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Laminin 332 in Squamous-Cell Carcinoma

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Laminin 332 in Squamous-Cell Carcinoma REVIEWS TUMOUR MICROENVIRONMENT Laminin 332 in squamous-cell carcinoma M. Peter Marinkovich Abstract | Basement membranes can be a barrier to tumour growth, but basement membrane molecules, including laminins, are also important autocrine factors produced by cancers to promote tumorigenesis. Many studies have shown the importance of laminin 332 (previously known as laminin 5) in this process, especially in squamous cell carcinoma. Through interactions with several cell-surface receptors (including α6β4 and α3β1 integrins, epidermal growth factor receptor and syndecan 1) and other basement membrane components (including type VII collagen), laminin 332 drives tumorigenesis through phosphatidylinositol-3 kinase (PI3K) and RAC1 activation, promoting tumour invasion and cell survival. The extracellular interactions of laminin 332 appear amenable to antibody-mediated therapies. Mohs’ surgery Squamous-cell carcinoma (SCC) is a highly invasive a scaffold on which epithelial cells and tissues can dif- A tissue-sparing technique for malignant neoplasm associated with a high risk of ferentiate, divide, migrate, develop and, in the case of complete excision of metastasis and morbidity. SCCs can arise in a wide malignant cancers, invade and metastasize5–8. In addi- cutaneous SCC tumours, which range of tissues causing skin, lung, oral, cervical, tion to serving as a scaffold, the epithelial BMZ itself uses frozen sections of marked excisional tissue boundries to gastric and colorectal cancers, among others. Given can exert a profound influence on cell behaviour. It can ascertain complete tumour the range of tissues it affects, SCC represents the dictate whether cells will proliferate, growth arrest, or clearance. most common cancer capable of metastatic spread undergo programmed cell death. The BMZ can influ- in the USA and worldwide1,2. In 1973, approximately ence whether cells will migrate or remain stationary. 480,000 cases of non-melanoma skin cancer were As will be shown in this Review, the BMZ produced by reported in the USA, whereas in 1994, the number carcinomas is required for tumour growth and cellular of cases had more than doubled, and was estimated or tissue invasion. to be between 900,000 and 1,200,000 cases1. Cervical In cancer research, BMZs have traditionally been SCC also causes significant morbidity and mortality, viewed as protective structures to defend against although it is hoped that the incidence of cervical SCC cancer spread, or as obstacles that in situ carcinomas will be reduced by human papillomavirus (HPV) vac- have to overcome to invade and metastasize9. The cines, one of which was recently approved by the US proteolytic cleavage of BMZ molecules by enzymes Food and Drug Administration. The risk of SCC is produced by carcinoma cells was once thought to sim- strongly linked with environmental factors, such as ply function in the degradation of the host matrix to sun exposure, viral infections and tobacco use. SCCs provide space for tumour extension10. Recent studies are associated with a high risk of recurrence, resulting have shown that the roles of the BMZ and extracellular in significant mortality and often requiring specialized matrix in cancer invasion and tumour development surgical techniques (Mohs’ surgery) for complete exci- are more complex. Indeed, we now know that carci- sion. SCCs often invade neighbouring tissues, and can noma cells depend on their own array of BMZ mol- also metastasize to the lymph nodes, lung and other ecules that they preferentially use as a substrate for VA Medical Center, Palo Alto, distant sites. All of these factors have led to the search invasion and proliferation. It is also now appreciated California, USA, and for non-surgical means of treating SCCs. that tumour-associated proteolytic enzymes have a Program in Epithelial Biology, Secretion, assembly and remodelling of extracellu- significant effect on modifying tumour-derived BMZ, Stanford University School lar matrix proteins into an organized structure termed and that proteolytic modifications of tumour-derived of Medicine, Stanford, California 94305, USA. the basement membrane zone (BMZ) is an essential BMZ molecules are a necessary prerequisite to inva- 3,4 e-mail: [email protected] function of epithelial tissues and cells . This process, sion and growth. This emerging view recognizes BMZ doi:10.1038/nrc2089 which also depends on stromal contributions, provides molecules in carcinomas as potential pro-tumorigenic 370 | MAY 2007 | VOLUME 7 www.nature.com/reviews/cancer © 2007 Nature Publishing Group REVIEWS At a glance Laminin 332 structure and function Laminins are large extracellular glycoproteins that • Laminin 332, a large multidomain molecule involved in cell adhesion and matrix are important components of all BMZs, and are assembly, is a prominent component of squamous-cell carcinoma (SCC) involved in several important biological processes11 extracellular matrix. The levels of laminin 332 expression in SCC tumours including tissue development, wound healing, and, as correlate with tumour invasion and patient prognosis. will be discussed in this Review, tumorigenesis. The • Proteolytic processing of the 2 and 3 chains of laminin 332 has been linked to γ α main role of laminin 332 (formerly termed laminin 5, cell migration and invasion. Members of the astacin family process the γ2 chain, and various enzymes, including astacin enzymes, matrix metalloproteinase 2 kalinin, nicein, ladsin and epiligrin) in normal tissues is (MMP2), MT1-MMP and plasmin process the α3 chain. in the maintenance of epithelial–mesenchymal cohesion in tissues exposed to external disruptive forces, including • The association of cells with laminin 332 occurs through α3β1 integrin in focal adhesions and 6 4 in stable anchoring contacts, which contain an assembly of the skin, stratified squamous mucosa, the amnion and α β 12 hemidesmosome proteins. the cornea . The crucial role of laminin 332 in epidermal adhesion was highlighted further by the demonstration • The binding of laminin 332 to β1 integrin promotes RHOA GTPase-driven non- directional migration, whereas the binding of laminin 332 to β4 integrin of its absence in the severe and lethal blistering disease, 13,14 promotes RAC1 GTPase-driven directional migration. Herlitz’s junctional epidermolysis bullosa (JEB) , owing 15,16 • An in vivo model of human SCC tumour development has shown the essential to underlying laminin 332 gene mutations . role of laminin-332, α6β4 integrin and collagen VII, which associate and drive Laminins are heterotrimers containing α, β and SCC tumorigenesis through phosphatidylinositol-3 kinase (PI3K) activation. γ chains (BOX 1). The structure of the laminin 111 • The laminin G4–5 domain is a proteolytic product of laminin 332 that promotes molecule (containing α1, β1 and γ1 chains), the most laminin 332 deposition, is expressed in healing wounds and might have a role in widely studied laminin, is viewed in comparison with SCC formation. laminin 332 (containing α3, β3 and γ2 chains) in FIG. 1. • The binding of collagen VII or the proteolytic processing of laminin 332 might Laminins typically form a cross-shaped structure when 17 regulate epidermal growth factor receptor (EGFR) activation, which functions in viewed by rotary shadowing electron microscopy . concert with α6β4 integrin signalling to drive SCC tumorigenesis. The long arm of the cross consists of domains I and II, which function primarily in the intramolecular assembly of laminin trimers. At the base of the long autocrine factors. Although tumour-derived BMZ arm is a globular structure termed the G domain, molecules do not form morphologically recognizable which contains five epidermal growth factor (EGF)- ultrastructural elements equivalent to those found in based repeats. Sequencing of the γ2 chain18 confirmed normal tissues, there are nonetheless some important the identity of laminin 332 as a member of the laminin intramolecular BMZ associations that are crucial in family. Laminin 332 is a highly specialized molecule, supporting carcinoma development. This will be the and although its long arm and G domain are roughly focus of this Review. the same size as the laminin 111 prototype, its short Box 1 | The laminin family Laminins are a family of Current name Chain Former name(s) proteins. To date, five α designation chains, three β chains and three γ chains have been Laminin 111 α1β1γ1 Laminin 1, EHS laminin identified. Localization of Laminin 211 α2β1γ1 Laminin 2, merosin these chains to various tissues leads to the formation Laminin 121 α1β2γ1 Laminin 3 of as many as 16 different Laminin 221 α2β2γ1 Laminin 4 laminin isoforms with distinct Laminin 332 Laminin 5, kalinin, nicein, epiligrin, ladsin and tissue-specific functions. α3β3γ2 The first laminin molecule to Laminin 3B32 α3Bβ3γ2 Laminin 5B be studied, laminin 111, was Laminin 321 Laminin 6, k-laminin originally purified from the α3β1γ1 murine Engelbreth-Holm- Laminin 411 α3β2γ1 Laminin 7 Swarm (EHS) tumour in the Laminin 311 4 1 1 Laminin 8 late 1970s90. Laminin 111 has α β γ Junctional epidermolysis been traditionally viewed as Laminin 421 α4β2γ1 Laminin 9a bullosa the prototypic laminin Laminin 511 α5β1γ1 Laminin 10 A group of inherited bullous molecule, even though disorders caused by gene recent evidence suggests Laminin 521 α5β2γ1 Laminin 11 mutations coding for proteins that the actual tissue such as laminin 332, which are Laminin 213 α2β1γ3 Laminin 12 distribution of laminin 111 in associated with the lamina Laminin 423 α4β1γ3
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