Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

Abstract

Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, ERα, ERβ and ERγ. ERα and ERβ appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma.

Female Sex Hormone Receptors in Gallbladder Cancer

“…2) [5,14,18,23]. Recent studies on role of estrogens in promoting abnormal cell proliferation, angiogensis, and the animal study implicating estrogens in gallbladder carcinogenesis lend further credence to this alternate theory [20,23].…”

“…Stones do not cause gallbladder stasis and altered lipid metabolism but are a consequence of the same. Important causes of both are female sex hormones [14,18,23]. Hence, it is possible that sex hormones could trigger off the carcinogenesis, as is suggested by recent animal studies [20], as well as the altered motility in gallbladder [14,18], with stone formation being merely coincidental, not causal.…”

MicroRNA-146b-5p inhibits the growth of gallbladder carcinoma by targeting epidermal growth factor receptor

“…At present, complete surgical resection is the only potentially curative treatment for GBC. However, few patients are eligible for this surgery due to the advanced stage at diagnosis (4). Although there have been significant advances in the management of GBC over the previous decade, the majority of treatments are palliative and aimed at improving quality of life through relief of pain and jaundice and by potentially prolonging survival time (5).…”

Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3‐kinase / ERK–MMP–laminin5γ2 signaling pathway

“…Before VM was reported, researchers attempted to use anti-angiogenesis as an alternative to frequently ineffective surgical resections and chemoradiotherapies, owing to the fact that glioma growth depends on abundant blood perfusion. 4 , 5 Research that involves targeting endothelial cells has been the basis for drug discovery and development. However, recent studies have found that anti-angiogenic therapy alone may not be effective; or worse, it may elicit greater malignancy.…”