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.
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
Devora Champa, Marika A Russo, Xiao-Hui Liao, Samuel Refetoff, Ronald A Ghossein, and Antonio Di Cristofano
Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers.
Roberto Bellelli, Maria Domenica Castellone, Ginesa Garcia-Rostan, Clara Ugolini, Carmelo Nucera, Peter M Sadow, Tito Claudio Nappi, Paolo Salerno, Maria Carmela Cantisani, Fulvio Basolo, Tomas Alvarez Gago, Giuliana Salvatore, and Massimo Santoro
Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2), and plasminogen activator, urokinase: uPA (PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer.
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.
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.
Claudia Bozza, Fabio Puglisi, Matteo Lambertini, Etin-Osa Osa, Massimo Manno, and Lucia Del Mastro
Breast cancer is the most common invasive cancer in women of reproductive age. In young women, chemotherapy may induce amenorrhea: it is still uncertain how to assess menopausal status in these patients despite the importance of its definition for choosing appropriate endocrine treatment. In the development of sensitive biomarkers for fertility and ovarian reserve, anti-Müllerian hormone (AMH) is considered a promising marker of ovarian reserve. The clearest data regarding a clinical use of AMH are related to the measurement of the ovarian pool in women who undergo IVF: the available data, also in breast cancer patients, seem to suggest that AMH measurement, before gonadotropin administration, can be a useful marker for the prediction of women at risk for poor-response or no response to ovarian stimulation. The utility of AMH as a potential marker of chemotherapy-induced ovarian follicular depletion and an early plasma marker of chemotherapy-induced gonadal damage has been evaluated both in young women after treatment for cancer in childhood and in young survivors of hematological malignancies and solid tumors. Several studies have demonstrated a potential utility of AMH, inhibin, or follicle-stimulating factor as biomarkers predicting infertility risk in breast cancer patients, but the studies conducted so far are not conclusive. Further studies are needed in order to define the regimen-specific action of chemotherapy on AMH levels, the percentage of post-treatment recovery of plasma levels of the hormone, and the relationship between menopausal status and AMH.
Shih-Ping Cheng, Chien-Liang Liu, Ming-Jen Chen, Ming-Nan Chien, Ching-Hsiang Leung, Chi-Hsin Lin, Yi-Chiung Hsu, and Jie-Jen Lee
CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with tumor progression and metastasis in hematologic and solid tumors. In this study, we found that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (P=0.043), extrathyroidal invasion (P=0.021), advanced TNM stage (P=0.006), and higher MACIS score (P=0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target.
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.
Caterina Tiozzo, Soula Danopoulos, Maria Lavarreda-Pearce, Sheryl Baptista, Radka Varimezova, Denise Al Alam, David Warburton, Rehan Virender, Stijn De Langhe, Antonio Di Cristofano, Saverio Bellusci, and Parviz Minoo
Even though the role of the tyrosine phosphatase Pten as a tumor suppressor gene has been well established in thyroid cancer, its role during thyroid development is still elusive. We therefore targeted Pten deletion in the thyroid epithelium by crossing Pten flox/flox with a newly developed Nkx2.1-cre driver line in the BALB/c and C57BL/6 genetic backgrounds. C57BL/6 homozygous Pten mutant mice died around 2 weeks of age due to tracheal and esophageal compression by a hyperplasic thyroid. By contrast, BALB/c homozygous Pten mutant mice survived up to 2 years, but with a slightly increased thyroid volume. Characterization of the thyroid glands from C57BL/6 homozygous Pten mutant mice at postnatal day 14 (PN14) showed abnormally enlarged tissue with areas of cellular hyperplasia, disruption of the normal architecture, and follicular degeneration. In addition, differing degrees of hypothyroidism, thyroxine (T4) decrease, and thyroid-stimulating hormone elevation between the strains in the mutants and the heterozygous mutant were detected at PN14. Finally, C57BL/6 heterozygous Pten mutant mice developed thyroid tumors after 2 years of age. Our results indicate that Pten has a pivotal role in thyroid development and its deletion results in thyroid tumor formation, with the timing and severity of the tumor depending on the particular genetic background.
Catherine Ory, Nicolas Ugolin, Céline Levalois, Ludovic Lacroix, Bernard Caillou, Jean-Michel Bidart, Martin Schlumberger, Ibrahima Diallo, Florent de Vathaire, Paul Hofman, José Santini, Bernard Malfoy, and Sylvie Chevillard
Both external and internal exposure to ionizing radiation are strong risk factors for the development of thyroid tumors. Until now, the diagnosis of radiation-induced thyroid tumors has been deduced from a network of arguments taken together with the individual history of radiation exposure. Neither the histological features nor the genetic alterations observed in these tumors have been shown to be specific fingerprints of an exposure to radiation. The aim of our work is to define ionizing radiation-related molecular specificities in a series of secondary thyroid tumors developed in the radiation field of patients treated by radiotherapy. To identify molecular markers that could represent a radiation-induction signature, we compared 25K microarray transcriptome profiles of a learning set of 28 thyroid tumors, which comprised 14 follicular thyroid adenomas (FTA) and 14 papillary thyroid carcinomas (PTC), either sporadic or consecutive to external radiotherapy in childhood. We identified a signature composed of 322 genes which discriminates radiation-induced tumors (FTA and PTC) from their sporadic counterparts. The robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 29 tumors (16 FTA and 13 PTC). After the histology code break by the clinicians, 26/29 tumors were well classified regarding tumor etiology, 1 was undetermined, and 2 were misclassified. Our results help shed light on radiation-induced thyroid carcinogenesis, since specific molecular pathways are deregulated in radiation-induced tumors.