Abstract
The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the receptor tyrosine kinases (RTK) epidermal growth factor receptor (EGFR; also called ERBB1), ERBB2, ERBB3, and ERBB4. This family is closely associated with the progression of cholangiocarcinoma (CC) through the regulation of cellular networks, which are enhanced during tumorigenesis, metastasis, and chemoresistance. Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment. This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma. It also discusses the developments and applications of various devising strategies for targeting the ErBb family through different inhibitors in various stages of clinical trials, which are essential for improving targeted clinical therapies.
Highlights
Biliary tract cancers are highly lethal malignant tumors that include cholangiocarcinoma (CC) and gallbladder cancer (GBC)
epidermal growth factor (EGF)-mediated Protein tyrosine kinase 6 (PTK6) activation promotes the proliferation of CC cells through the formation of PTK6/epidermal growth factor receptor (EGFR) and PTK6/ERBB2 complexes, which in turn activate Src associated in mitosis of 68 kDa (SAM68); high levels of both PTK6 and EGFR expression are closely correlated with the upregulation of Ki67 as a prognostic marker of cancer [32]
It will be important to investigate how ERBB family members contribute to CC cancer progression in more detail to identify unpredicted functions of this protein family and to develop potential therapeutic strategies with other conventional therapeutic agents for expanding clinical trials
Summary
Biliary tract cancers are highly lethal malignant tumors that include cholangiocarcinoma (CC) and gallbladder cancer (GBC). EGF and its receptor EGFR are highly upregulated in 59.5% (22/37), and 32.4 (12/37) of patients with ICC, and these expressions showed no correlation with metastases of ICC. Another report revealed that EGFR is highly expressed in 44.7% (17/38) of ICC patients, and its upregulation is closely correlated with poor differentiation, lymph node metastasis, and aberrant p53 expression [10]. EGF-mediated PTK6 activation promotes the proliferation of CC cells through the formation of PTK6/EGFR and PTK6/ERBB2 complexes, which in turn activate Src associated in mitosis of 68 kDa (SAM68); high levels of both PTK6 and EGFR expression are closely correlated with the upregulation of Ki67 as a prognostic marker of cancer [32]. The upregulation of c-Met is closely correlated with the overexpression of EGFR and reduced survival in patients with ICC or ECC [39]. ERBB2-induced gene expression profiles as determined by microarray analysis included cytokeratin 20 (Krt20), Sry-related HMG box gene-17 (Sox17), amphiregulin (Areg), MUC1, and sphingosine kinase 1 (Sphk1) among the genes strongly correlated with tumor growth and metastases of CC cells [42]
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