Abstract
Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment.
Highlights
Cholangiocarcinoma (CCA) is one of the most aggressive and lethal malignancies in humans
Intrinsic resistance to drug cytotoxicity is a key feature of normal cholangiocytes since they are equipped with a rich repertoire of defense enzymatic activities that protect them from toxic compounds present in bile and/or hepatic blood [9]
Our recent studies show that cultured human CCA cells treated with leukemia inhibitory factor (LIF) are protected from apoptosis induced by gemcitabine and cisplatin, an effect mediated by a STAT3- and mitogen-activated protein kinase (MAPK)-independent, phosphoinositide 3-kinase (PI3K)/Akt-dependent myeloid cell leukemia (Mcl)-1 upregulation
Summary
Cholangiocarcinoma (CCA) is one of the most aggressive and lethal malignancies in humans. CCA has been little studied, largely because of the lack of experimental models, limited availability of tissue samples and a lower priority for research funding compared with other more common malignant diseases [5]. This has led to persistent gaps in knowledge, in the field of therapy and treatment strategies. Liver transplantation is available only for carefully-selected cases in just a few, highly-specialized liver centers [6,7] Both surgical procedures are further complicated by high rates of recurrence [6,7] and the likely advanced stage of malignant disease at diagnosis. We attempt to apply reviewed data (based on a systematic literature search) to suggest how the avoidance of normal apoptotic mechanisms in cancer cells may cause chemoresistance in CCA
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