Expression of COX-2 and VEGF-C in cholangiocarcinomas at different clinical and pathological stages

You, Zhen; Bei, Lanxin; Cheng, Lei; Cheng, Nan‐Sheng

doi:10.4238/2015.june.9.9

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…Cyclo-Oxygenase-2 (COX-2) is an inflammatory mediator that increases prostaglandin production and is known to be raised in tissue samples of PSC and cholangiocarcinoma [99, 111]. High COX-2 levels can stimulate growth in cholangiocarcinoma, and COX-2 inhibitors can induce apoptosis and inhibit proliferation by decreasing Akt pathway stimulation and activating p21 and other cyclin-dependent kinase inhibitors [112, 113].…”

Section: Pathogenesismentioning

confidence: 99%

Molecular Pathogenesis of Cholangiocarcinoma

2019

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Background Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. Risk Factors for cholangiocarcinogenesis Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. Molecular pathogenesis of cholangiocarcinoma Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. Conclusion Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.

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Section: Pathogenesismentioning

confidence: 99%

Molecular Pathogenesis of Cholangiocarcinoma

2019

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“…Studies also show that COX-2 is related to angiogenesis. COX-2 is highly expressed in CCA tissues, especially advanced CCA (52). COX-2 inhibitors have been approved for adjuvant treatment of CCA, but in vitro experiments show that they have no inhibitory effect on the growth of tumor cells.…”

Section: Vegf/vegfr Signaling Pathwaymentioning

confidence: 99%

“…COX-2 inhibitors have been approved for adjuvant treatment of CCA, but in vitro experiments show that they have no inhibitory effect on the growth of tumor cells. COX-2 inhibitors can inhibit the expression and secretion of VEGF-C, thereby affecting the invasion of cholangiocarcinoma (52). MiR-101 can also inhibit COX-2 or directly target the 3' untranslated region of VEGF mRNA to inhibit VEGF transcription (53).…”

Section: Vegf/vegfr Signaling Pathwaymentioning

confidence: 99%

Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer

Wang

Chen

et al. 2021

Front. Oncol.

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Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.

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“…Yoshikawa et al analyzed the VEGF levels in both intrahepatic and extrahepatic CCA, demonstrating that their expression is higher in both tumors compared to the control and also proved that high VEGF levels clinically correlated with intrahepatic metastasis [87]. Most recently, other authors analyzed the expression of cyclooxygenase 2 (COX2) and VEGF-C in different stages of CCA to elucidate their clinical (based on tumor infiltration) and pathological (based on cell differentiation) involvement in this disease [91]. COX2 and VEGF-C result overexpressed in a late clinical and pathological stage of CCA indicating their contribution in tumor cell differentiation and in metastatic process [91].…”

Section: Vascular Endothelial Growth Factors (Vegfs) and Placental Grmentioning

confidence: 99%

“…Most recently, other authors analyzed the expression of cyclooxygenase 2 (COX2) and VEGF-C in different stages of CCA to elucidate their clinical (based on tumor infiltration) and pathological (based on cell differentiation) involvement in this disease [91]. COX2 and VEGF-C result overexpressed in a late clinical and pathological stage of CCA indicating their contribution in tumor cell differentiation and in metastatic process [91]. Benckert et al evaluated the expression of VEGF/VEGFR and their interaction with TGF-β/TGF-β receptor pathway on human CCAs after surgical resection and they found that these two growth factors are up-regulated and could thus be responsible for neoangiogenesis [85].…”

Section: Vascular Endothelial Growth Factors (Vegfs) and Placental Grmentioning

confidence: 99%

Role of the Angiogenic Factors in Cholangiocarcinoma

et al. 2019

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Angiogenesis plays a fundamental role in tumor growth and progression. It is regulated by several growth factors, including vascular endothelial growth factor protein family (VEGF) and its receptors, which are probably the most important factors responsible for the development of new vessels. The VEGF family includes several members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF), and their receptors VEGFR-1, VEGFR-2 and VEGFR-3. Other relevant factors are represented by angiopoietins, thrombospondin-1, and endothelins. However, since the therapeutic benefit associated with VEGF-targeted therapy is really complex, a better understanding of these pathways will lead to future advances in the use of these agents for clinic management of tumors. Here we present a review regarding the role of angiogenic factors in cholangiocarcinoma, which arise from cholangiocytes, the epithelial cells of bile ducts. They are rare and aggressive neoplasms with a poor prognosis and limited treatment options, classified as intrahepatic, perihilar, and distal cholangiocarcinoma based on their anatomical location. Therefore, the identification of specific signaling pathways or new tumor biomarkers is crucial in order to develop more effective anti-angiogenic therapies.

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Expression of COX-2 and VEGF-C in cholangiocarcinomas at different clinical and pathological stages

Cited by 7 publications

References 19 publications

Molecular Pathogenesis of Cholangiocarcinoma

Molecular Pathogenesis of Cholangiocarcinoma

Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer

Role of the Angiogenic Factors in Cholangiocarcinoma

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