The Matricellular Receptor LRP1 Forms an Interface for Signaling and Endocytosis in Modulation of the Extracellular Tumor Environment.

Bart Van Gool,Stéphane Dedieu,Hervé Emonard,Anton J M Roebroek

doi:10.3389/fphar.2015.00271

Abstract

The membrane protein low-density lipoprotein receptor related-protein 1 (LRP1) has been attributed a role in cancer. However, its presumably often indirect involvement is far from understood. LRP1 has both endocytic and signaling activities. As a matricellular receptor it is involved in regulation, mostly by clearing, of various extracellular matrix degrading enzymes including matrix metalloproteinases, serine proteases, protease inhibitor complexes, and the endoglycosidase heparanase. Furthermore, by binding extracellular ligands including growth factors and subsequent intracellular interaction with scaffolding and adaptor proteins it is involved in regulation of various signaling cascades. LRP1 expression levels are often downregulated in cancer and some studies consider low LRP1 levels a poor prognostic factor. On the contrary, upregulation in brain cancers has been noted and clinical trials explore the use of LRP1 as cargo receptor to deliver cytotoxic agents. This mini-review focuses on LRP1’s role in tumor growth and metastasis especially by modulation of the extracellular tumor environment. In relation to this role its diagnostic, prognostic and therapeutic potential will be discussed.

Highlights

The matricellular receptor low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a multifunctional receptor implicated in both endocytosis and signaling pathways (Lillis et al, 2008)
Several groups reported decreased lipoprotein receptor related-protein 1 (LRP1) expression (Figure 1C) levels in various cancer cell lines and tissues, assigning a tumor suppressive role to this receptor (Kancha et al, 1994; de Vries et al, 1996; Gilardoni et al, 2003). These findings provided a rationale for earlier studies in which decreased binding and uptake of α2-macroglobulin (α2M), an LRP1 ligand, were observed in multiple cancer cell lines (Van Leuven et al, 1979; Saksela et al, 1981, 1984; Jensen et al, 1989)
Via a diverse array of interactions LRP1 modulates various pathways involved in cancer

Summary

INTRODUCTION

The matricellular receptor low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a multifunctional receptor implicated in both endocytosis and signaling pathways (Lillis et al, 2008). Several groups reported decreased LRP1 expression (Figure 1C) levels in various cancer cell lines and tissues, assigning a tumor suppressive role to this receptor (Kancha et al, 1994; de Vries et al, 1996; Gilardoni et al, 2003). These findings provided a rationale for earlier studies in which decreased binding and uptake of α2-macroglobulin (α2M), an LRP1 ligand, were observed in multiple cancer cell lines (Van Leuven et al, 1979; Saksela et al, 1981, 1984; Jensen et al, 1989). LRP1-SNRNP25 expression was increased in both tumors via the LRP1 promoter activity of the fusion gene compared to the wild-type SNRNP25 expression in other osteosarcomas specimen

A MULTITUDE OF CANCER-MODIFYING PATHWAYS

CONCLUSION