A complex of α₆ integrin and E‐cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin‐like 6

Abstract

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α6 integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α6 integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α6 integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.

Phosphatase of regenerating liver: a novel target for cancer therapy

“…It has been shown that PRL can interact with integrin proteins (71,72,73,74,75) (Figure 2). When up-regulated, PRL can dephosphorylate integrin β, enhancing integrin β binding with Src kinases (which, in turn, decreases the coupling of integrins to actin and impairs integrin-mediated adhesion) (73, 74, 75).…”

“…When up-regulated, PRL can dephosphorylate integrin β, enhancing integrin β binding with Src kinases (which, in turn, decreases the coupling of integrins to actin and impairs integrin-mediated adhesion) (73, 74, 75). Furthermore, PRL overexpression has been shown to suppress integrin α (but not integrin β) expression levels (71,72,73,74). The down-regulation of integrin α by PRL-3 is hypothesized to be carried out via inhibition of c-fos and that integrin α binding to PRL can inhibit its interaction with the β subunit (71,72,73,74).…”

“…Furthermore, PRL overexpression has been shown to suppress integrin α (but not integrin β) expression levels (71,72,73,74). The down-regulation of integrin α by PRL-3 is hypothesized to be carried out via inhibition of c-fos and that integrin α binding to PRL can inhibit its interaction with the β subunit (71,72,73,74). E-cadherin, γ-catenin, and vinculin are also down-regulated with PRL-3 over-expression, while mesenchymal markers fibronectin and Snail are up-regulated (70).…”

The Neuronal Pentraxin-2 Pathway Is an Unrecognized Target in Human Neuroblastoma, Which Also Offers Prognostic Value in Patients

“…In addition, they provide data only on the tumor cells, without taking into account their microenvironment and tumor/normal tissue interactions, which play critical roles in tumorigenesis (13). Therefore, we have recently developed a multidisciplinary approach to investigate high-risk neuroblastoma in the context of its native protein architecture, and characterized a set of specific peptide ligand motifs for neuroblastoma-targeted drug delivery in vivo (14).…”

Cancer Cells with Stem Cell-Like Phenotypes and Liver Metastasis from Colon Carcinoma

“…However, the differential tropism from CRC to several target sites is still not well explained, including the mechanisms that drive hepatic homing. There have been a few studies performed on liver colonization by metastatic cells [17], on the modulation of pharmacological response by the liver microenvironment [18], and on the existence of peptide ligands specific for liver metastasis [19]. However, there have been no studies in this direction involving SCLCs.…”