Laminin isoforms in tumor invasion, angiogenesis and metastasis

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Abstract

Laminins are a growing family of αβγ heterotrimeric proteins, commonly found in basement membranes (BMs). These large molecules promote cell adhesion and migration via integrins and other cell-surface receptors. Over 12 laminin isoforms are presently known. The various isoforms have a cell- and tissue-specific expression and are differentially recognized by integrins. Expression of laminin isoforms in tumors usually reflects expression in their normal counterparts. However, during tumor invasion, loss of the BM barrier occurs and a discontinuous pattern of laminin staining is observed. In carcinomas, tumor cells at the invading front strongly express intracellularly the γ2 chain, a component of laminin-5. Remodeling of the vascular BM is observed during angiogenesis, and penetration of several BMs occurs during tumor dissemination and metastasis. Thus, disregulated cell–laminin interactions are major traits of malignant disorders.

Introduction

Invasion of other tissues and spreading throughout the body to form new tumors are major properties of cancer cells which often lead to death of the host.1 These phenomena are the result of complex interactions of tumor cells with host cells and extracellular matrices (ECMs).1., 2. Basement membranes (BMs), dense sheets of ECM, separate epithelium from connective tissue and surround vascular endothelium, muscle cells, lipocytes and Schwann cells.3., 4., 5. They provide mechanical support to tissues, maintain polarity and organization of cells, and mediate cell adhesion, migration, proliferation, and differentiation, cellular activities which are disregulated in cancer cells. Tumor cells must cross several BMs during their progression: when leaving the primary tumor, during intravasation and extravasation, and during invasion of other tissues such as muscles or nerves.6 Moreover, remodeling of the vascular BMs by host endothelial cells occurs in tumor angiogenesis to recruit new vessels essential for tumor growth.7 Together with type IV collagens, nidogens, and perlecan, laminins are the major component of BMs.3., 4., 5. The present review summarizes the structural and functional diversity of laminins and their relevance to cancer biology. Due to space limitations, reviews published by other scientists will be widely used as references.

Section snippets

Laminin chains, domains, isoforms, and tissue distribution

Laminins are a growing family of large multidomain αβγ heterotrimeric glycoproteins with adhesive, migration-promoting and signaling functions.3., 4., 5. The first laminin, presently known as laminin-1 (α1β1γ1), was isolated over 20 years ago from the matrix of the mouse Engelbreth–Holm–Swarm (EHS) tumor as a cross-shaped protein of disulfide-linked chains of about 200 and 400 kDa (Figure 1).3 Following molecular cloning of its three chains (α1, β1, and γ1) at the end of the 1980s, several

Laminin-binding integrins and laminin biological functions

Laminins affect cell behavior, including cell adhesion, migration and, differentiation, through integrins, a large family of αβ heterodimeric proteins.3., 5., 11., 12., 13., 14., 15. Integrins recognize mainly laminin α chains and hence determine cell adhesion to laminin isoforms. Although some functions might be common to all laminin variants, others may be unique and isoform specific, depending on the tissue or organ in which they are abundant (Table 2).5., 12., 13. The physiological

Laminin isoforms in tumor invasion

As major components of BMs, laminins constitute linear structural barriers and separate different tissue compartments.3., 4., 5. These BMs are lost or penetrated by tumor cells during invasion and metastasis (Figure 3).6 By immunohistochemistry with antiserum to laminin-1, early studies showed discontinuities in the BMs of malignant tumors but not in those of their benign counterpart.6., 55. The fragmentation or absence of BM structures seen in malignant tumors may be due to active proteolytic

Laminin isoforms in angiogenesis

Angiogenesis, the recruitment of new blood vessels, is essential for tumor growth and metastasis.7 New capillaries develop as sequential steps, originating mainly at sites of local degradation of the BM which surrounds the microvascular endothelial cells. Thereafter, endothelial cells migrate, proliferate, and differentiate to form a capillary sprout, while interacting with ECM components.82 In early studies, examination by immunoperoxidase of neovascularization in the murine cornea with

Laminin isoforms in metastasis

Following angiogenesis, primary tumor cells intravasate,7 apparently by penetrating the vascular BM-rich in laminin-8 and -10 (Figure 3). Though the molecular basis of this step is poorly understood, degradation of BM components by MMPs and other proteinases may be involved. Once in the circulation, large tumor cells and cell aggregates are often covered with platelets,95 a phenomenon which may enhance tumor metastasis. Interestingly, blood platelets contain and, following stimulation, secrete

Concluding remarks

A wealth of data has accumulated on laminins over the last two decades. The structural studies have indicated an enormous diversity whose functional relevance we are only beginning to understand. It is clear, though, that the pivotal role of laminins in cell adhesion, migration, differentiation, proliferation, survival, and tissue localization directly implicates these molecules in cancer biology. Continued work is needed to understand in detail the disregulated cell–laminin interactions during

Acknowledgements

MP’s research was supported by Cancerfonden and Karolinska Institutet. The authors thank Dr B. Chambers for revising the English text and Dr Ari Tuuttila for printing the figures.

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