Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice.

Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.

EpCAM: A new therapeutic target for an old cancer antigen.

The use of monoclonal antibodies as adjuvants to cancer chemotherapy has drawn considerable interest in recent years, due to the success of several novel agents against a broad range of targets. One such target is EpCAM (aka GA733-2, KSA, 17-1A antigen), a human cell surface glycoprotein expressed on some normal and most neoplastic epithelial cells. It is now widely recognized as having an important role in tumor biology, especially in colorectal cancer, and since its original discovery in the early 1980s, the known mechanism by which it functions has steadily evolved. Initial studies of monoclonal antibodies directed against EpCAM demonstrated the presence of anti-idiotype networks involving both B and T cells, antibody-dependent cell cytotoxicity, and complement mediated cell death as mechanisms of tumor growth inhibition. Recently, a novel receptor for EpCAM has been described that is a member of the inhibitory group of immunoglobulin-like receptors and is present on lymphocytes, monocytes, dendritic cells, and NK cells. Neoplastic cells that interact with this receptor, named LAIR-1, may enact an immunologic escape, and thus confer a selective advantage for their growth and spread. This novel mechanism of action may add to our current understanding of how monoclonal antibodies targeted against EpCAM inhibit tumor growth. Passive vaccination with this antibody may induce a tertiary anti-idiotypic network which correlates with clinical outcome, but the mechanism behind this outcome in select patients with minimal residual disease may additionally involve a novel blockade of tumor specific immunosuppression. This review will focus on the initial discoveries of EpCAM's cellular adhesion properties, its role in normal and neoplastic cell function, its distribution and presumed mechanism of action, and clinical studies of EpCAM as a therapeutic target. Clinical trials of edrecolomab, one such monoclonal antibody, in patients with colon cancer will be reviewed and updated. While phase III trials of edrecolomab have not demonstrated improved efficacy as adjuvant therapy for stage III colon cancer, newer agents with improved affinity, less chimerism, and improved delivery may still demonstrate benefit.

Opening up to precompetitive collaboration.

In order to enhance biomedical research and development efficiency and innovation, nontraditional research collaborations have emerged that feature the sharing of information, resources, and capabilities. Although many of these so-called precompetitive collaborations are in the field of oncology, the lessons they offer are broadly applicable to other subfields of translational medicine.

A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells.

Tumors evade immune surveillance despite the frequent expression of tumor-associated Ags (TAA). Tumor cells escape recognition by CD8(+) T cells through several mechanisms, including down-regulation of MHC class I molecules and associated Ag-processing machinery. However, although it is well accepted that optimal anti-tumor immune responses require tumor-reactive CD4(+) T cells, few studies have addressed how tumor cells evade CD4(+) T cell recognition. In this study, we show that a common TAA, GA733-2, and its murine orthologue, mouse epithelial glycoprotein (mEGP), function in blocking MHC class II-restricted Ag presentation by dendritic cells. GA733-2 is a common TAA that is expressed normally at low levels by some epithelial tissues and a subset of dendritic cells, but at high levels on colon, breast, lung, and some nonepithelial tumors. We show that ectopic expression of mEGP or GA733-2, respectively, in dendritic cells derived from murine bone marrow or human monocytes results in a dose-dependent inability to stimulate proliferation of Ag-specific or alloreactive CD4(+) T cells. Dendritic cells exposed to cell debris from tumors expressing mEGP are similarly compromised. Furthermore, mice immunized with dendritic cells expressing mEGP from a recombinant adenovirus vector exhibited a muted anti-adenovirus immune response. The inhibitory effect of mEGP was not due to down-regulation of functional MHC class II molecules or active suppression of T cells, and did not extend to T cell responses to superantigen. These results demonstrate a novel mechanism by which tumors may evade CD4(+) T cell-dependent immune responses through expression of a TAA.