Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

Abstract

For many years, extracellular matrix (ECM) was considered to function as a tissue support and filler. However, we now know that ECM proteins control many cellular events through their interaction with cell-surface receptors and cytoplasmic signaling pathways. For example, they regulate cell proliferation, cell division, cell adhesion, cell migration, and apoptosis. We focus in this review on a laminin isoform, laminin-332 (formerly termed laminin-5), a major component of the basement membrane (BM) of skin and other epithelial tissues. It is composed of 3 subunits (α3, β3, and γ2) and interacts with at least two integrin receptors expressed by epithelial cells (α3β1 and α6β4 integrin). Mutations in either laminin-332 or integrin α6β4 result in junctional epidermolysis bullosa, a blistering skin disease, while targeting of laminin-332 by autoantibodies in cicatricial pemphigoid leads to dysadhesion of epithelial cells from their underlying connective tissue. Abnormal expression of laminin-332 and its integrin receptors is also a hallmark of certain tumor types and is believed to promote invasion of colon, breast and skin cancer cells. Moreover, there is emerging evidence that laminin-332 and its protease degradation products are not only found at the leading front of several tumors but also likely induce and/or promote tumor cell migration. Thus, in this review, we focus specifically on the role of laminin-332 and its integrin receptors in adhesion, proliferation, and migration/invasion of cancer cells. Finally, we discuss strategies for the development of laminin-332-based antagonists for the treatment of malignant tumors.

Detection of differentially expressed genes and association with clinicopathological features in laryngeal squamous cell carcinoma

“…Laminin expression is a prerequisite for normal embryonic development (17). Abnormal expression of LAMA332 and its integrin receptors is a hallmark of certain types of tumor and is considered to promote the invasion of colon, breast and skin cancer cells (18). Our present study confirmed these previous findings, although its role in laryngeal cancer requires further study.…”

Dynamic Interactions of Epidermal Collagen XVII with the Extracellular Matrix

“…4 A major component of epithelial basement membranes, which represent highly specialized ECM, is laminin 332, and its interactions with keratinocyte integrins ␣3␤1 and ␣6␤4 guide cell migration, differentiation, and proliferation. 5,6 In basal keratinocytes of the epidermis, the adhesion receptors are embedded in larger protein complexes, the hemidesmosomes (HDs), which can be observed as electron-dense ultrastructural components facing the basement membrane. 7 HDs play an important role in cell attachment to the epidermal basement membrane, as shown indirectly by abnormalities of HDs in congenital and acquired blistering diseases, such as junctional epidermolysis bullosa and pemphigoid diseases.…”

“…19 Despite the limitations of such assays, the suggestion of a partnership between these two HD components is intriguing and has high pathophysiologic significance because aberrant expression of laminin 332 and collagen XVII has been suggested to be involved in the invasion and proliferation of various cancer cells. 6,20 In this context, it is important to note that two different physiologic forms of collagen XVII exist: a full-length transmembrane form and a released ectodomain. Proteinases of the ADAM family cleave the Ecto-ColXVII within the juxtamembranous noncollagenous 16th A (NC16A) domain, 4,17 yielding a shorter form of the protein, Ecto-ColXVII, which remains stable in the ECM and is likely to interact with other ECM proteins.…”

Junctional and Dystrophic Epidermolysis Bullosa

“…At the molecular level, core of each hemidesmosome comprises of four transmembrane proteins, 180 kDa-bullous pemphigoid antigen (BP180, type XVII collagen, BPAG2),  integrins and CD151 tetraspanin protein [7]. Both BP180 and  integrin interacts with laminin-332 at the BMZ [9]. integrin is the unique integrin, because the other integrins normally attach to actin, while  integrin attaches to intermediate filament, keratin [10]. integrin attaches to intermediate filament by plectin [10]. BP180 tethers keratin through the interaction with BP230 in the cytoplasm [10].…”