Thyroid cancer is the most common malignant disease of the endocrine system. Previous studies indicate a rapid increase in the incidence of thyroid cancer in recent decades, and this increase has aroused the great public concern. The aim of this study was to analyze the trends in incidence, mortality and clinical-pathological patterns of thyroid cancer in Zhejiang province. Population-based incidence and mortality rates of thyroid cancer were collected from eight cancer registries in Zhejiang from 2000 to 2012. The incidence and mortality rates were age-standardized to Segi’s world population. A Joinpoint model was used to examine secular trends in age-adjusted thyroid cancer rates with the Joinpoint Regression Program Version 4.0.0. Thyroid cancer patients were recruited from Zhejiang Cancer Hospital from 1972 to 2014. Patient demographics, tumor histology and tumor size were compared among the different periods of 1972–1985, 1986–1999 and 2000–2014. The age-standardized incidence rate of thyroid cancer in Zhejiang cancer registries was 2.75/105 in 2000, and increased to 19.42/105 in 2012. Additionally, we observed significantly increasing incidence rates with the Annual Percent Change (APC) of 22.86% (95%CI, 19.2%–26.7%). The age-standardized mortality of thyroid cancer in Zhejiang cancer registries was 0.23/105 in 2000 and 0.25/105 in 2012. No significant change in mortality rate was found. We observed a rapid increase in the proportions of papillary thyroid carcinoma (PTC) in 12,508 patients with thyroid carcinoma identified in the Zhejiang Cancer Hospital from 1972 to 2014 while the proportions of poorly differentiated thyroid cancer (PDTC), medullary thyroid carcinoma (MTC) and follicular thyroid carcinoma (FTC) decreased over the decades. In the PTC cases, the proportion of patients with maximum tumor diameter (MTD) < 1 cm dramatically and significantly increased from 0 in 1972–1985 to 32.1% in 2000–2014. A rapid increase in incidence and a stable trend in mortality of thyroid cancer were found in the distribution of thyroid cancer. Most of the increased incidence was PTC, especially the papillary thyroid microcarcinoma (PTMC) with MTD < 1 cm. This increase in incidence might be due to increased diagnosis with advanced technology.

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.Graphical Abstract

Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.

Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.