Amato Giaccia

Postdoctoral Advisees

Laura Castellini, Denise Chan, Renata Colavitti, Elizabeth Finger, Adam Krieg, Erinn Rankin, Olga Razorenova

Research Interests

Research in my lab focuses on the cellular response to stresses found in the tumor microenvironment, especially low oxygen conditions (tumor hypoxia). Our long-term goal is to identify and characterize the molecular and physiological changes induced by the tumor microenvironment that influence the malignant progression of transformed cells. Thus, by understanding the molecular changes which are important for tumor cells to survive in nutrient and oxygen depleted conditions, potentially new targets for cancer therapy will be identified. For the last few years, we have been studying three phenotypes of cells invoked under hypoxic conditions: 1) cessation of cell proliferation under low oxygen conditions, 2) cell death induced by low oxygen conditions, and 3) the angiogenic switch of dormant tumors to rapidly expanding tumors. Let me briefly discuss each of these projects and their potential clinical significance.1) Hypoxia induces a G1/early S-phase cell-cycle arrest. This arrest is different from the cell-cycle arrest induced by gentoxic stress, but may share some of the same genetic determinants such as the retinoblastoma (Rb) tumor suppressor gene. Phosphorylation of Rb is essential for G1 to S-phase progression in the cell-cycle and is controlled by cyclin-cdk activity. Cyclin-cdk activity is controlled by a group of small molecular weight inhibitors which bind to these complexes and inhibit their kinase activity. At present, our data suggest that two of these inhibitors, p21 and p27, are essential in controlling hypoxia/reoxygenation induced cell-cycle arrest. We are continuing to use a combination of genetic and biochemical approaches to examine the state of this pathway in transformed tumor cells to determine whether loss of this checkpoint plays any role in genomic instability. In addition, we are also investigating the complexity of this arrest to determine whether other pathways also contribute to this arrest at different oxygen tensions.2) Hypoxia is a potent...

Publications

• Short hairpin RNA interference therapy for ischemic heart disease. Huang M, Chan DA, Jia F, Xie X, Li Z, Hoyt G, Robbins RC, Chen X, Giaccia AJ, Wu JC "Circulation" 2008 ; 14 Suppl (118) : S226-33
• Oxygen sensitivity of reporter genes: implications for preclinical imaging of tumor hypoxia. Cecic I, Chan DA, Sutphin PD, Ray P, Gambhir SS, Giaccia AJ, Graves EE "Mol Imaging" 2007 Jul-Aug ; 4 (6) : 219-28
• HIF gene expression in cancer therapy. Chan DA, Krieg AJ, Turcotte S, Giaccia AJ "Methods Enzymol" 2007 : (435) : 323-45
• Imaging tumoral hypoxia: oxygen concentrations and beyond. Graves EE, Giaccia AJ "Oncology (Williston Park)" 2007 ; 3 (21) : 368-76; discussion 377-8, 384
• Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells. Sutphin PD, Chan DA, Li JM, Turcotte S, Krieg AJ, Giaccia AJ "Cancer Res" 2007 ; 12 (67) : 5896-905