At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct ‘professional’ ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.
Rabii Ameziane El Hassani, Camille Buffet, Sophie Leboulleux, and Corinne Dupuy
Brian Hung-Hin Lang, Chung-Yau Lo, Wai-Fan Chan, King-Yin Lam, and Koon-Yat Wan
A number of risk-group stratification or staging systems have been found useful at stratifying patients with differentiated thyroid carcinoma into risk groups. Those identified as high risk could be subjected to more aggressive treatment, while those at low risk could be spared of such treatment. However, the best stratification system in patients with follicular thyroid carcinoma (FTC) remains unclear. Through a comprehensive MEDLINE search from 1965 to 2005, a total of 18 different staging systems were identified in the literature and 14 of them were applicable to 171 patients, with FTC managed at our institution from 1961 to 2001. Cancer-specific survivals (CSS) were calculated by Kaplan–Meier method and were compared by log-rank test. Using Cox proportional hazards analysis, the relative importance of each staging system in determining CSS was calculated by the proportion of variation in survival time explained (PVE). CSS were predicted by 13 out of the 14 staging systems significantly (P < 0.001). The three highest ranked staging systems by PVE were the new American Joint Commitee on Cancer/Union Internationale Centre le Cancer 6th edition, tumour, node, metastases (TNM; 22.4), followed by the Clinical Class (21.2) and the metastases, age, completeness of resection, invasion, size (MACIS; 20.4). In conclusion, 13 out of the 14 presently available staging systems predicted CSS significantly in FTC. When predictability was measured by PVE, the TNM system was found to have the best predictability and thus, should be the stratification system of choice for FTC in the future.
Anna Angelousi, Eva Kassi, Narjes Ansari-Nasiri, Harpal Randeva, Gregory Kaltsas, and George Chrousos
Circadian rhythms at a central and peripheral level are operated by transcriptional/translational feedback loops involving a set of genes called ‘clock genes’ that have been implicated in the development of several diseases, including malignancies. Dysregulation of the Clock system can influence cancer susceptibility by regulating DNA damage and repair mechanisms, as well as apoptosis. A number of oncogenic pathways can be dysregulated via clock genes’ epigenetic alterations, including hypermethylation of clock genes’ promoters or variants of clock genes. Clock gene disruption has been studied in breast, lung and prostate cancer, and haematological malignancies. However, it is still not entirely clear whether clock gene disruption is the cause or the consequence of tumourigenesis and data in endocrine neoplasms are scarce. Recent findings suggest that clock genes are implicated in benign and malignant adrenocortical neoplasias. They have been also associated with follicular and papillary thyroid carcinomas and parathyroid adenomas, as well as pituitary adenomas and craniopharyngiomas. Dysregulation of clock genes is also encountered in ovarian and testicular tumours and may also be related with their susceptibility to chemotherapeutic agents. The most common clock genes that are implicated in endocrine neoplasms are PER1, CRY1; in most cases their expression is downregulated in tumoural compared to normal tissues. Although there is still a lot to be done for the better understanding of the role of clock genes in endocrine tumourigenenesis, existing evidence could guide research and help identify novel therapeutic targets aiming mainly at the peripheral components of the clock gene system.
Feng Wu, Fuxingzi Li, Xiao Lin, Feng Xu, Rong-Rong Cui, Jia-Yu Zhong, Ting Zhu, Su-Kang Shan, Xiao-Bo Liao, Ling-Qing Yuan, and Zhao-Hui Mo
Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.
Giuseppe Palladino, Tiziana Notarangelo, Giuseppe Pannone, Annamaria Piscazzi, Olga Lamacchia, Lorenza Sisinni, Girolamo Spagnoletti, Paolo Toti, Angela Santoro, Giovanni Storto, Pantaleo Bufo, Mauro Cignarelli, Franca Esposito, and Matteo Landriscina
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone upregulated in several human malignancies and involved in protection from apoptosis and drug resistance, cell cycle progression, cell metabolism and quality control of specific client proteins. TRAP1 role in thyroid carcinoma (TC), still unaddressed at present, was investigated by analyzing its expression in a cohort of 86 human TCs and evaluating its involvement in cancer cell survival and proliferation in vitro. Indeed, TRAP1 levels progressively increased from normal peritumoral thyroid gland, to papillary TCs (PTCs), follicular variants of PTCs (FV-PTCs) and poorly differentiated TCs (PDTCs). By contrast, anaplastic thyroid tumors exhibited a dual pattern, the majority being characterized by high TRAP1 levels, while a small subgroup completely negative. Consistently with a potential involvement of TRAP1 in thyroid carcinogenesis, TRAP1 silencing resulted in increased sensitivity to paclitaxel-induced apoptosis, inhibition of cell cycle progression and attenuation of ERK signaling. Noteworthy, the inhibition of TRAP1 ATPase activity by pharmacological agents resulted in attenuation of cell proliferation, inhibition of ERK signaling and reversion of drug resistance. These data suggest that TRAP1 inhibition may be regarded as potential strategy to target specific features of human TCs, i.e., cell proliferation and resistance to apoptosis.
Urbain Weyemi, Bernard Caillou, Monique Talbot, Rabii Ameziane-El-Hassani, Ludovic Lacroix, Odile Lagent-Chevallier, Abir Al Ghuzlan, Dirk Roos, Jean-Michel Bidart, Alain Virion, Martin Schlumberger, and Corinne Dupuy
NADPH oxidase 4 (NOX4) belongs to the NOX family that generates reactive oxygen species (ROS). Function and tissue distribution of NOX4 have not yet been entirely clarified. To date, in the thyroid gland, only DUOX1/2 NOX systems have been described. NOX4 mRNA expression, as shown by real-time PCR, was present in normal thyroid tissue, regulated by TSH and significantly increased in differentiated cancer tissues. TSH increased the protein level of NOX4 in human thyroid primary culture and NOX4-dependent ROS generation. NOX4 immunostaining was detected in normal and pathologic thyroid tissues. In normal thyroid tissue, staining was heterogeneous and mostly found in activated columnar thyrocytes but absent in quiescent flat cells. Papillary and follicular thyroid carcinomas displayed more homogeneous staining. The p22phox protein that forms a heterodimeric enzyme complex with NOX4 displayed an identical cellular expression pattern and was also positively regulated by TSH. ROS may have various biological effects, depending on the site of production. Intracellular NOX4–p22phox localization suggests a role in cytoplasmic redox signaling, in contrast to the DUOX localization at the apical membrane that corresponds to an extracellular H2O2 production. Increased NOX4–p22phox in cancer might be related to a higher proliferation rate and tumor progression but a role in the development of tumors has to be further studied and established in the future.
Pedro Weslley Rosario, Gabriela Franco Mourão, Maurício Buzelin Nunes, Marcelo Saldanha Nunes, and Maria Regina Calsolari
Recently, it was proposed that some papillary thyroid carcinomas (PTC) will no longer be termed ‘cancer’ and are christened as ‘noninvasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP). As this is a recent definition, little information is available about NIFTP. The objective of this study was to report the frequency, ultrasonographic appearance, cytology result and long-term evolution of cases of NIFTP seen at our institution. We excluded tumours ≤1 cm. The sample consisted of 129 patients. Sixty-four patients were submitted to total thyroidectomy and 65 to lobectomy. These patients with NIFTP did not receive radioiodine. NIFTP corresponded to 15% of cases diagnosed as PTC >1 cm. An ultrasonographic appearance considered to be of low suspicion for malignancy was common in NIFTP (32.5%), whereas a highly suspicious appearance was uncommon (5%). NIFTP frequently exhibited indeterminate cytology (62%), while malignant cytology was uncommon (4%). The patients were followed up for 12–146 months (median 72 months) after surgery. None of the patients developed structural disease during follow-up. Comparing the concentrations of thyroglobulin (Tg) and anti-Tg antibodies (TgAb) obtained 6–12 months after surgery and in the last assessment, none of the patients exhibited an increase in these markers.
M M Muresan, P Olivier, J Leclère, F Sirveaux, L Brunaud, M Klein, R Zarnegar, and G Weryha
The presence of distant metastases from differentiated thyroid carcinoma decreases the 10-year survival of patients by 50%. Bone metastases represent a frequent complication especially of follicular thyroid cancer and severely reduce the quality of life causing pain, fractures, and spinal cord compression. Diagnosis is established by correlating clinical suspicion with imaging. Imaging is essential to detect, localize, and assess the extension of the lesions and should be used in conjunction with clinical evidence. Bone metastases are typically associated with elevated markers of bone turnover, but these markers have not been evaluated in differentiated thyroid cancer. Skeletal and whole-body magnetic resonance imaging and fusion 2-deoxy-2-[18F]fluoro-d-glucose whole-body positron emission tomography/computed tomography (PET/CT) are the best anatomic and functional imaging techniques available in specialized centers. For well-differentiated lesions, iodine-PET scan combined 124I-PET/CT is the newest imaging development and 131I is the first line of treatment. Bisphosphonates reduce the complications rate and pain, alone or in combination with radioiodine, radionuclides, or external beam radiotherapy and should be employed. Surgery and novel minimally invasive consolidation techniques demand an appropriate patient selection for best results on a multimodal approach. Basic research on interactions between tumor cells and bone microenvironment are identifying potential novel targets for future more effective therapeutic interventions for less differentiated tumors.
Zhenying Guo, Heather Hardin, and Ricardo V Lloyd
Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well-differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well-differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well-differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem-like cell (CSC) model suggests that a small number of cells within a cancer, known as CSCs, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease. This review discusses current studies about thyroid CSCs, the processes of epithelial-to-mesenchymal transition (EMT), and mesenchymal-to-epithelial transition that provide plasticity to CSC growth, in addition to the role of microRNAs in CSC development and regulation. Understanding the biology of CSCs, EMT and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers.
Jennifer A Woyach and Manisha H Shah
The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodine-refractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I–III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.