Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

Abstract

Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.

Keywords: Colorectal cancer; Metastatic cascade; Liver metastasis; Liver sinusoids; Neovascularization

Core tip: The multi-step process of colorectal hepatic metastases includes numerous molecular pathways and cellular interactions with potential clinical interest. Mutations at the initial site of colorectal carcinogenesis, such as p53 and APC, neoplastic cell interrelationship with the stromal macrophages, neoangiogenesis through growth factors, such as the vascular endothelial growth factor and platelet-derived growth factor, the role of hepatic sinusoidal cells, such as Kupffer cells, the expression of adhesion molecules, including the selectins and the integrins, are all crucial stages/events within the metastatic process. The exploration and analysis of recent research data may contribute to a better understanding of their clinical significance and may lead to new therapeutic strategies.