Obesity and thyroid cancer: is leptin the (only) link?

Thyroid cancer is the most common endocrine malignancy and ranks as the fifth most common cancer diagnosed in women. In the past 4 decades, the incidence of thyroid cancer has maintained a steady upward trend, and 60 000 new cases are expected in 2013 (1). This rise cannot be explained only by the increased detection of small tumors thanks to the use of neck ultrasounds and ultrasound-guided fine needle aspiration biopsies, because the upward trend started well before these screening practices became so common, and also because there is an increase in the prevalence of larger tumors. The notion that in the same timeframe the prevalence of obesity has increased in parallel to that of thyroid cancer has led to several studies testing the hypothesis that the two might be causally linked. However, although obesity has been positively associated with a growing number of tumor types (reviewed in Refs. 2–5), its connection with thyroid cancer has not been firmly established. Several large-scale prospective studies suggest that there is a positive association between body mass index and thyroid cancer risk, especially in women (6–8). However, another study failed to establish a relationship between obesity and more aggressive histological features of thyroid cancer (9). The article by Kim and colleagues (10) in this issue of Endocrinology addresses in vivo, in a relevant mouse model, the link between obesity and thyroid cancer development. By comparing the incidence and biological behavior of follicular thyroid tumors in Thrb,Pten / mice fed regular chow or a high-fat diet (HFD), the authors establish a direct role of diet-induced obesity in increasing the aggressiveness of these tumors, as measured by tumor size, proliferative index, and presence of foci of anaplasia. Notably, they found no differences in the overall prevalence of hyperplasia and capsular invasion. This would suggest that obesity impacts the biological behavior of already established thyroid lesions, rather than their initiation rate (ie, risk). However, it must be noted that the prevalence of hyperplasia and invasion are already close to 100% in the control group, thus precluding any further increase. Future studies should be designed to analyze the prevalence at earlier time points to assess the rate of tumor initiation. From a mechanistic point of view, the authors provide evidence of increased serum levels of leptin and of activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) 3 cascade, one of leptin’s downstream effector pathways. Thus, for the first time, a direct link is shown between obesity-induced signals and thyroid cancer-promoting effectors. Earlier reports have associated increased STAT3 activation with anaplastic thyroid cancer, underlining the relevance of the findings presented in this paper. It is interesting, however, that STAT3 activation has recently been inversely associated with papillary thyroid cancer behavior, both in clinical specimens (11) and in mouse models (12). It is thus possible that the mechanisms proposed by Kim and colleagues (10) apply to a distinct subset of thyroid tumors, i.e., follicular carcinomas and their dedifferentiated derivatives. Additional studies in which HFD effects are studied in models of papillary thyroid cancer will address this issue. Although Kim and colleagues (10) emphasize in their mouse model the association between obesity, increased leptin levels, and activation of the JAK/STAT pathway, it is important to underline that there are a number of additional leptin-mediated pathways that might further contribute to the increased aggressiveness of thyroid tumors in