Biomedical subjects

Brad St Croix

Publications and source records attributed to Brad St Croix.

5 recordsLinked to original sources

PubMed2006

Tumor endothelial marker 1 (Tem1) functions in the growth and progression of abdominal tumors.

Tumor endothelial marker 1 (Tem1; endosialin) is the prototypical member of a family of genes expressed in the stroma of tumors. To assess the functional role of Tem1, we disrupted the Tem1 gene in mice by targeted homologous recombination. Tem1(-/-) mice were healthy, their wound healing was normal, and tumors grew normally when implanted in s.c. sites. However, there was a striking reduction in tumor growth, invasiveness, and metastasis after transplantation of tumors to abdominal sites in mice without functional Tem1 genes. These data indicate that the stroma can control tumor aggressiveness and that this control varies with anatomic site. Therefore, they have significant implications for the mechanisms underlying tumor invasiveness and for models that evaluate this process.

Abdominal Neoplasms↗

PubMed2004

Identification of a binding partner for the endothelial cell surface proteins TEM7 and TEM7R.

Tumor endothelial marker 7 (TEM7) was recently identified as an mRNA transcript overexpressed in the blood vessels of human solid tumors. Here, we identify several new variants of TEM7, derived by alternative splicing, that are predicted to be intracellular (TEM7-I), secreted (TEM7-S), or on the cell surface membrane (TEM7-M) of tumor endothelium. Using new antibodies against the TEM7 protein, we confirmed the predicted expression of TEM7 on the cell surface and demonstrated that TEM7-M protein, like its mRNA, is overexpressed on the endothelium of various tumor types. We then used an affinity purification strategy to search for TEM7-binding proteins and identified cortactin as a protein capable of binding to the extracellular region of both TEM7 and its closest homologue, TEM7-related (TEM7R), which is also expressed in tumor endothelium. The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain. These studies establish the overexpression of TEM7 protein in tumor endothelium and provide new opportunities for the delivery of therapeutic and imaging agents to the vessels of solid tumors.

Alternative Splicing↗

PubMed2004

TEM8 interacts with the cleaved C5 domain of collagen alpha 3(VI).

Tumor endothelial marker (TEM)8 was uncovered as a gene expressed predominantly in tumor endothelium, and its protein product was recently identified as the receptor for anthrax toxin. Here, we demonstrate that TEM8 protein is preferentially expressed in endothelial cells of neoplastic tissue. We used the extracellular domain of TEM8 to search for ligands and identified the alpha 3 subunit of collagen VI as an interacting partner. The TEM8-interacting region on collagen alpha 3(VI) was mapped to its COOH-terminal C5 domain. Remarkably, collagen alpha 3(VI) is also preferentially expressed in tumor endothelium in a pattern concordant with that of TEM8. These results suggest that the TEM8/C5 interaction may play an important biological role in tumor angiogenesis.

Collagen Type VI↗

PubMed2004

Tumor endothelial markers: new targets for cancer therapy.

PURPOSE OF REVIEW: Targeting the endothelial cells that line tumor infiltrating blood vessels is a new anticancer strategy that has gained widespread support from biologists and clinicians. Here we highlight different approaches currently being used to target tumor endothelium and discuss new avenues for intervention that have been opened through the recent identification of tumor endothelial markers (TEMs). RECENT FINDINGS: The ability of Avastin to prolong survival in a Phase III clinical trial of human colorectal cancer has established the validity of the anti-angiogenic approach. However, realization of the full potential of a vascular targeting strategy may require the exploitation of molecules which are highly restricted in expression to tumor endothelium. Here we explore the potential of TEMs as new targets for cancer therapy. Current knowledge of these markers and their relation to other family members in the context of tumor angiogenesis is discussed. In particular, we highlight those molecules which, by virtue of their structure, cell-surface location and expression pattern, appear to hold promise as targets for future drug development. The identification of TEM8 as the anthrax toxin receptor and the successful targeting of this receptor in preclinical tumor models make this molecule a particularly attractive candidate for future vascular targeting studies. SUMMARY: Technological advances in cellular fractionation and genomics enabled the identification of several markers preferentially expressed on human tumor endothelium. Studies of these TEMs are expected to aid in our understanding of angiogenesis and could lead to the development of new imaging and diagnostic agents for cancer.

Antibodies, Monoclonal↗

PubMed2003

Identifying tumor origin using a gene expression-based classification map.

Identifying the primary site in cases of metastatic carcinoma of unknown origin has profound clinical importance in managing cancer patients. Although transcriptional profiling promises molecular solutions to this clinical challenge, simpler and more reliable methods for this purpose are needed. A training set of 11 serial analysis of gene expression (SAGE) libraries was analyzed using a combination of supervised and unsupervised computational methods to select a small group of candidate genes with maximal power to discriminate carcinomas of different tissue origins. Quantitative real-time PCR was used to measure their expression levels in an independent validation set of 62 samples of ovarian, breast, colon, and pancreatic adenocarcinomas and normal ovarian surface epithelial controls. The diagnostic power of this set of genes was evaluated using unsupervised cluster analysis methods. From the training set of 21,321 unique SAGE transcript tags derived from 11 libraries, five genes were identified with expression patterns that distinguished four types of adenocarcinomas. Quantitative real-time PCR expression data obtained from the validation set clustered tumor samples in an unsupervised manner, generating a self-organized map with distinctive tumor site-specific domains. Eighty-one percent (50 of 62) of the carcinomas were correctly allocated in their corresponding diagnostic regions. Metastases clustered tightly with their corresponding primary tumors. A classification map diagnostic of tumor types was generated based on expression patterns of five genes selected from the SAGE database. This expression map analysis may provide a reliable and practical approach to determine tumor type in cases of metastatic carcinoma of clinically unknown origin.

Adenocarcinoma↗