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Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

¹ Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California; ² Dermatology Service, VA Palo Alto Health Care System, Palo Alto, California; and ³ IFR128 BioSciences Lyon-Gerland, Institut de Biologie et Chimie des Protéines, UMR 5086, Centre National de la Recherche Scientifique, Univ. Lyon1, Lyon, France

Requests for reprints: M. Peter Marinkovich, Program in Epithelial Biology, Stanford University School of Medicine, Room 2145, 269 Campus Drive, Stanford, CA 94305. Phone: 650-498-5425; Fax: 650-723-8762; E-mail: mpm{at}stanford.edu.

Key Words: laminin • carcinoma • basement membrane • extracellular matrix

Laminin-332 is critical for squamous cell carcinoma (SCC) tumorigenesis, but targeting it for cancer therapy has been unachievable due to key role of laminin-332 in promoting tissue integrity. Here, we show that a portion of laminin-332, termed G45, which is proteolytically removed and absent in normal tissues, is prominently expressed in most human SCC tumors and plays an important role in human SCC tumorigenesis. Primary human keratinocytes lacking G45 (G45) showed alterations of basal receptor organization, impaired matrix deposition, and increased migration. After SCC transformation, the absence of G45 domain in G45 cells was associated with deficient extracellular signal-regulated kinase and phosphotidylinositol 3-kinase (PI3K) pathway activation, impaired invasion, deficient metalloproteinase activity, and absent tumorgenicity in vivo. Expression of G45 or activated PI3K subunit in G45 cells reversed these abnormalities. G45 antibody treatment induced SCC tumor apoptosis, decreased SCC tumor proliferation, and markedly impaired human SCC tumorigenesis in vivo without affecting normal tissue adhesion. These results show a remarkable selectivity of expression and function for laminin-332 G45 in human SCC tumorigenesis and implicate it as a specific target for anticancer therapy. [Cancer Res 2008;68(8):2885–94]

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