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Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD as a risk factor for TC, although this issue remains controversial. Prevention of autoimmune disease and cancer is the ultimate goal for clinicians and scientists, but it is not always feasible. Thus, new treatments, that overcome the current barriers to prevention and treatment of TC and AITD are needed. Alkaloids are secondary plant metabolites endowed with several biological activities including anticancer and immunomodulatory properties. In this perspective, alkaloids may represent a promising source of prophylactic and therapeutic agents for TC and AITD. This review encompasses the current published literature on alkaloids effects on TC and AITD, with a specific focus on the pathways involved in TC and AITD development and progression.

Although the evolution of differentiated thyroid cancer (DTC) is usually indolent, some tumors grow fast, metastasize, and may be fatal. Viruses have been associated with many human tumors, especially the Epstein-Barr virus (EBV), which shows a high viral load in DTC. In order to evaluate the ability of the virus to cause morphological and molecular changes in neoplastic thyroid cell lines TPC-1, BCPAP, and 8505C, a viral adaptation was performed for the analysis of EBV cytopathic effect (CPE), viral kinetics and gene expression analysis of oncogenes KRAS, NRAS, HRAS, and TP53. Comparison of inoculated cells with non-inoculated control cells showed that all tumor cell lines were permissive to the virus. The virus caused CPE in the TPC-1 and 8505C, but not in BCPAP cells. Viral kinetic was similar in both BCPAP and 8505C with a point of eclipse at 24 h post infection. TPC-1 cell line displayed a decreasing growth curve, with highest viral load right after inoculation, which decreased over time. There was hyperexpression of TP53 and NRAS in BCPAP cell (p = 0.012 and p = 0.0344, respectively). The 8505C cell line presented NRAS hyperexpression (p = 0.0255), but lower TP53 expression (p = 0.0274). We concluded that neoplastic thyroid cell lines are permissive to EBV that the virus presents different viral kinetic patterns in different cell lines and produces a CPE on both well-differentiated and undifferentiated thyroid cell lines. We also demonstrated that EBV interferes in oncogene expression in thyroid neoplastic cell lines, suggesting that these effects could be related to different tumor progression patterns.

The chemokine receptor CCR6, selectively bound by CCL20, is involved in the metastatic spread of cancer cells. Tumor necrosis factor-α (TNF-α) displays a complex pro-tumorigenic actions, but it is unknown whether this cytokine could modulate the expression of chemokine receptors in thyroid tumors. The membrane expression of CCR6 was assessed by flow cytometry and immunofluorescence, in primary cultures of normal human thyroid (NHT) cells and in thyroid cancer cell lines (TPC-1 and BCPAP), both in basal conditions and after stimulation with TNF-α. In basal conditions, CCR6+ cells were virtually absent in NHT cells (0.4 ± 0.4 %), while they were detected in TPC-1 (23.6 ± 6.6 %) and in BCPAP (12.9 ± 9.4 %) tumor cells (ANOVA F: 10.534; p < 0.005). The incubation with TNF-α significantly increased the percentage of CCR6+ cells in TPC-1 (23.6 ± 6.6 % vs. 33.1 ± 8.7; p < 0.033) and in BCPAP (12.9 ± 9.4 % vs. 18.1 ± 11.5; p < 0.030), but not in NHT (0.4 ± 0.4 % vs. 0.2 ± 0.3; NS) cells. The magnitude of the TNF-α effect was similar for TPC-1 and BCPAP (∼40 % vs. baseline) cells. TPC-1 cells were characterized by a greater amount of CCR6 per cell as compared with BCPAP cells, both in basal conditions (148.3 ± 33.7 fluorescence intensity vs. 102.5 ± 22.1 p < 0.016) and after TNF-α stimulation (147.8 ± 46.3 fluorescence intensity vs. 95.3 ± 18.5; p < 0.025). Cell migration assays showed that TNF-α treatment significantly increased the rate of migrated cells in those cells in which it also increased the membrane expression of CCR6 (TPC-1 and BCPAP) as compared to basal condition (p < 0.05 for both TPC-1 and BCPAP cells). No effect was observed in NHT cells in which TNF-α stimulation had no effect in terms of CCR6 expression. We first report that TNF-α enhances the expression of CCR6 in thyroid tumor cells, thus providing evidence that TNF-α increases the metastatic potential of thyroid tumors.

Thyroid cancer is the most common endocrine malignancy and the incidence is rising. Currently, there are no effective treatments for patients with advanced forms of thyroid cancer. Anaplastic thyroid represents the most severe form of the disease with 95% mortality at 6 months. It is therefore critical to better understand the mechanisms involved in thyroid cancer development and progression in order to develop more effective therapeutic strategies. Cell lines derived from thyroid tumors represent a critical tool to understand the oncogenic mechanisms driving thyroid cancer, as well as preclinical tools to study the efficacy of new therapies in vitro and in vivo. For thyroid cancer, the development of new therapies has been hampered by the lack of thyroid cancer cell lines in the widely used NCI-60 panel which has been used to screen over 100,000 anti-cancer drugs. In addition, the recent discovery that ~20 out of 40 existing thyroid cancer cell lines are either redundant or misidentified with cell lines of other tissue lineages has further hampered progress in the field. Of the available cell lines, 23 were identified as unique and presumably of thyroid origin based on the expression of thyroid-specific genes. Thus, there is a great need for validated thyroid cancer cell lines representing different stages of disease in addition to distinct oncogenic mutations. New, authenticated thyroid cancer cell lines are beginning to be developed, adding to the tools available to study genes and pathways important for thyroid cancer pathogenesis. In summary, the use of validated thyroid cancer cell lines that closely recapitulate disease is critical for the discovery of new drug targets and ultimately new therapies.