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Laminin 332 in squamous-cell carcinoma

Key Points

  • Laminin 332, a large multidomain molecule involved in cell adhesion and matrix assembly, is a prominent component of squamous-cell carcinoma (SCC) extracellular matrix. The levels of laminin 332 expression in SCC tumours correlate with tumour invasion and patient prognosis.

  • Proteolytic processing of the γ2 and α3 chains of laminin 332 has been linked to cell migration and invasion. Members of the astacin family process the γ2chain, and various enzymes, including astacin enzymes, matrix metalloproteinase 2 (MMP2), MT1-MMP and plasmin process the α3 chain.

  • The association of cells with laminin 332 occurs through α3β1 integrin in focal adhesions and α6β4 in stable anchoring contacts, which contain an assembly of hemidesmosome proteins.

  • The binding of laminin 332 to β1 integrin promotes RHOA GTPase-driven non-directional migration, whereas the binding of laminin 332 to β4 integrin promotes RAC1 GTPase-driven directional migration.

  • An in vivo model of human SCC tumour development has shown the essential role of laminin-332, α6β4 integrin and collagen VII, which associate and drive SCC tumorigenesis through phosphatidylinositol-3 kinase (PI3K) activation.

  • The laminin G4–5 domain is a proteolytic product of laminin 332 that promotes laminin 332 deposition, is expressed in healing wounds and might have a role in SCC formation.

  • The binding of collagen VII or the proteolytic processing of laminin 332 might regulate epidermal growth factor receptor (EGFR) activation, which functions in concert with α6β4 integrin signalling to drive SCC tumorigenesis.

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.

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Figure 1: Comparison between laminin 111 and laminin 332.
Figure 2: Laminin 332 promotes two separate integrin-mediated epithelial adhesion contacts.
Figure 3: A model of human squamous cell carcinoma tumorigenesis.
Figure 4: Multiple laminin 332 domains coordinately promote tumorigenesis.
Figure 5: Possible mechanisms for laminin processing and collagen VII binding in tumorigenesis.

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Acknowledgements

This work was supported by the Veterans Affairs Office of Research and Development, and by the US National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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Mohs' surgery

A tissue-sparing technique for complete excision of cutaneous SCC tumours, which uses frozen sections of marked excisional tissue boundries to ascertain complete tumour clearance.

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Integrins are transmembrane heterodimeric BMZ receptors consisting of and subunits that comprise a family of 20 currently identified members. Individual members of the integrin family have specific BMZ-recognition profiles and often distinct patterns of signal transduction when activated by ligand binding.

Matrigel

A commercially available basement membrane extract derived from the murine Engelbreth-Holm-Swarm (EHS) tumour. Matrigel primarily contains the proteins laminin 111, type IV collagen, nidogen and perlecan.

Focal adhesion

A structure that provides dynamic cell adhesion in vivo, which involves integrin-mediated binding to the extracellular matrix and connections to the actin cytoskeleton.

Stable anchoring contact

A structure that provides stable cell adhesion in vivo consisting of an assembly of hemidesmosomal components.

Hemidesmosomes

Specialized condensations of basal keratinocyte plasma membrane that contain a number of specialized basement membrane components. These structures provide additional stable adhesion in the face of external disruptive forces.

Keratinocytes

Specialized epithelial cells that make up the stratified squamous epithelium of skin and mucosal tissues.

Galvanotaxis

The responsive movement of cells along the direction of an electrical field.

Recessive dystrophic epidermolysis bullosa

An inherited bullous disorder caused by COL7A1 gene mutations, and a deficiency of collagen VII.

Astacin family

A group of zinc endopeptidases named after the digestive enzyme astacin isolated from the stomach-like cardia of the freshwater crayfish Astacis astacus.

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Marinkovich, M. Laminin 332 in squamous-cell carcinoma. Nat Rev Cancer 7, 370–380 (2007). https://doi.org/10.1038/nrc2089

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