Laminin-332-integrin interaction: a target for cancer therapy?
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 (alpha3beta3 and gamma3 and interacts with at least two integrin receptors expressed by epithelial cells (alpha3beta1 and alpha6beta4 integrin. Mutations in either laminin-332 or integrin alpha6beta4 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.
Tsuruta
Daisuke
D
Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan. dtsuruta@med.osaka-cu.ac.jp
Kobayashi
Hiromi
H
Imanishi
Hisayoshi
H
Sugawara
Koji
K
Ishii
Masamitsu
M
Jones
Jonathan C R
JC
D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D016023:Integrins; D045726:Metalloproteases; D011494:Protein Kinases; D000097794:Kalinin