Phone: (303) 724-1542
The overall theme of research in this laboratory is to understand at the molecular level how individual tumor cells or the tumor as a whole behave when exposed to ionizing radiation or chemotherapeutics drugs. The hope is that knowledge gained from our studies will facilitate a better understanding of tumor biology as well as the rationale development of agents / approaches that can enhance current cancer treatments.
Most of the research activities in the lab are focused on the following areas:
1. Molecular mechanisms of activation of HIF genes by radiation and chemotherapy. - The hypoxia inducible transcription factor HIF-1 is known to control many important genes. Among these are genes the activate angiogenesis (e.g. VEGF), vascular tone (e.g. adrenomedulin and iNOS), erythropoiesis (e.g.EPO), and glucose metabolism (e.g. GAPDH). Numerous studies have shown that it plays key roles in tumor growth and metastasis. Low oxygen tension was thought to be the only mechanism that activates HIF-1. Recently, however, studies in our laboratory and others indicate that radiation can up-regulate HIF-1 through a hypoxia-independent pathway. At the molecular level, nitric oxide-mediated nitrosylation of the ODD (oxygen-dependent degradation) domain appears to be responsible for this stabilization. We are now carrying out in-depth mechanistic studies of this mechanism and its implications for cancer therapy.
2. Molecular Imaging approaches to study cancer signal transduction. - Another major area of our laboratory is to design various novel reporters that allow us to "visualize" individual cell types and/or signaling pathways in experimental animals. For example, we can visualize the activities of HIF-1 in vivo by observing a modified luciferase reporter gene that can accurately recapitulate the activities of the HIF-1 gene. Such capabilities allow us to monitor the behaviors of individual cells or the activities of individual cell types non-invasively and accurately in vivo, which in many cases can significantly advance our understanding of biological processes that are otherwise difficult to study.
3. Novel approaches to enhance conventional cancer therapy. - In addition, we are also developing various approaches that can enhance radiotherapy / chemotherapy based on mechanistic understandings. One example is development of a tumor-selective adenovirus vector that can deliver a siRNA minigene that selectively knocks down the DNA-PKcs gene, which can sensitize tumor cells to radiation significantly because DNA-PKcs is a key gene responsible for repairing double strand breaks in DNA, the dominant mechanism through which radiation and some chemotherapeutic drugs kill tumor cells.
4. Mechanistic investigations of radiation-induced mutagenesis and carcinogenesis.
Finally, we are studying the mechanisms through which ionizing radiation induces mutagenesis and carcinogenesis in mammalian cells. One project deals with studying the mechanism involved in radiation induced persistent genomic instability, which can occur in the progeny of cells 20-30 generations after exposure to ionizing radiation. Understanding these mechanisms will facilitate a better risk estimate of our exposure to radiation either on earth or in space.
1. Huang, Q., Shan, S, Braun, R.D., Lanzen, J., Anyrhambatla, G., Kong, G., Borelli, M., Corry, P., Dewhirst, M.W., and Li, C-Y. GFP based non-invasive, in vivo monitoring of gene expression(1999). Nature Biotechnology, 17: 1033-1035.
2. Li, C-Y., Huang, Q., Braun, R.D., Lanzen, J., Hu, K., Lin, P., Dewhirst, M.W. Initial stages of tumor cells-induced angiogenesis:evaluation via skin window chambers in rodent models(2000) Journal of the National Cancer Institute, 92: 143-127.
3. Li, C-Y., Little, JB. Hu, K., Zhang, W., Zhang, L., Dewhirst, MW., Huang, Q. Persistent genetic instability in cancer cels induced by non-DNA damaging stress exposures (2001). Cancer Research 60: 428-432
4. Zhang, X., Hu, K., and Li. C-Y. Protection against oxidized LDL-induced vascular endothelial cell death by integrin-linked kinase (2001). Circulation 104: 2762-2766.
5. Huang, Q., Wang, H., Zhang, XW., Yan, B., Dewhirst, MW., and Li, C-Y. A conditionally replicative adenovirus targeted to telomerase-positive cancer cells. (2004) Clinical Cancer Research. 4:1439-1445
6. Moeller, B. J.; Cao, Y., Li, C. Y., Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors; Role of reoxygenation, free radicals, and stress granules (2004) Cancer Cell. 5: 429-441.
7.Zhang,X., Wang, H., Kon, T., Huang, Q., Dewhirst, MW., and Li, C-Y. Enhancement of tumor cell death in vitro and radiation therapy in vivo by use of an siRNA targeted to HIF1-a (2004). Cancer Research. Vol 64:8139-42.
8. Moeller, B., Dreher, M., Rabbani, Z., Schroeder, T., Cao, Y., Li, CY., and Dewhirst, M.W. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity(2005). Cancer Cell. 8: 99-110.
9. Liu, S., Wang, H, Kon, T. and Li, C-Y. Significant enhancement of cancer radiation therapy by use of adenovirus-mediated secretable GRP94/gp96 expression. (2005) Cancer Research 65: 9126-9131
10. Yan, B. Wang, H., Peng, Y., Hu, Y., Wang, H., Zhang, X., Chen, Q., Bedford, J.S., Dewhirst, M.W., and Li, C-Y. Apoptotic DNA fragmentation as a checkpoint for genomic instability (2006). Proceedings of the National Academy of Sciences 103:1504-1509.
11. Yan, B., Wang, H., Rabbani, Z., Zhao, Y., Li, W., Yuan, Y., Li, F., Dewhirst, MW., and Li, C-Y. Tumor necrosis factor alpha is a potent endogenous mutagen that promotes cellular transformation (2006), Cancer Research, 66:11565-11570.
12. Li, F., Sonveax, P., Rabbani, P., Liu, S., Yan, B., Huang, Q., Vujaskovic, Z., Dewhrist, MW., Li, C-Y. Regulation of HIF-1a through S-nitrosylation (2007). Molecular Cell (in Press)