Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Abstract

The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

Notch signalling pathway in development of cholangiocarcinoma

“…Hence, together these all data suggest that RBPJ is a key component of Notch signalling pathway in CCA. It is of worth considering that Notch 1 exhibits its cancerous activity in assistance with its transcription factor, Sox-9, which is a well-established Notch target gene which is involved in biliary specification of hepatic progenitor cells[ 69 , 71 ]. Also, the continuous up-regulation in expression of Sox-9 correlates with the transformation of precancerous lesions in full-fledged CCA[ 71 , 72 ].…”

“…It is of worth considering that Notch 1 exhibits its cancerous activity in assistance with its transcription factor, Sox-9, which is a well-established Notch target gene which is involved in biliary specification of hepatic progenitor cells[ 69 , 71 ]. Also, the continuous up-regulation in expression of Sox-9 correlates with the transformation of precancerous lesions in full-fledged CCA[ 71 , 72 ]. Hes1: Hes1 (Hairy and enhancer of split-1) is a basic helix-loop-helix transcription factor, which is one of the key regulators of organogenesis and target genes of the Notch signalling cascade, is involved in the development of IH-CCA.…”

Circ_HIPK3 Knockdown Inhibits Cell Proliferation, Migration and Invasion of Cholangiocarcinoma Partly via Mediating the miR-148a-3p/ULK1 Pathway

“… 5 The main obstacles to CCA treatment are the firmness and early invasion of the tumor. 6 Unfortunately, even with surgical treatment, the recurrence rate of CCA is high (49–64%), and the 5-year survival rate of patients after resection is less than 45%. 6 The risk factors and molecular pathogenesis of CCA need to be further explored in order to identify markers conducive to early diagnosis and targeted therapy to improve patient survival.…”

The Advancement of Long Non-Coding RNAs in Cholangiocarcinoma Development

“…Cholestasis and inflammation are key pathological factors in CCA [10]. Some oncogenes such as TP53, KRAS, FGFR2, IDH1, IDH2 are proved to be associated with CCA [11]. ECC usually leads to bile duct obstructive symptoms including painless jaundice and acute cholangitis while ICC develops as intrahepatic mass with non-specific symptoms such as abdominal pain or cachexy [12,13].…”