Currently, obesity affects one third of population among US adults [42], and China has become a big country of obesity and the incidence of obesity in China ranked first worldwide in the year of 2014 [43]. Nowadays, lots of studies both clinical studies and experimental researches showed the closely relationship between malignancies (including colon, esophagus, kidney, liver, breast, endometrium, pancreas and prostate as well as non-Hodgkin's lymphoma and multiple myeloma) and obesity/overweight, even affect its occurrence, development and prognosis [44-46]. Because of the increasing incidence of thyroid carcinoma during the past decades, lots of scientists focus on study the risk factors of thyroid carcinoma. It was found that the incidence of thyroid carcinoma has increased along with a marked rising rate of obesity [4-6]. Furthermore, obesity is been the independent risk factor for thyroid carcinoma [47]. Increased insulin resistance, elevated serum cholesterol level and upregulated COX2 expression may be the target of the correlation between obesity and thyroid carcinoma [48]. Nevertheless, the mechanisms linking obesity with thyroid cancer have not yet been fully elaborated.
“Obesity problem” has attracted more since adipose tissues have been recognized as an endocrine organ. And it is thought to be the largest endocrine organ with complex functions [49]. Adipokines, refer to various enzymes, hormones, cytokines, growth factors, proteins and other biological active substances secreted by adipocytes, such as adiponectin, leptin, resistin and interleukin. The concentration of these adipokines, such as TNF-α, IL-6 and leptin, were significantly higher in obese subjects and the elevated levels have been linked to obesity, and even positively correlated with body mass index [50-54]. It is reported that adipokines take part in insulin sensitivity, inflammation and proliferation [55-56], and the later have been recognized as an important factor that results in the tumorigenesis and developing. So adipokines may be one of the targets linking obesity with thyroid cancer.
TNF-α
TNF-α, produced by adipose tissue and inflammatory cells, can lead to inflammatory response, necrocytosis, and assist other cytokines to kill tumor cells, and improve the anti-tumor ability. Meanwhile, TNF-α plays an important role in the process of inflammation, insulin resistance, diabetes and obesity. A moderate amount of TNF-α has a protective effect, while an excessive amount will cause damage, which may lead to a resistant of tumor cells to TNF-associated apoptosis-induced ligands when the microenvironment of apoptosis is maladjusted. TNF-α has the ability to promote the production of granulocyte-colony stimulating factor by thyroid fibroblasts [57], which may play an important role in thyroid cancer. TNF-α can stimulate the vasoactive mediators such as interleukin and prostaglandin [58], and these mediators can promote the proliferation of tumor cells and significantly reduce the immune function. TNF-α can also induce an increased expression of vascular endothelial growth factor (VEGF) [59], the later can promote the proliferation of tumor cells and provide conditions for tumors metastasis.
In conclusion, urprisingly, the results of clinical studies provide evidence for basic research. Simonovic SZ et al. [34] evaluated cytokine profiles (determined in supernatants obtained from whole blood cultures) in 13 patients with DTC before and 7 days after radioactive iodine (131-I) therapy and 13 control subjects, and found that the expression of TNF-α in DTC patients is higher than control subjects, and it showed a decreased level after 131-I therapy than those before therapy. However, no statistical difference found for the limited sample size. Another study conducted by Kobawala TP et al. [39], with more patients (67 patients with benign thyroid disease, 83 PTC patients and 67 healthy individuals), determined the circulating levels of TNF-α, and it was found that the serum level of TNF-α was significantly higher in PTC patients than benign thyroid disease patients, and the later was also significantly higher than healthy individuals. Furthermore, serum TNF-α was reported to be a significant prognosticator for overall survival in PTC patients. What a pity, opposite result was reported in a case-control study that included 475 DTC cases and 1016 matched cancer-free cohort participants, and found that TNF-a was not associated with thyroid risk in either gender [60].
Although clinical studies showed a difference, based on current evidence, we can still supposed that TNF-α may be involved in the tumorigenesis and development of thyroid cancer, and its monitoring may indirectly reflect the severity and prognosis of disease. What’s more, more clincal studies and basic reseaches should be conducted in the future.
IL-6
IL-6, a multifunctional cytokine, plays important roles in different types of cells including tumor cells. It is reported that elevated serum IL-6 level is closely related to the tumorigenesis and development of a variety of tumors [61]. A strong positive association between the serum IL-6 and the progression and poor prognosis of tumors in patients with several types of tumor was already found [62–64]. Serum IL-6 level in thyroid cancer has been evaluated in numerous studies including in vivo and in vitro studies. Provatopoulou X et al. [35] found that serum IL-6 were significantly higher in malignant and benign thyroid diseases compared to healthy controls. However, other studies show a different result that no significance different of IL-6 was found between thyroid cancer and non-thyroid cancer [16, 23, 35-36, 41]. A limited sample size, different inclusion criterias, different population characteristics, or different pathological type of thyroid cancer may explain such a difference. For in vitro research, IL-6 was also found to be expressed in thyroid cancer cell lines and a potential role of IL-6 in PTC was confirmed indirectly [65].
The mechanism may be the followings below. Tumor cells including esophageal cancer, lung cancer, colorectal cancer and melanoma were found have the function of autocrine IL-6, which can affect the growth and proliferation of tumor cells and participate in the tumor growth and metastasis by acting on the membrane receptors on the cell surface [66]. Also, IL-6R was found associated with the characterization of thyroid nodules’ malignancy and tumor aggressiveness [41]. In addition, Iliopoulos D et al. [67] found that Src (non-somatic tyrosine kinase family oncogene) can induce the normal epithelial cell transformation by activating NF-kB, and this transformation take part in tumorigenesis. IL-6 plays an important regulatory role in this process.
Totally, the data above support that IL-6 is critical for thyroid cancer, but the detail mechanism remain to be further study.
Leptin
Leptin, a circulating hormone secreted by adipocytes, exerts its biological effect by combing with its receptor, which is mainly present in the hypothalamus. Meanwhile, gene of leptin receptor is also expressed in many other tissues, such as lung, liver and kidney. It is reported that obesity and overweight can lead to a high level of serum leptin, it may because that obesity always accompany with insulin resistance and hyperinsulinemia, and insulin enhance the expression of leptin. Moreover, leptin acts as a growth factor in a variety of human cells, including both normal cells and tumor cells, by stimulating leptin mediates JAK/STAT3 pathway, RhoA/LIMK1/Cofilin pathway, and MAPK/ERK pathway, acting on the process of differentiation, proliferation and apoptosis thus stimulate the tumorigenesis and development of tumors [68]. Kim WG et al. [69] evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (Thrb (PV/PV) Pten (+/-) mice) and found that obesity increases the frequency of anaplasia of thyroid cancer and exacerbates thyroid cancer progression that were mediated by increased activation of the JAK2 signaling transducer and activator of STAT3 signaling pathway and induction of STAT3 target gene expression. Leptin is always reported a high expression on solid tumors [70], and it is confirmed that serum leptin level is significantly increased in thyroid cancer (mainly PTC), while other studies showed a same results in cancer tissues [11, 15, 21, 33, 37]. Yu Xiao et al. [21] conducted a clinical study comparing the level of serum leptin in 58 PTC patients (including 29 patients with lymph node metastasis) and 26 thyroid adenoma patients in Dalian, China, and found that patients with lymph node metastasis have a higher level of leptin than those without lymph node metastasis. Leptin can induce the expression of vascular endothelial growth factor and promote neovascularization in tumor tissue [71]. In addition, it can also inhibit the apoptosis through Bcl-2 dependent mechanism. Meanwhile, leptin receptor presents in all thyroid cancer cells. It is overexpressed in PTC and is involved in tumor invasion and lymph node metastasis [72-73]. Thus, it is concluded that leptin may be involved in the tumorigenesis and metastasis of thyroid cancer through a complex pathway and a monitoring may have some significance.
Adiponectin
Compared to lean women, overweight/obese women had lower serum adiponectin levels and this difference has statistical significance [74]. In addition, adiponectin is negatively associated with a variety of benign and malignant tumors, especially those associated with obesity and insulin resistance, such as leukemia [75], renal carcinoma [76], gastric carcinoma [77] and colon cancer [78]. What’s more, the association of Adiponectin with potential tumor-limiting functions has been widely proposed [79].
Otvos L Jr et al. [80] tried in vitro experiments and proved that adiponectin can inhibit the metastasis of cancer cells. Mitsiades N et al. [81] measured circulating adiponectin levels in ptaients with PTC and found that it is independently and inversely associated with the risk of thyroid cancer. As the receptor that binds to adiponectin for biological effects, adiponectin receptor had been reported closely correlated with the development of PTC. Adiponectin receptor-1 and -2 are higher expression in PTC tissues than that in the surrounding normal tissues and this is thought to be associated with a better prognosis [82].
However, other studies have shown different results [13,27] and more studies should be done furtherly to support the anti-tumor effect of adiponectin, and increase the level of adiponectin in circulating blood may improve the prognosis of thyroid neoplasms and provide new ideas for the prevention and treatment of thyroid neoplasms.
From the above, we can conclude that adipokines play an important role in the tumorigenesis and development of thyroid cancer, especially TNF-α, IL-6 and leptin. And this may explain why increased incidence of obesity and thyroid cancer are consistent. So, weight loss or adipokine intervention, and even research and application of targeted drugs may be useful for thyroid cancer prevention and treatment in the future.
However, some limitations in our meta-analysis should be taken into account. First, some data were not normally distributed and were reported in the form of median and quartile, and therefore these data were calculated by formulas. Second, due to the insufficient database access, six articles are not available in full, and therefore could not be included in this meta-analysis. Third, all the included studies were cross-sectional case-control study and the dynamic changes of these adipokines in preoperative and postoperative were not provided. All these limitations above should be improved in the future study, thus a strong conclusion could be get.
In summary, our meta-analysis suggests that adipokines, including TNF-α, IL-6 and leptin are associated with thyroid carcinoma. Nevertheless, it is not conclusive for adiponectin due to the limited number of the clinical studies. Therefore, larger sample sizes of different ethnic population are required to confirm and update our findings.