Targeting Angiogenesis in Biliary Tract Cancers: An Open Option

Abstract

Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.

Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma

“…20 Management of early stage and locally advanced BTCs includes surgery and chemo-radiotherapy while systemic chemotherapy is the main treatment of metastatic disease. 21 As concerns the second-line systemic therapy following progression after first-line treatment, no established protocol has been determined although fluoropyrimidine-based therapy (either in monotherapy or in combination with other cytotoxics) is sometimes used. 22 Moreover, experimental targeted therapies for the advanced stages are also considered as primary treatment options.…”

Application of Laparoscopic Radical Resection for Type III and IV Hilar Cholangiocarcinoma Treatment

“…Bleeding should be treated carefully in the period of operation. However, these tumors are often greywhite scirrhous masses with a poor vascularization, unlike hepatocarcinoma [15]. If the portal vein is affected, portal vein resection and reconstruction are required.…”

Role of the Angiogenic Factors in Cholangiocarcinoma

“…The pathogenesis of CCA is closely linked to the formation of a new vascular network that provides more oxygen and nutrients, thus influencing cell survival, tumor growth, and the development of metastasis [67][68][69]. It involves different mechanisms, whose investigation could be important in the identification of novel potential therapeutic approaches.…”

“…This improper development of tumor blood vessels is linked to the abnormal levels of growth factors secreted by tumor and stromal cells, including vascular endothelial growth factor (VEGF), angiopoietins (Angs), platelet-derived growth factor (PDGF-B), and transforming growth factor (TGF-β). In addition, the production of VEGF-A and TGFβ cause the polarization of macrophage toward the pro-angiogenic phenotype M2 [69]. The anti-angiogenic therapies could correct the structural and functional defects of tumor blood vessels.…”