Inflammation and Progression of Cholangiocarcinoma: Role of Angiogenic and Lymphangiogenic Mechanisms

Abstract

Cholangiocarcinoma (CCA), or cancer of the biliary epithelium is a relatively rare but aggressive form of biliary duct cancer which has a 5-year survival rate post metastasis of 2%. Although a number of risk factors are established for CCA growth and progression, a careful evaluation of the existing literature on CCA reveals that an inflammatory environment near the biliary tree is the most common causal link between the risk factors and the development of CCA. The fact that inflammation predisposes affected individuals to CCA is further bolstered by multiple observations where the presence and maintenance of an inflammatory microenvironment at the site of the primary tumor plays a significant role in the development and metastasis of CCA. In addition, mechanisms activating the tumor vasculature and enhancing angiogenesis and lymphangiogenesis significantly contribute to CCA aggressiveness and metastasis. This review aims to address the role of an inflammatory microenvironment-CCA crosstalk and will present the basic concepts, observations, and current perspectives from recent research studies in the field of tumor stroma of CCA.

The Tumor Microenvironment in Cholangiocarcinoma Progression

“…First, TAMs induce tumoral angiogenesis by secreting proangiogenic factors, such as VEGFs and angiopoietins. ( 34 ) Second, TAMs contribute to CCA cell proliferation by activating the Wnt/β‐catenin pathway upon release of Wnt3a and Wnt7b. ( 35,36 ) Third, TAMs can suppress antitumor functions of T cells and contribute to tumor growth through increased expression of hypoxia inducible factor‐1 (HIF‐1α), which is associated with increased metastases and poor survival rates in patients with CCA.…”

New insights on the role of vascular endothelial growth factor in biliary pathophysiology

“…• Sprouting lymphangiogenesi s (VEGFR3 expression and VEGF-C secretion) [141] • Fibrogenesis (VEGF-C and VEGF-D secretion) • tumor lymphangioge nesis in CCA (VEGFR2 and VEGFR3 expression) [141], [113] J o u r n a l P r e -p r o o f -no results reported NA [150] J o u r n a l P r e -p r o o f Design drug-repurposing studies for anti-angiogenic therapies in PLD.…”

Role of Chemokines in the Biology of Cholangiocarcinoma

“…Among the immune cell types infiltrating the desmoplastic stroma, TAMs play a crucial role in regulating angiogenesis, lymphangiogenesis, tumor proliferation and modulating ECM changes [ 1 ], through the release of inflammatory mediators [ 8 ].…”

“…CCA represents the second most frequent hepatic malignancy, accounting for 10–20% of all primary liver cancers [ 2 , 3 ] and its incidence is increasing dramatically [ 3 ]; accordingly, CCA mortality has increased worldwide in the last decades [ 4 , 5 , 6 , 7 , 8 ].…”