title: Bridging hypoxia, inflammation and estrogen receptors in thyroid cancer progression.
abstract: Thyroid cancer is a common endocrine-related cancer with a higher incidence in women than in men. Thyroid tumors are classified on the basis of their histopathology as papillary, follicular, medullary, and undifferentiated or anaplastic. Epidemiological and in vitro or in vivo studies have suggested a correlation between incidence of thyroid malignancies and hormones. In particular, growing evidence indicates a role of estrogens and estrogen receptors (ERs) in thyroid tumorigenesis, reprogramming and progression. In this scenario, estrogens are hypothesized to contribute to the observed female predominance of thyroid cancer in reproductive years. However, the precise contribution of estrogens in thyroid proliferative disease initiation and progression is not well understood. HIF-1α and NF-κB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression and resistance to chemotherapy. In fact, HIF-1α and NF-κB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic and differentiation reprogramming, inflammatory-reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement, they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7 and some TLRs are activated by HIF-1α; and that, in turn, alarmin receptors strongly activate NF-κB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these inhibitors are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors to achieve a reduction of metastasis formation and, more importantly, a net increase in survival. This review highlights the central role of HIF-1α activated in hypoxic regions of the tumor, of NF-κB activation and proinflammatory gene expression in transformed thyroid cells to understand their progression toward malignancy. The role of ER-α will be underlined, considering also its role in reprogramming cancer cells.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, 324, Viale Regina Elena, 00161 Roma, Italy; Laboratory of Molecular and Cellular Pathology - IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tafani
authors.affiliation: Department of Human Anatomy, Sapienza University of Rome, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: De Santis
authors.affiliation: UOC of Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Coppola
authors.affiliation: UOC of Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy.
authors.forename: Giulietta A
authors.initials: GA
authors.lastname: Perrone
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, 324, Viale Regina Elena, 00161 Roma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Carnevale
authors.affiliation: Department of Surgical Pathology, IRCCS Istituto Regina Elena, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Russo
authors.affiliation: Laboratory of Molecular and Cellular Pathology - IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Pucci
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carpi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, 324, Viale Regina Elena, 00161 Roma, Italy.
authors.forename: Mariano
authors.initials: M
authors.lastname: Bizzarri
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, 324, Viale Regina Elena, 00161 Roma, Italy; Laboratory of Molecular and Cellular Pathology - IRCCS San Raffaele Pisana, Rome, Italy. Electronic address: matteoantonio.russo@uniroma1.it.
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D018450:Disease Progression; D015195:Drug Design; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011960:Receptors, Estrogen
keywords: Cellular and molecular rehabilitation; ER-α; HIF-1α; Hypoxia; Inflammation; NF-κB; Reprogramming cancer cells; Thyroid Cancer