in normal growth, development and metabolism. Over a century of research has supported a relationship between thyroid hormones and the pathophysiology of various cancer types. In vitro studies as well as research in animal models demonstrated an effect of the thyroid hormones T3 and T4 on cancer proliferation, apoptosis, invasiveness and angiogenesis. Thyroid hormones mediate their effects on the cancer cell through several non-genomic pathways including activation of the plasma membrane receptor integrin αvβ3. Furthermore, cancer development and progression are affected by dysregulation of local bioavailability of thyroid hormones. Case-control and population-based studies provide conflicting results regarding the association between thyroid hormones and cancer. However, a large body of evidence suggests that subclinical and clinical hyperthyroidism increase the risk of several solid malignancies while hypothyroidism may reduce aggressiveness or delay the onset of cancer. Additional support is provided from studies in which dysregulation of the thyroid hormone axis secondary to cancer treatment or thyroid hormone supplementation was shown to affect cancer outcomes. Recent preclinical and clinical studies in various cancer types have further shown promising outcomes following chemical reduction of thyroid hormones or inhibition or their binding to the integrin receptor. This review provides a comprehensive overview of the preclinical and clinical research conducted so far.

Male Predominance of Gastric Cancer among Patients with Hypothyroidism from a Defined Geographic Area

“…Moreover, it has been reported that GC accumulates triiodothyronine (T3) through the overexpression of transthyretin involved in cellular T3 import [22]. The increased intracellular T3 concentration directly contributes to cancer progression, by different pathways [23]. In human surveys, similarly, iodine prophylaxis was effective in decreasing the incidence and death rate for GC in iodine-deficient areas [24].…”

Errare humanum est, sed in errare perseverare diabolicum: methodological errors in the assessment of the relationship between I-131 therapy and possible increases in the incidence of malignancies

“…For years, it has been established that both Graves' disease [15] and hyperthyroidism in general [16] are causative of an increasing cancer incidence. As larger thyroids and more severe hyperthyroidism in Graves' disease are in clinical practice associated with higher activities necessary for effective treatment, it could very well be that it is the hyperthyroidism per se that is causing the excess cancer mortality-there is a considerable body of evidence showing this.…”

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“…The promoter region of GPD2 contains thyroid hormone response elements (TRE) which respond to the thyroid hormones, particularly triiodothyronine (T3), that can activate mGPDH transcription in a tissue-specific manner. This information is particularly important since T3 has been shown as cancer growth promoting factor in many cancer models, including breast, prostate, thyroid, lungs and renal cancer [3]. In fact, in a recent study, we observed T3mediated upregulation in mGPDH expression in human thyroid cancer cells [4].…”