Colorectal Cancer Metastases Settle in the Hepatic Microenvironment Through α5β1 Integrin

Abstract

Colorectal cancer (CRC) metastasis dissemination to secondary sites represents the critical point for the patient's survival. The microenvironment is crucial to cancer progression, influencing tumour cell behaviour by modulating the expression and activation of molecules such as integrins, the cell-extracellular matrix interacting proteins participating in different steps of the tumour metastatic process. In this work, we investigated the role of α5β1 integrin and how the microenvironment influences this adhesion molecule, in a model of colon cancer progression to the liver. The culture medium conditioned by the IHH hepatic cell line, and the extracellular matrix (ECM) proteins, modulate the activation of α5β1 integrin in the colon cancer cell line HCT-116, and drives FAK phosphorylation during the process of cell adhesion to fibronectin, one of the main components of liver ECM. In these conditions, α5β1 modulates the expression/activity of another integrin, α2β1, involved in the cell adhesion to collagen I. These results suggest that α5β1 integrin holds a leading role in HCT-116 colorectal cancer cells adhesion to the ECM through the modulation of the intracellular focal adhesion kinase FAK and the α2β1 integrin activity. The driving role of the tumour microenvironment on CRC dissemination, here detected, and described, strengthens and adds new value to the concept that α5β1 integrin can be an appropriate and relevant therapeutic target for the control of CRC metastases.

Focal adhesion kinase: predictor of tumour response and risk factor for recurrence after neoadjuvant chemoradiation in rectal cancer

“…Focal adhesion kinase is typically located at structures known as focal adhesions from where it transduces signals into cells that control multiple cancer-related events, including migration, invasion, angiogenesis, protection of cells from suspension-induced cell death and proliferation in three-dimensional matrices [30][31][32][33][34].…”

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

“…Expressed in the proliferative cells in the normal gut at the fetal stage but not in the adult, its resurgence in CRC cells both in primary tumours and in vitro is indicative of an oncofetal pattern of expression [10,11]. Two of the RGD-dependent integrins, α5β1 and αVβ6, appear to contribute to the metastatic process of CRCs [12,13]. Interestingly, the β6 subunit is expressed at very low levels in epithelia under normal conditions but is detected in both CRC primary tumours and metastasis where it acts through various mechanisms and systems to promote cancer progression [12].…”

MicroRNA-330-5p negatively regulates ITGA5 expression in human colorectal cancer

“…Integrin α5β1 recognizes the arginine-glycine-aspartic acid sequence in its ligand fibronectin, which is one of the proteins organizing the extracellular matrix. Recently, it was revealed that integrin α5β1 promotes metastasis of CRC cells in the hepatic microenvironment (18). Furthermore, ITGA5 was shown to regulate peritoneal dissemination of ovarian cancer cells and adhesion and invasion of CRC cells, thus affecting metastasis (19)(20)(21)(22).…”