Hypothyroidism in Pancreatic Cancer: Role of Exogenous Thyroid Hormone in Tumor Invasion—Preliminary Observations

Abstract

According to the epidemiological studies, about 4.4% of American general elderly population has a pronounced hypothyroidism and relies on thyroid hormone supplements daily. The prevalence of hypothyroidism in our patients with pancreatic cancer was much higher, 14.1%. A retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (Whipple procedure) or distal pancreatectomy and splenectomy (DPS) at Thomas Jefferson University Hospital, Philadelphia, from 2005 to 2012. The diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. To further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, MiaPaCa-2 and AsPC-1. We found that hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion, and about twice as likely to have higher T stage, nodal spread, and overall poorer prognostic stage (P < 0.05). Pancreatic cancer cell line studies demonstrated that exogenous thyroid hormone treatment increased cell proliferation, migration, and invasion (P < 0.05). We conclude that exogenous thyroid hormone may contribute to the progression of pancreatic cancer.

Thyroid Hormones and Cancer: A Comprehensive Review of Preclinical and Clinical Studies

“…Furthermore, T3 attenuated the activity of cyclin-CDK complexes, which resulted in reduced pRb phosphorylation and G1 cell cycle arrest. In contrast, the proliferation, migration, and invasion of pancreatic cancer cells was stimulated by T3 in vitro (62). These results fit observations of patients in which hypothyroidism treated with TH supplementation correlated with increased risk of tumor progression and poor prognosis (62).…”

“…In contrast, the proliferation, migration, and invasion of pancreatic cancer cells was stimulated by T3 in vitro (62). These results fit observations of patients in which hypothyroidism treated with TH supplementation correlated with increased risk of tumor progression and poor prognosis (62). Thyroid hormones were shown to potentiate cytotoxic effects of chemotherapeutics in pancreatic cancer cells (63).…”

The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology

“…When a specific blocker for α V β 3 is used, reduced PANC-1 tumor mass in a mouse xenograft model, increased proapoptotic BcLx-s expression, reduced tumor hemoglobin content (a marker of angiogenesis), and decreased expression of epidermal growth factor receptor (EGFR) could be observed [ 113 ]. A recent study [ 114 ] showed that although the prevalence of hypothyroidism in patients with pancreatic cancer was 14.1%, exogenous thyroid hormone treatment in pancreatic cancer cell lines also significantly increased cell proliferation, migration, and invasion, suggesting that exogenous thyroid hormone may contribute to the progression of pancreatic cancer. On the other hand, the tumor-suppressive and antiangiogenic effects of THs were also reported.…”

Incorporating multiple sets of eQTL weights into gene‐by‐environment interaction analysis identifies novel susceptibility loci for pancreatic cancer

“…Among the top five genes identified from the interaction tests (Table 4), Lysine‐specific demethylase 3A ( KDM3A ) had a p < .01 in the replication data set. The only set of weights available for KDM3A was derived from the thyroid, a tissue found to be relevant with pancreatic cancer (Gullo et al, 1991; Sarosiek et al, 2016). This gene would be missed by using the aGE test ( p > .05).…”