Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?

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Cholangiocarcinoma (CC) is a rare, malignant neoplasm that can develop from any site within the intrahepatic or extrahepatic biliary tree. Although the key steps of cholangiocarcinogenesis remain unknown, it has been hypothesized that CC may develop through two key premalignant precursor lesions: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). These lesions probably are analogous to pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm, respectively. This article outlines the molecular basis of cholangiocarcinogenesis through the BilIN and IPNB pathways. It highlights the genetic mutations that alter cellular proliferation, tumor suppression, and impairment of critical mucinous, cell-adhesion, and matrix proteins.

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Biliary intraepithelial neoplasia

BilIN is characterized by a flat or micropapillary growth of atypical biliary epithelium. It previously was called “atypical biliary epithelia” and “biliary dysplasia.” BilIN is characteristically a microscopic lesion that can progress to tubular adenocarcinoma. These premalignant lesions are classified commonly into three grades based on the degree of cellular and structural atypia: BilIN-1, BilIN-2, and BilIN-3.7, 8

BilIN typically is found in large intrahepatic biliary ducts and rarely is

Intraductal papillary neoplasm of the bile duct

IPNB is a macroscopic lesion characterized by prominent papillary growth of atypical biliary epithelium with a fibrovascular core and overproduction of mucin.9 IPNB, like BilIN, occurs in bile ducts associated with chronic inflammatory conditions such as hepatolithiasis or choledochocysts. IPNB can transform into two types of invasive cancers, each with different biologic behavior and prognosis: mucinous carcinoma or tubular adenocarcinoma.10 The histologic subtype of the invasive cancers

Cell-cycle proteins

Cyclin D1 is a proto-oncogene that is an important regulator of cell-cycle progression from the G1 to S phase. The cyclin D1 protein forms a complex with cyclin-dependent kinase-4 and -6 (CDK4 and CDK6) that allows cells to progress into S phase by phosphorylation and inactivation of the retinoblastoma protein.13 Cyclin D1 is overexpressed in many cancers, including intrahepatic CC, a consequence of gene amplification or defective regulation at the posttranscriptional level.14, 15, 16 Cyclin D1

Tumor suppressor genes

DPC4 (Smad4) is a tumor suppressor gene located on chromosome 18q and is a member of a highly conserved family of proteins involved in the transduction of signals from the transforming growth factor beta (TGF-β) family.21 DPC4 has been implicated in carcinogenesis through transmission of TGF-β epithelial growth inhibition signals.21 DPC4 mutations have been demonstrated in several reports of CC. Hahn and colleagues22 showed that 16% of resected biliary tract cancers had a mutation in the DPC4

Mucinous proteins

Mucin core proteins (MUC) are members of the mucin protein family that encode organ-specific glycoproteins produced by many epithelial tissues.33 MUC are anti-adhesion molecules that, when altered, may facilitate cancer cell invasion through the basement membranes.34, 35 These proteins disrupt the normal adhesive interactions between cellular integrins and the extracellular matrix.36, 37 Abnormal levels of sialylated MUC1 protein have been demonstrated in many adenocarcinomas, including

Cell-adhesion proteins

Alterations in normal cell-adhesion molecules may be an important determinant of cancer invasion and metastatic potential. E-cadherin is a tumor suppressor gene that produces a transmembrane protein involved in epithelial cell adhesion.41 The extracellular domain functions through calcium-dependent, homophilic interactions with the extracellular matrix. The intracellular portion is a catenin-like protein that transmits signals related to cell adhesion. Reduced expression of E-cadherin and/or

Matrix proteins

MMPs are critical proteins that metabolize extracellular matrix. Their physiologic activity is a complex dynamic between MMP activity, MMP inhibitors (ie, TIMP-1, TIMP-2), and the extracellular milieu (ie, electrolytes, stroma, and other chemical mediators). Overexpression of MMP may promote epithelial cancer invasion and metastasis. Several studies have demonstrated an increased expression of membrane-type metalloproteinase-1 (MT1)-MMP and MMP-7 in resected CC.47, 48 MT1-MMP degrades type 1

Summary

Two key premalignant lesions, BilIN and IPNB, have been implicated in the development of CC. These tumors share similarities with their pancreatic analogues, PanIN and IPMN. Each of these lesions follows different tumorigenic pathways with distinct genetic alterations (Table 1). Lesions of the BilIN and PanIN lineage develop a gradual progression of mutations in cyclin D1, p21, and p53 with greater loss of DPC4 and molecular cell adhesion expression. BilIN lesions have significantly higher

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