Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

Abstract

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 signalregulated 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]

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

“…Remarkably, this antibody treatment inhibits SCC tumor proliferation, increases tumor cell apoptosis, and inhibits human SCC tumorigenesis. It does so without impacting normal tissue structure [130].…”

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…However, it was later discovered that a specific domain of laminin-332, G45, is present only in tumor tissue and promotes tumor formation and progression. 20 Blocking antibodies against G45 were shown in a pre-clinical model to be effective against SCC tumor formation through blockade of PI3K and ERK signaling, but to have no effect on normal skin homeostasis. 20 This is one of the few examples of targeting specific ECM ligands for cancer therapy, but highlights the need for a deeper understanding of how the role of adhesion signaling and specific ECM ligands differ between various homeostatic and pathologic states.…”

Laminins of Hydra ECM: A Comparative Analysis of Hydra and Vertebrate Laminins Based on Current Genomic and ETS DataBases

“…In addition, laminins are central to many human diseases such as, muscular dystrophy type-1A [23], Pierson syndrome, epidermolysis bullosa [24][25][26], laryngo-onychocutaneous syndrome [27], and tumorigenesis [28,29].…”