Tsuruta Daisuke, Kobayashi Hiromi, Imanishi Hisayoshi, Sugawara Koji, Ishii Masamitsu, Jones Jonathan C R
Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
Curr Med Chem. 2008;15(20):1968-75. doi: 10.2174/092986708785132834.
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.
多年来，细胞外基质（ECM）被认为起着组织支撑和填充的作用。然而，我们现在知道，ECM蛋白通过与细胞表面受体和细胞质信号通路相互作用，控制着许多细胞活动。例如，它们调节细胞增殖、细胞分裂、细胞黏附、细胞迁移和细胞凋亡。在本综述中，我们重点关注一种层粘连蛋白异构体，层粘连蛋白-332（以前称为层粘连蛋白-5），它是皮肤和其他上皮组织基底膜（BM）的主要成分。它由3个亚基（α3β3和γ3）组成，并与上皮细胞表达的至少两种整合素受体（α3β1和α6β4整合素）相互作用。层粘连蛋白-332或整合素α6β4的突变会导致交界性大疱性表皮松解症，一种皮肤水疱病，而瘢痕性类天疱疮中自身抗体靶向层粘连蛋白-332会导致上皮细胞与其下方结缔组织的黏附障碍。层粘连蛋白-332及其整合素受体的异常表达也是某些肿瘤类型的标志，并且被认为促进结肠、乳腺和皮肤癌细胞的侵袭。此外，越来越多的证据表明，层粘连蛋白-332及其蛋白酶降解产物不仅存在于几种肿瘤的前沿，而且可能诱导和/或促进肿瘤细胞迁移。因此，在本综述中，我们特别关注层粘连蛋白-332及其整合素受体在癌细胞黏附、增殖和迁移/侵袭中的作用。最后，我们讨论了开发基于层粘连蛋白-332的拮抗剂用于治疗恶性肿瘤的策略。
