ABSTRACT
BACKGROUND/AIM: Tumor endothelial marker 8 (TEM8) is a tumor endothelial-associated antigen that is having an increasingly recognized role in tumor biology. The expression of TEM8 in triple-negative breast cancer (TNBC) has not yet been characterized. MATERIALS AND METHODS: We hypothesize that TEM8 is overexpressed in TNBC and in metastatic TNBC in lymph nodes (LN) compared to normal breast tissue and normal lymphatic tissue, respectively. We studied expression of TEM8 in cases of primary (n=17) and metastatic (n=2) TNBC using immunohistochemical analyses. RESULTS: All cases demonstrated increased expression of TEM8 in tumor tissue compared to non-cancerous breast tissue. TEM8 was expressed at a higher level in the stroma adjacent to the TNBC in all cases, with focal immunoreactive areas within the tumor. TEM8 was not expressed in normal lymphoid tissue, but showed expression at sites of LN metastases. CONCLUSION: TEM8 would appear to represent a new biologic target for designing novel diagnostic or therapeutic approaches for TNBC.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Neoplasm Proteins/metabolism , Receptors, Cell Surface/metabolism , Antibodies, Neoplasm/immunology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Female , Humans , Immunohistochemistry , Lymph Nodes/pathology , Microfilament Proteins , Neoplasm Proteins/immunology , Receptors, Cell Surface/immunologyABSTRACT
Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P < 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature.
Subject(s)
Colorectal Neoplasms/blood supply , Receptors, Peptide/metabolism , Animals , Base Sequence , Biomarkers, Tumor , Blotting, Western , Cell Line, Tumor , Colorectal Neoplasms/metabolism , DNA Primers , Enzyme-Linked Immunosorbent Assay , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Microfilament Proteins , Receptors, Cell Surface , Recombinant Fusion Proteins/pharmacologyABSTRACT
Safe and effective delivery of genetic material to mammalian tissues would significantly expand the therapeutic possibilities for a large number of medical conditions. Unfortunately, the promise of gene therapy has been hampered by technical challenges, the induction of immune responses, and inadequate expression over time. Despite these setbacks, progress continues to be made and the anticipated benefits may come to fruition for certain disorders. In terms of delivery, nonviral vector systems are particularly attractive as they are simple to produce, can be stored for long periods of time, and induce no specific immune responses. A significant drawback to nonviral systems has been the lack of persistent expression, as plasmids are lost or degraded when delivered to living tissues. The recent application of integrating transposons to nonviral gene delivery has significantly helped to overcome this obstacle, because it allows for genomic integration and long-term expression. Recent advances in transposon-based vector systems hold promise as new technologies that may unlock the potential of gene therapy; however, technical and safety issues still need refinement.
