BACKGROUND:Cells adapt to hypoxia by transcriptional induction of genes that participate in regulation of angiogenesis, glucose metabolism and cell proliferation. The primary factors mediating cell response to low oxygen tension are hypoxia inducible factors (HIFs), oxygen-dependent transcription activators. The stability and activity of theα subunits of HIFs are controlled by hydroxylation reactions that require ascorbate as a cofactor. Therefore, deficiency of intracellular vitamin C could contribute to HIFs overactivation. In this study, we investigated whether vitamin C content of human thyroid lesions is associated with HIF-1α and HIF-2α protein levels.

METHODS:Expression of HIF-1α and HIF-2α as well as vitamin C content was analyzed in thyroid lesions and cultured thyroid carcinoma cell lines (FTC-133 and 8305c) treated with hypoxia-mimetic agent (cobalt chloride) and ascorbic acid. The expression of HIFs and hypoxia-induced glucose transporters were determined by Westernblots while quantitative real-time PCR (qRT-PCR) was performed to detect HIFs mRNA levels. Ascorbate and dehydroascorbate levels were measured by HPLC method.

RESULTS:We found an inverse correlation between vitamin C level and HIF-1α but not HIF-2α expression in thyroid lesions. These results agree with our in vitro study showing that vitamin C induced a dose - dependent decrease of HIF-1α but not HIF-2α protein level in thyroid cancer cells FTC-133 and 8305C. The decreased HIF-1α expression was correlated with reduced expression of hypoxia-related glucose transporter 1 (GLUT1) in thyroid cancer cells.

CONCLUSION:The results demonstrate that HIF-1α activation is associated with vitamin C content in thyroid lesions. Our study suggests that high tumor tissue ascorbate level could limit the expression of HIF-1α and its targets in thyroid lesions.

BACKGROUND:Anaplastic thyroid cancer is an aggressive and fatal malignancy. Many advanced cancers are characterized by glucose dependency, leading to oxidative stress and cellular proliferation. Therefore, we sought to determine if a low glucose environment (in vitro) or a ketogenic diet (in vivo) could inhibit anaplastic thyroid cancer tumor growth when combined with the antioxidant N-acetylcysteine.

METHODS:In vivo, nude mice were injected with the anaplastic thyroid cancer cell line 8505C (n = 6/group). Group 1 was fed a standard diet; Group 2 was fed a ketogenic diet; Group 3 was given standard diet with N-acetylcysteine (40 mM in the drinking water); and Group 4 was fed ketogenic diet with N-acetylcysteine. Tumor volumes, ketones, and glucose were measured. H&E stains and immunohistochemistry for Ki-67 and Caspase 3 were performed on the tumors. In vitro, 8505C cells were cultured in high glucose (25 mM), low glucose (3 mM), high glucose plus N-acetylcysteine (200 uM), or low glucose plus N-acetylcysteine for 96 hours. We performed CyQUANT proliferation (Thermo Fisher Scientific, Waltham, MA), Seahorse glycolytic stress (Agilent, Santa Clara, CA), and reactive oxidative stress assays.

RESULTS:Ketogenic diet plus N-acetylcysteine decreased in vivo tumor volume compared to standard diet (22.5 ± 12.4 mmvs 147± 54.4 mm, P<.05) and standard diet plus N-acetylcysteine (P<.05). Blood ketone levels were significantly higher for the mice in the ketogenic diet group compared to standard diet (1.74 mmol/L vs 0.38 mmol/L at week 5, P<.001). However, blood glucose levels were not significantly different between ketogenic diet and standard diet groups. Cells cultured in low glucose plus N-acetylcysteine had significantly reduced proliferation compared to high glucose (98.1± 5.0 relative fluorescence units vs 157.8 ± 2.1 relative fluorescence units, P<.001). Addition of N-acetylcysteine to low glucose lowered glycolysis function compared to high glucose (39.0± 2.2 mpH/min/cell vs 89.1 ± 13.2 mpH/min/cell, P<.001) and high glucose plus N-acetylcysteine (37.4± 2.5 mpH/min/cell vs 70.3 ± 3.3 mpH/min/cell, P<.001). Low glucose plus N-acetylcysteine decreased reactive oxidative stress compared to high glucose (119± 34.7 relative fluorescence units vs 277 ± 16.0 relative fluorescence units, P = .014).

CONCLUSION:The combination of a ketogenic diet or glucose restriction with the antioxidant- N-acetylcysteine significantly reduced tumor growth in vivo and in vitro. Further studies are warranted to explore these metabolic therapies in anaplastic thyroid cancer.

We present the case of a 74 year old patient suffering from primary Non Hodgkin's lymphoma of the thyroid and Sjogren's syndrome. A massively enlarging goitre, causing breathlessness in a female patient previously treated for autoimmune inflammation of the thyroid (Hashimoto's disease) and Sjogren's syndrome, indicated the need for a fine needle aspiration biopsy (FNA) of the thyroid gland. Non Hodgkin's lymphoma of the thyroid was diagnosed and chemotherapy was begun. After 10 months of cytostatic treatment clinical tests and imaging indicated complete local regression. However, two months after cessation of chemotherapy the patient suffered a relapse of the disease owing to infiltration of the central nervous system. During the course of palliative radiotherapy the patient died. The main purpose for presenting this case was to describe the problem of primary lymphoma of the thyroid in cases of autoimmune disease. As many years of immunisation may lead to carcinogenesis it is important to raise awareness among medical staff with regard to cases of chronic autoimmune disease. In cases of Hashimoto's autoimmune disease of the thyroid, monitoring of the anti-thyroid antibodies is indicated, at least annually, as an increase in the concentration of these antibodies over a period of at least seven years would suggest further development of autoimmune disease. If such conditions are accompanied by tumours of the thyroid, surgery should be considered. It is worth keeping in mind that the thyroid can be a site for extra-lymphatic lymphoma.

Well-differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy that has an excellent prognosis with a 5-year survival rate of about 98%. However, approximately 50% of the patients with DTC who present with distant metastases (advanced DTC) die from the disease within 5 years of initial diagnosis even after getting the appropriate therapy. Apart from recent advancements in chemotherapy agents, the potential role of metabolic interventions, including the use of metformin, ketogenic diet, and high-dose vitamin C in the management of advanced cancers have been investigated as a less toxic co-adjuvant therapies. The role of vitamin C has been of interest again after a preclinical mice study showed that high-dose vitamin C is selectively lethal to KRAS and BRAF mutant colorectal cancer cells by targeting the glutathione pathway. This raises the possibility of utilizing high-doses of vitamin C in the treatment of aDTC where KRAS and BRAF mutations are common. Similarly, alteration of cellular metabolism by low-carbohydrate ketogenic diets can be an important therapeutic strategy to selectively kill cancer cells that mainly survive on glycolysis. Among thepotential adjuvant therapies proposed in this paper, metformin is the only agent that has shown benefit in human model of aDTC, the others have shown benefit but in preclinical/animal studies only and need to be further evaluated in large clinical trials. In conclusion, in addition to concurrent chemotherapy options, these metabolic interventions may have a great potential as co-adjuvant therapy in the management of aDTC.

Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated by the endocannabinoid system (ECS), which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death. However, many studies investigated these effects using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical animal models and to examine the current standing of cannabinoids that are being tested in human cancer patients.

BACKGROUND: Protection from thyroid carcinoma due to certain dietary factors was suggested by several studies, but the findings were relatively inconsistent. The role of micronutrients has not yet been systematically analyzed. To investigate the relationship between micronutrient intake and thyroid carcinoma risk, the authors used data from a case-control study conducted in northern Italy between 1986 and 1992. METHODS: The study included 399 incident, histologically confirmed thyroid carcinoma cases and 617 controls admitted to the hospital for acute, nonneoplastic, nonhormone-related diseases. RESULTS: Retinol intake showed a direct association with thyroid carcinoma risk, with odds ratios (ORs) of 1.39 (95% confidence Interval [CI], 0.9-2.0) in the third quartile of consumption and 1.52 (95% CI, 1.0-2.3) in the highest quartile, whereas beta-carotene had an inverse relationship, with ORs of 0.63 (95% CI, 0.4-0.9) in the third quartile of consumption and 0.58 (95% CI, 0.4-0.9) in the highest quartile compared with the lowest quartile. Some protection was observed for measures of vitamin C intake (with an OR of 0.72) and vitamin E (with an OR of 0.67) for the highest quartile of consumption, although the estimates were not statistically significant, and were reduced after adjustment for beta-carotene intake. No clear pattern in risk appeared for vitamin D, lolate, calcium, thiamin, or riboflavin. The inverse relationship between beta-carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas. CONCLUSIONS: In this study, a significant inverse association between beta-carotene and thyroid carcinoma was observed, and some protection against thyroid carcinoma from vitamins C and E was also suggested.

Treatment of thyroid cancer has incurred much focus because of its high prevalency. As a new strategy treating thyroid cancer, hyperthermia takes several advantages compared with surgery or chemotherapy, including minimal invasion, low systematic toxicity and the ability to enhance the immunogenicity of cancer cells with the expression Hsp70 which serves as Toll-like receptors-4 (TLR-4 agonist). However, Hsp70 as a molecular chaperone can protect cells from heat induced apoptosis and therefore compromise the tumor killing effect of hyperthermia. In this study, to solve this problem, a combined hyperthermia therapy was employed to treat thyroid cancer. We prepared a probe with the tumor targeting agent AG to monitor thyroid tumor issue and generate heat to kill tumor cells in vivo. At the same time Quercetin (inhibitor of HSP70) and lipopolysaccharide (LPS) (agonist of TLR-4) were used for the combined hyperthermia therapy. The results showed that compared with free IR820, AG modification facilitated much enhanced cellular uptake and greatly pronounced tumor targeting ability. The combined therapy exhibited the most remarkable tumor inhibition compared with the single treatments both in vitro and in vivo. These findings verified that the new therapeutic combination could significantly improve the effect of hyperthermia and shed light on a novel clinical strategy in thyroid cancer treatment.