|
|
Research Description:
Our research efforts are directed towards the understanding of how the ever-changing tumor microenvironment promotes the progressive nature of human cancers. Decades of cancer research have come to a conclusion that cancer is, in essence, a genetic disease acquiring dynamic changes in the genome. The development of human cancers requires a complex succession of genetic alterations over time, thereby conferring selective growth advantages on cells undergoing transformation through the activation of oncogenes and the inactivation of tumor-suppressor genes. The genetic changes occur progressively at both nucleotide and chromosome levels, resulting in gene mutation, inactivation, and amplification, and chromosome loss, gain, and translocation. However, how does human cancer acquire genetic instability? Why human cancers become genetically unstable? Do cancer cells gain an advantage by acquiring genetic instability? These are the fundamental questions that we attempt to answer by incorporating the tumor microenvironment into cancer biology in order to identify the molecular pathways leading to genetic instability. Our overall goal is to understand the underlying mechanisms of tumor progression in search for a cure for cancer.
The tumor microenvironment is characterized by low oxygen tension (or hypoxia), acidic pH, and nutrient deprivation. We have been particularly interested in the role of hypoxia in tumor development, and have demonstrated recently that the hypoxia-inducible factor 1a (HIF-1a), a master regulator of oxygen homeostasis, induces genetic instability by inhibiting DNA repair gene expression. In particular, hypoxia down-regulates DNA repair genes such as MSH2 and NBS1. Inactivation of the mismatch repair gene MSH2 is responsible for microsatellite instability and is directly linked to hereditary nonpolyposis colorectal cancers. Likewise, genetic defect in NBS1 gene is the cause of the Nijmegan breakage syndrome, which is characterized by chromosomal instability and a predisposition to malignancies. At the molecular level, we have identified a novel HIF-1a-c-Myc pathway that accounts for the hypoxic suppression of DNA repair genes. Based on these findings, we hypothesize that HIF-1a mediated hypoxic suppression of DNA repair results in genetic instability, thereby driving tumor development and progression.
To test this hypothesis, we are using cell culture and mouse models to ascertain whether activation of the HIF-1a-c-Myc pathway is sufficient to accelerate tumor formation and metastasis. Among various types of solid tumors, glioblastoma--the most frequently occurring and mostly deadly human intracranial tumor--is of our particular interest because of the presence of extreme hypoxia within the tumor and its salient feature of local invasion. Immunohistochemical staining of human glioblastomas has revealed that HIF-1a is especially overexpressed in areas surrounding necrosis and at the peripheral where local invasion takes place. So is HIF-1a overexpression essential to glioblastoma progression via the induction of genetic instability? Is genetic instability an underlying cause of chemoresistance frequently seen in glioma patients? We attempt to address these questions by employing a variety of techniques including cytogenetics, comparative genomic hybridization, and bioinformatics. Moreover, we have identified cell-cycle genes such as CDC25A and CDNK1A, which are also regulated by the HIF-1a-c-Myc pathway. We are interested in identifying additional target genes of this pathway with microarray technology and characterizing the relevant signaling pathways with biochemical and proteomic methods.
Research Keywords:
Brain tumors, Cell cycle, DNA repair, Genetic Instability, Hypoxia, Metastasis, Tumor progression