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Review
. 2006 Feb;97(2):91-8.
doi: 10.1111/j.1349-7006.2006.00150.x.

Laminin-5 (laminin-332): Unique biological activity and role in tumor growth and invasion

Kaoru Miyazaki  1
Affiliations
Review

Laminin-5 (laminin-332): Unique biological activity and role in tumor growth and invasion

Kaoru Miyazaki. Cancer Sci. 2006 Feb.

Abstract

The development and progression of tumor cells is controlled by their interactions with neighboring host cells and a variety of microenvironmental factors including extracellular matrix (ECM) molecules, growth factors and proteinases. Cell-adhesive ECM proteins are a prerequisite for growth and migration of many types of cells. Their interactions with integrins and other cell surface receptors induce intracellular signaling that regulates the actin cytoskeleton and gene expression. The basement membrane protein laminin-5 is a notable cell adhesion molecule, which promotes cellular adhesion and migration much more efficiently than other ECM proteins. There is accumulating evidence that laminin-5 is involved in tumor growth and progression. With special reference to laminin-5, this article reviews the regulatory mechanisms of cellular adhesion and migration by ECM molecules and their significance in tumor progression.

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Figures

Figure 1
Figure 1
Regulation of cellular functions by integrin signaling. Integrins, when bound to extracellular matrix (ECM) molecules, induce intracellular signaling pathways through scaffold proteins, cytoskeletal proteins, protein kinases and other signal mediators. In concert with the signal transduction from receptor tyrosine kinases (RTK), the integrin‐mediated signaling regulates actin organization and gene expression, leading to changes in cellular functions such as adhesion, motility, morphology, proliferation, apoptosis and differentiation. The activation of two small GTPases, Rac and Cdc42, and phosphatidylinositol‐3‐kinase (PI3K) is particularly important for tumor cell motility and invasion.
Figure 2
Figure 2
Two distinct types of morphology of well‐differentiated human gastric carcinomas.( 10 ) (a) Tumor cells forming glandular structures surrounded by continuous basement membranes (BM). The laminin‐5 in the BM was immunostained for the laminin γ2 chain (arrows). (b) Tumor cells invading the stroma. Only invading or budding tumor cells show strong intracellular staining for the γ2 chain. Note that invading tumor cells in the right panel have lost the epithelial cell polarity, which is seen in the tumor cells on the neoplastic BM in the left panel. The laminin γ2 chain was immunostained with the anti γ2‐chain monoclonal antibody D4B5.
Figure 3
Figure 3
Comparison of domain structures of (a) laminin‐1 and (b) laminin‐5. (a) Laminins containing the α1, α2 and α5 chains have a typical cross‐shaped structure. (b) Several domains present in the short arms of the three laminin‐1 chains are absent in those of the α3, β3 and γ2 chains of laminin‐5. The following letters indicate the functional domains capable of binding to the respective ligands: Agr, agrin; Col, collagen; αDG, α‐dystroglycan; Fub2, fibullin‐2; Hep, heparin; HSPG/Synd, heparansulfate proteoglycans/syndecan; Int, integrin; Nd, nidogen. Pol indicates a site for self‐polymerization.
Figure 4
Figure 4
(a) Cell‐scattering activity and (b) cell‐spreading activity of laminin‐5. (a) The rat liver cell line BRL was incubated with (right) or without (left) 60 ng/mL of purified laminin‐5 for 2 days in serum‐free culture.( 19 ) Marked cell scattering is seen with laminin‐5. (b) The human bladder carcinoma cell line EJ‐1 was incubated in a serum‐free medium for 6 h on culture plates precoated with (right) or without (left) 0.3 µg/mL laminin‐5. The cells were fixed and then examined by scanning electron microscopy in collaboration with Dr H. Sawada, Yokohama City University Medical School (unpublished data). EJ‐1 cells can not spread on the non‐coated plate (left), but they rapidly spread and migrate on the laminin‐5 substrate, forming notable lamellipodia (right).
Figure 5
Figure 5
Regulation of activities of laminin‐5 by proteolytic processing of α3 and γ2 chains. In many cultures, the α3 chain is almost completely cleaved between the LG3 and LG4 domains, while the γ2 chain is partially cleaved at domain III to produce the 105‐kDa chain. Arrows in the left model indicate the cleavage sites. The processing of the α3 chain converts a less active laminin‐5 to an active form regarding both adhesion and motility activities. The processing of the γ2 chain converts laminin‐5 from a static adhesion state to a migratory state. The α3 and γ2 chain fragments released from laminin‐5 by the proteolytic cleavages, both of which contain a heparin‐binding site, modulate cellular adhesion and migration independently or in concert with processed laminin‐5.( , In rat laminin‐5, the 105‐kDa γ2 chain is further cleaved by MT‐MMP at the site shown by a dotted arrow to produce an 80‐kDa γ2 chain and a 30‐kDa domain III fragment.( 37 ) Another dotted arrow indicates a proteolytic cleavage of the β3 chain, which occurs far less frequently than that of the γ2 chain.( 28 )
Figure 6
Figure 6
A model for regulation of tumor cell migration by laminin‐5 and its γ2 chain fragments. In situ carcinoma cells often deposit laminin‐5 onto the underlying basement membrane (BM) structures (left side) (also see the left panel of Fig. 2). The laminin‐5 (red circles) assembled into the BM matrix stably anchors these cells to the BM through interaction with integrin α6β4. When the BM structures are not synthesized or disrupted, tumor cells are able to migrate into interstitial stroma (right side). Tumor cells at the invasion front overexpress the laminin γ2 chain monomer rather than the laminin‐5 trimer (see the right panel of Fig. 2). Proteolytic fragments of the laminin γ2 monomer (blue diamonds) may promote the tumor cell invasion by binding to EGF receptor and other unidentified receptors.( 52 ) It is also possible that laminin‐5 that has not been assembled into the BM structure stimulates tumor cell invasion as a soluble ligand.
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