Targeting a tumor-specific laminin domain critical for human carcinogenesis.
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 (DeltaG45) showed alterations of basal receptor organization, impaired matrix deposition, and increased migration. After SCC transformation, the absence of G45 domain in DeltaG45 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 DeltaG45 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.
Tran
Mark
M
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Rousselle
Patricia
P
Nokelainen
Pasi
P
Tallapragada
Sruthi
S
Nguyen
Ngon T
NT
Fincher
Edgar F
EF
Marinkovich
M Peter
MP
D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004820:Epidermolysis Bullosa / Q000235:genetics / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012879:Skin Physiological Phenomena; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D000097794:Kalinin