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The αvβ6 integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of αvβ6 expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of αvβ6 in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent αvβ6 expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate αvβ6 expression. Detroit 562 cells showed αvβ6-dependent adhesion and activation of transforming growth factor-β (TGF-β) that was inhibited >90% with an αvβ6 blocking antibody, 6.3G9. Although both recombinant soluble TGF-β receptor type-II (rsTGF-βRII-Fc) and 6.3G9 inhibited TGF-β–mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-βRII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by αvβ6 antibodies, our findings support a role for αvβ6 in human cancer and underscore the therapeutic potential of function blocking αvβ6 antibodies. [Cancer Res 2008;68(2):561–70]

The urokinase plasminogen activator system is involved in angiogenesis and tumor growth of malignant gliomas, which are highly neovascularized and so may be amenable to antiangiogenic therapy. In this paper, we describe the activity of Å6, an octamer capped peptide derived from the non-receptor-binding region of urokinase plasminogen activator. Å6 inhibited human microvascular endothelial cell migration but had no effect on the proliferation of human microvascular endothelial cells or U87MG glioma cells in vitro . In contrast, Å6 or cisplatin (CDDP) alone suppressed subcutaneous tumor growth in vivo by 48% and 53%, respectively, and, more strikingly, the combination of Å6 plus CDDP inhibited tumor growth by 92%. Such combination treatment also greatly reduced the volume of intracranial tumor xenografts and increased survival of tumor-bearing animals when compared with CDDP or Å6 alone. Tumors from the combination treatment group had significantly reduced neovascularization, suggesting a mechanism involving Å6-mediated inhibition of endothelial cell motility, thereby eliciting vascular sensitivity to CDDP-mediated toxicity. These data suggest that the combination of an angiogenesis inhibitor that targets endothelial cells with a cytotoxic agent may be a useful therapeutic approach.

Human malignant tumors grown as xenografts in immunocompromised animals have been used extensively to study tumor growth and tumor response to therapy. The endothelium functions as an effective barrier between the intravascular space and the tumor cells. In a previous study we used species-specific monoclonal antibodies against endothelial cell adhesion molecules to demonstrate the host origin of the endothelium in xenotransplanted pancreatic islet grafts [Am J Pathol 1995;146:1397-1405]. We now investigated in this study whether the vascular endothelium of different xenografted human malignant tumors expresses mouse (= host)- or human (= graft)-specific CD31 (platelet endothelial cell adhesion molecule, PECAM-1) adhesion molecules.Cultured human prostate, kidney, and colon cancer cells (passages 15-17) were transplanted subcutaneously into 8-week-old athymic nude mice and removed after another 8 weeks. The avidin biotin peroxidase method was utilized on frozen sections to demonstrate that the endothelium of the vasculature of all three human xenografts expressed mouse (= host)-specific CD31, but not human (= graft)-specific CD31.The presence between the intravascular space and the human tumor cells of a mouse-derived endothelium, expressing mouse-specific antigens, needs to be taken into careful consideration when evaluating results of antitumor therapies in these animal models. This caveat pertains particularly to the study of novel cell- or tissue-specific treatment modalities, such as antibody-targeted drugs, toxins or radionuclides, 'immuno'-liposomes, or tumor vaccines.