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Articles by P Tan
Total Records ( 2 ) for P Tan
  Y Wang , S Mao , B Li , P Tan , D Feng and J. Wen
 

Hepatitis C virus (HCV) infection is a leading cause of liver-related morbidity and mortality throughout the world. There is no vaccine available and current therapy is only partially effective. Since HCV infects only a minority of hepatocytes, we hypothesized that induction of apoptosis might be a promising approach for the treatment of hepatitis C. In the present study, recombinant caspase-3 gene (re-caspase-3) was used because it has the ability to induce apoptosis that is independent of the initiator caspases. An HCV-specific promoter is required to regulate the cytotoxic caspase-3 expression in HCV-infected cells. It has been reported that HCV core protein can specifically activate the 2',5'-oligoadenylate synthetase (OAS) gene promoter in human hepatocytes. Therefore, we constructed an expression vector consisting of the re-caspase-3 under the OAS gene promoter (pGL3-OAS-re-caspase-3) and then investigated its effect on HCV core-positive liver cells. It was found that the pGL3-OAS-re-caspase-3 construct induced apoptosis in HCV core-positive liver cells, but not in normal liver cells. These results strongly suggested that the transfer of the re-caspase-3 gene under the OAS promoter was a novel targeting approach for the treatment of HCV infection.

  M. d. M Inda , R Bonavia , A Mukasa , Y Narita , D. W. Y Sah , S Vandenberg , C Brennan , T. G Johns , R Bachoo , P Hadwiger , P Tan , R. A DePinho , W Cavenee and F. Furnari
 

Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/EGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the EGFR lesion. We hypothesized that the minor EGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by EGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf–/– astrocytes that express EGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.

 
 
 
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