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

Daisuke      Tsuruta; Hiromi      Kobayashi; Hisayoshi      Imanishi; Koji      Sugawara; Masamitsu      Ishii; Jonathan   C.R.   Jones

doi:10.2174/092986708785132834

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.

Keywords: Integrin, laminin, cancer, basement membrane, proteolysis, cell signaling, cell adhesion, gene expression