Biomedical subjects

Mary Philip

Publications and source records attributed to Mary Philip.

5 recordsLinked to original sources

PubMed2006

A mutant chaperone converts a wild-type protein into a tumor-specific antigen.

Monoclonal antibodies have become important therapeutic agents against certain cancers. Many tumor-specific antigens are mutant proteins that are predominantly intracellular and thus not readily accessible to monoclonal antibodies. We found that a wild-type transmembrane protein could be transformed into a tumor-specific antigen. A somatic mutation in the chaperone gene Cosmc abolished function of a glycosyltransferase, disrupting O-glycan Core 1 synthesis and creating a tumor-specific glycopeptidic neo-epitope consisting of a monosaccharide and a specific wild-type protein sequence. This epitope induced a high-affinity, highly specific, syngeneic monoclonal antibody with antitumor activity. Such tumor-specific glycopeptidic neo-epitopes represent potential targets for monoclonal antibody therapy.

Acetylgalactosamine↗

PubMed2006

Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) and are often thought to represent a spectrum of a single disease. The malignant cells in T-ALL and T-LL are morphologically indistinguishable, and they share the expression of common cell surface antigens and cytogenetic characteristics. However, despite these similarities, differences in the clinical behavior of T-ALL and T-LL are observed. PROCEDURE: We analyzed the gene expression profiles of T-ALL and T-LL samples obtained from Children's Oncology Group (COG) tumor banks using DNA arrays. Immunohistochemistry was also performed to validate the expression of selected targets. RESULTS: Unsupervised hierarchical clustering of all samples showed complete segregation of T-ALL and T-LL into distinct clusters. Next, we identified the top 201 genes that best differentiated T-ALL from T-LL using significance analysis of microarrays (SAM), a supervised statistical approach. Genes representing several functional groups were differentially expressed in T-LL and T-ALL. Prediction analysis of microarrays (PAM) identified a subset of genes, which accurately classified all 19 T-ALL and T-LL samples with an overall misclassification error rate of 0. Immunohistochemical validation of protein expression of selected genes identified by microarray analysis confirmed overexpression of MLL-1 in T-LL tumor cells compared to T-ALL and CD47 in T-ALL tumors cells when compared to T-LL. CONCLUSIONS: Despite significant similarities between the malignant T-cell precursors, clear differences in the gene expression profiles were observed between T-ALL and T-LL implying underlying differences in the biology of the two entities.

Bone Marrow↗

PubMed2004

Long-term suppression of tumor growth by TNF requires a Stat1- and IFN regulatory factor 1-dependent IFN-gamma pathway but not IL-12 or IL-18.

Tumor cells engineered to secrete TNF were used as a model to examine how persistently high local concentrations of TNF suppress tumor growth. TNF secretion had no effect on tumor cell proliferation in vitro but caused a very impressive growth arrest in vivo that was dependent on both bone marrow- and non-bone marrow-derived host cells expressing TNFR. Suppression also required an endogenous IFN-gamma pathway consisting minimally of IFN-gamma, IFN-gamma receptor, Stat1, and IFN regulatory factor 1 since mice with targeted disruption of any of the four genes failed to arrest tumor growth. The ability of these mice to suppress tumor growth was restored after they were reconstituted with bone marrow cells from Wt mice. Interestingly, mice lacking the major IFN-gamma-inducing cytokines IL-12 and IL-18 or T cells, B cells, and the majority of NK cells that are potential sources of IFN-gamma nevertheless inhibited tumor development. Moreover, multiple lines of evidence indicated that local release of IFN-gamma was not required to inhibit tumor formation. These results strongly suggest a novel function for the endogenous IFN-gamma pathway that without measurable IFN-gamma production or activity affects the ability of TNF to suppress tumor development.

Animals↗

PubMed2004

Priming of naive T cells inside tumors leads to eradication of established tumors.

The tumor barrier comprised of nonantigenic stromal cells may contribute to the failure of tumor rejection. The tumor-necrosis factor superfamily member LIGHT (also known as TNFSF-14) is a ligand of stromal cell-expressed lymphotoxin-beta receptor and T cell-expressed herpes viral entry mediator (HVEM). Here we show that forced expression of LIGHT in the tumor environment induces a massive infiltration of naive T lymphocytes that correlates with an upregulation of both chemokine production and expression of adhesion molecules. Activation of these infiltrating T cells, possibly through HVEM, leads to the rejection of established, highly progressive tumors at local and distal sites. Our study indicates that targeting the tumor barrier may be an effective strategy for cancer immunotherapy.

Animals↗

PubMed2004

Inflammation as a tumor promoter in cancer induction.

Opposing effects of inflammation on cancer have been described. Acute inflammation usually counteracts cancer development, while chronic inflammation promotes cancer development. Just as inactivation of the p53 pathway may be universal in the neoplasia, the activation of the NFkappaB pathway may, conversely, be frequent in carcinogenesis, and a requirement for inflammation and promotion. TNF, a key pro-inflammatory cytokine when binding to TNF receptor 1 (TNFR1), may cause survival or apoptosis, dependent on biochemical modifications that determine the type of complex formed; one complex causes NFkappaB activation and gives a cell survival signal (pro-oncogenic), while the other (modified) complex recruits caspases and causes apoptosis (anti-oncogenic). Fas-ligand (FasL)-Fas interaction can also result in opposing effects on carcinogenesis due to similar mechanisms. While IL-6 counteracts apoptosis and can promote cancer development, interferons can increase DNA repair and stabilize p53, thereby be anti-oncogenic.

Animals↗