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

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

Tetrac Delayed the Onset of Ocular Melanoma in an Orthotopic Mouse Model

Ocular melanoma research, the most common primary intraocular malignancy in adults, is hindered by limited in vivo models. In a series of experiments using melanoma cells injected intraocularly into mouse eyes, we developed a model for ocular melanoma. Inoculation of 5 × 105 B16F10 cells led to rapid tumor growth, extensive lung metastasis, and limited animal survival, while injection of 102 cells was sufficient for intraocular tumors to grow with extended survival. In order to improve tumor visualization, 102 melanoma cells (B16F10 or B16LS9) were inoculated into Balb/C albino mouse eyes. These mice developed intraocular tumors that did not metastasize and exhibited extended survival. Next, we studied the therapeutic potential of inhibitor of the thyroid hormones-αvβ3 integrin signaling pathway in ocular melanoma. By utilizing tetraiodothyroacetic acid (tetrac), a thyroid hormone derivative, a delay in tumor onset in the B16F10 (integrin+) arm was observed, compared to the untreated group, while in the B16LS9 cells (integrin–) a similar rate of tumor onset was noticed in both experimental and control groups. In summary, following an optimization process, the mouse ocular melanoma model was developed. The models exhibited an extended therapeutic window and can be utilized as a platform for investigating various drugs and other treatment modalities

Cell Free Expression of hif1α and p21 in Maternal Peripheral Blood as a Marker for Preeclampsia and Fetal Growth Restriction

Preeclampsia, a severe unpredictable complication of pregnancy, occurs in 6% of pregnancies, usually in the second or third trimester. The specific etiology of preeclampsia remains unclear, although the pathophysiological hallmark of this condition appears to be an inadequate blood supply to the placenta. As a result of the impaired placental blood flow, intrauterine growth restriction (IUGR) and consequential fetal oxidative stress may occur. Consistent with this view, pregnancies complicated by preeclampsia and IUGR are characterized by up-regulation of key transcriptional regulators of the hypoxic response including, hif1α and as well as p53 and its target genes. Recently, the presence of circulating cell-free fetal RNA has been documented in maternal plasma. We speculated that pregnancies complicated by preeclampsia and IUGR, will be associated with an abnormal expression of p53 and/or hif1α related genes in the maternal plasma. Maternal plasma from 113 singleton pregnancies (72 normal and 41 complicated pregnancies) and 19 twins (9 normal and 10 complicated pregnancies) were collected and cell free RNA was extracted. The expression of 18 genes was measured by one step real-time RT-PCR and was analyzed for prevalence of positive/negative expression levels. Results indicate that, among the genes examined, cell free plasma expressions of p21 and hif1α were more prevalent in pregnancies complicated by hypoxia and/or IUGR (p<0.001). To conclude, we present in this manuscript data to support the association between two possible surrogate markers of hypoxia and common complications of pregnancy. More work is needed in order to implement these findings in clinical practice

Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer

Abstract Ovarian cancer is a highly aggressive disease and novel treatments are required. Thyroid hormones binding to αvβ3 integrin produced growth-promoting activities in ovarian cancer and we hypothesized that natural thyroid hormone derivatives may antagonize these actions. The effect of three antagonists, tetraiodoacetic acid (tetrac), triiodothyroacetic acid (triac) and 3-iodothyronamine (T1AM), on cell proliferation, cell death and DNA damage was studied in two ovarian cancer cell lines (OVCAR3 and A2780), normal hamster ovary control cells (CHOK1) and αvβ3-deficient or transfected HEK293 cells. A differential inhibition of cell proliferation was observed in ovarian cancer cells compared to CHOK1. In OVCAR3, an induction of cell cycle regulators was further shown. Apoptosis was confirmed (annexin-PI, SubG1/cell-cycle, apoptotic genes, caspase-3 and poly ADP ribose polymerase-1 (PARP-1) cleavage) and was reversed by a pan-caspase inhibitor. Induction in apoptosis inducing factor (AIF) was observed, suggesting a parallel caspase-independent mechanism. Integrin-involvement in triac/T1AM apoptotic action was shown in αvβ3-transfected HEK293 cells. Lastly, in ovarian cancer models, key proteins that coordinate recognition of DNA damage, ataxia-telangiectasia mutated (ATM) and PARP-1, were induced. To conclude, the cytotoxic potential of thyroid hormone derivatives, tetrac, triac and T1AM, in ovarian cancer may provide a much-needed novel therapeutic approach

Contributions of Thyroid Hormone to Cancer Metastasis

Acting at a cell surface receptor on the extracellular domain of integrin &alpha;v&beta;3, thyroid hormone analogues regulate downstream the expression of a large panel of genes relevant to cancer cell proliferation, to cancer cell survival pathways, and to tumor-linked angiogenesis. Because &alpha;v&beta;3 is involved in the cancer cell metastatic process, we examine here the possibility that thyroid hormone as l-thyroxine (T4) and the thyroid hormone antagonist, tetraiodothyroacetic acid (tetrac), may respectively promote and inhibit metastasis. Actions of T4 and tetrac that are relevant to cancer metastasis include the multitude of synergistic effects on molecular levels such as expression of matrix metalloproteinase genes, angiogenesis support genes, receptor tyrosine kinase (EGFR/ERBB2) genes, specific microRNAs, the epithelial&ndash;mesenchymal transition (EMT) process; and on the cellular level are exemplified by effects on macrophages. We conclude that the thyroid hormone-&alpha;v&beta;3 interaction is mechanistically linked to cancer metastasis and that modified tetrac molecules have antimetastatic activity with feasible therapeutic potential

Joint distribution of p21 and hif1α in the study population.

<p>No expression (−), Positive (+).</p