Cholangiocarcinoma pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
*[ | *In cholangiolar cells, proinflammatory [[cytokines]] such as [[TNF-α]] and [[IL-6]], stimulate the expression of inducible nitric oxide synthase (iNOS), enhancing NO production. Reactive oxygen species, together with NO interact with DNA and inhibit DNA repair mechanisms. The result is the promotion of mutagenesis. | ||
* | *In addition, NO and several cytokines can inhibit cholangiocyte [[apoptosis]], both directly, by the nitrosylation of caspase, and indirectly, through the stimulation of [[Cyclooxygenase|cyclooxygenase 2]] (COX-2), the rate-limiting enzyme in [[prostaglandin]] biosynthesis. Via prostaglandin E2 production, this enzyme is able to inhibit [[apoptosis]] and activate the cell cycle. | ||
*COX-2 can be activated by members of the [[EGFR]] (epidermal growth factor receptor) family, in particular the tyrosine kinase ErbB-2 ([[HER2/neu]]). This is overexpressed in a moderate proportion of cholangiocarcinomas, mostly of the extrahepatic cholangiocarcinoma type, as well as in animal models of cholangiocarcinogenesis. Moreover, a high [[ErbB-2]] expression has also been associated with increased invasiveness, proliferation, and mobility of cholangiocarcinoma cells. | |||
*Previous ‘‘in vitro’’ studies have suggested an indirect mutagenic ability of most hydrophobic bile acids, such as deoxycholic acid, which may favor cholangiocarcinogenesis. It has been reported that this effect could be due to EGFR pathway-dependent upregulation of COX-2. However, some studies have shown that bile acids do not induce direct damage in [[DNA]] but act as promoters, stimulating cholangiolar cells proliferation, probably via the activation of growth factors, such as EGFR. | |||
*Furthermore, it should be noted that the membrane receptor TGR5, which responds to bile acids, is overexpressed in cholangiocarcinoma and confers resistance to apoptosis. | |||
*In contrast, the nuclear receptor FXR, which also behaves as a bile acid sensor, seems to play a role in the protection against the development of cholangiocarcinoma. | |||
*The expression of the [[VEGF|vascular endothelial growth factor-C]] (VEGF-C), an important lymphangiogenetic factor, has been found elevated in approximately 50% of cholangiocarcinoma analysed. Interestingly, VEGF-C upregulation was associated with a worse prognosis in patients with intrahepatic cholangiocarcinoma. The activation of VEGF receptor (VEGFR) stimulates the proliferation and migration of [[endothelial cells]], and these effects are enhanced by estrogens, through the induction of the expression of VEGFR. | |||
In experimental models of chemically induced cholangiocarcinoma in rats a significant increase in the expression of [[IL-6]] has been found in tumor cells. Moreover, IL-6 has also been found to be elevated in the serum of patients with cholangiocarcinoma. This cytokine is known to play a key role in cholangiocyte malignization. First, IL-6 favors the ability of these cells to elude apoptosis by upregulation of the antiapoptotic protein Mcl-1 (myeloid cell leukemia-1) through the [[STAT|STAT3]] and [[AKT]] signaling pathways. Second, IL-6 activates mitogen-activated protein kinase p38, which promotes cell proliferation and stimulates telomerase activity. It reduces senescence in malignized cholangiocytes. | |||
==Associated Conditions== | ==Associated Conditions== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]
Overview
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Pathogenesis
- The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma.[1]
- Malignant transformation of cholangiocytes into cholangiocarcinoma include following stages:[2]
- Hyperplasia
- Metaplasia
- Dysplasia
- Frank carcinoma
- Progression of malignancy is believed to be due to:[2][3][4]
- Inflammation
- Obstruction of bile ducts
- Biliary intraepithelia neoplasia
- Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts.
Genetics
- In cholangiolar cells, proinflammatory cytokines such as TNF-α and IL-6, stimulate the expression of inducible nitric oxide synthase (iNOS), enhancing NO production. Reactive oxygen species, together with NO interact with DNA and inhibit DNA repair mechanisms. The result is the promotion of mutagenesis.
- In addition, NO and several cytokines can inhibit cholangiocyte apoptosis, both directly, by the nitrosylation of caspase, and indirectly, through the stimulation of cyclooxygenase 2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis. Via prostaglandin E2 production, this enzyme is able to inhibit apoptosis and activate the cell cycle.
- COX-2 can be activated by members of the EGFR (epidermal growth factor receptor) family, in particular the tyrosine kinase ErbB-2 (HER2/neu). This is overexpressed in a moderate proportion of cholangiocarcinomas, mostly of the extrahepatic cholangiocarcinoma type, as well as in animal models of cholangiocarcinogenesis. Moreover, a high ErbB-2 expression has also been associated with increased invasiveness, proliferation, and mobility of cholangiocarcinoma cells.
- Previous ‘‘in vitro’’ studies have suggested an indirect mutagenic ability of most hydrophobic bile acids, such as deoxycholic acid, which may favor cholangiocarcinogenesis. It has been reported that this effect could be due to EGFR pathway-dependent upregulation of COX-2. However, some studies have shown that bile acids do not induce direct damage in DNA but act as promoters, stimulating cholangiolar cells proliferation, probably via the activation of growth factors, such as EGFR.
- Furthermore, it should be noted that the membrane receptor TGR5, which responds to bile acids, is overexpressed in cholangiocarcinoma and confers resistance to apoptosis.
- In contrast, the nuclear receptor FXR, which also behaves as a bile acid sensor, seems to play a role in the protection against the development of cholangiocarcinoma.
- The expression of the vascular endothelial growth factor-C (VEGF-C), an important lymphangiogenetic factor, has been found elevated in approximately 50% of cholangiocarcinoma analysed. Interestingly, VEGF-C upregulation was associated with a worse prognosis in patients with intrahepatic cholangiocarcinoma. The activation of VEGF receptor (VEGFR) stimulates the proliferation and migration of endothelial cells, and these effects are enhanced by estrogens, through the induction of the expression of VEGFR.
In experimental models of chemically induced cholangiocarcinoma in rats a significant increase in the expression of IL-6 has been found in tumor cells. Moreover, IL-6 has also been found to be elevated in the serum of patients with cholangiocarcinoma. This cytokine is known to play a key role in cholangiocyte malignization. First, IL-6 favors the ability of these cells to elude apoptosis by upregulation of the antiapoptotic protein Mcl-1 (myeloid cell leukemia-1) through the STAT3 and AKT signaling pathways. Second, IL-6 activates mitogen-activated protein kinase p38, which promotes cell proliferation and stimulates telomerase activity. It reduces senescence in malignized cholangiocytes.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Fava, G.; Lorenzini, I. (2012). "Molecular Pathogenesis of Cholangiocarcinoma". International Journal of Hepatology. 2012: 1–7. doi:10.1155/2012/630543. ISSN 2090-3448.
- ↑ 2.0 2.1 Sirica A (2005). "Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy". Hepatology. 41 (1): 5–15. PMID 15690474.
- ↑ Holzinger F, Z'graggen K, Büchler M. "Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma". Ann Oncol. 10 Suppl 4: 122–6. PMID 10436802.
- ↑ Gores G (2003). "Cholangiocarcinoma: current concepts and insights". Hepatology. 37 (5): 961–9. PMID 12717374.