Keck School of Medicine
USC / Norris Comprehensive Cancer Center
- Cancer Biology,
- Developmental Biology
- Cardiovascular & Skeletal Muscle Diseases
- Signal Transduction
Research OverviewIn our body, there are two major circulatory systems, the blood vascular system and the lymphatic vascular system. The two systems share functional and anatomical similarities: the most important function of these systems is to carry fluids (blood and lymph fluids) and both systems mainly consist of vessels that are lined with a cell type called endothelial cells. Although the two systems were described by Hippocrates, the blood vascular system has been extensively studied, whereas the lymphatic system has been unintentionally neglected for a long time, despite its vital roles. While the blood vascular system is a circular system where blood leaves and returns to the same organ (heart), the lymphatic system is an blunt ended linear system, which begins at the peripheral tissues or various organs and ends to its connection to the vein. The lymphatic vessels deliver tissue fluids, cells and macromolecules to the blood vascular system for recirculation. In addition to this tissue fluid homeostasis, the lymphatic system is essential for proper immune functions and absorption of molecules in the digestive system. Unfortunately, many tumors spread to other parts of body through lymphatic vessels.
The long term goal of my laboratory is to understand the molecular mechanisms underlying the physiological and pathological lymphangiogenesis. Our immediate focus is devoted to three major topics.
� To define the molecular mechanism of lymphatic reprogramming by KSHV and its pathological significance in KS tumorigenesis.
� To understand the molecular mechanism of physiological lymphangiogenesis (during and post development).
� To delineate the molecular interactions between lymphatic endothelial cells and metastatic tumor cells
Regarding our first goal, we have recently found that the homeobox protein Prox1 functions as a key regulator in a genetic program specifying lymphatic cell fate in vitro. Prox1 could reprogram blood vascular endothelial cells to adopt a lymphatic endothelial cell phenotype. This study revealed that adult blood vascular endothelial cells can be further reprogrammed to lymphatic endothelial cells by expressing the key regulator, Prox1, providing a new insight into post-developmental cell fate specification. This finding of Prox1-mediated lymphatic reprogramming provided a novel conceptual paradigm of cell-fate reprogramming during tumorigenesis of Kaposi sarcoma (KS). KS is the most common neoplasm in HIV-positive patients. Although KS tumor cells were identified to be endothelial cells, their histogenetic origin remained controversial because the KS-tumor cells express both blood vascular and lymphatic endothelial cell markers. I found that KS-associated herpes virus (KSHV)-infection of vascular endothelial cells resulted in reprogramming of these cells to adopt a lymphatic-specific phenotype and that this viral-mediated host cell fate reprogramming involved upregulation of Prox1. Based on our evidences, we built a hypothesis that KSHV may infect blood vascular endothelial cells (resident and/or circulating precursor cells) and subsequently reprogram their cell fate toward lymphatic endothelial cells. The molecular mechanism underlying this KSHV-induced cell fate reprogramming remains to be studied. Its pathological significance in KS tumorigenesis also remains to be investigated.(See related articles: Hong et al, Dev. Dyn. 2002, Hong et al, Cell & Tissue Res. 2003, Hong et al, Nat. Genet, 2004).
The second goal of our laboratory is to study the molecular mechanism underlying physiological lymphatic vessel growth during and after development. We have recently defined that vascular endothelial growth factor (VEGF)-A, previously thought to function on blood vessels, also plays an important role in lymphangiogenesis (Hong et al, FASEB 2004). Also, we have reported that Prox1, the master control gene of lymphatic development, upregulates fibroblast growth factor receptor (FGFR)-3 by a direct interaction to its binding sites present in the FGFR-3 promoter (Shin et al, Mol. Biol. Cell, 2006). We will further study the molecular mechanism of lymphatic system development.
The third goal of our lab is to define the molecular interactions between tumor cells and lymphatic endothelial cells which may be essential for tumor spread. We are currently working on communications between them using the genomic and proteomic approaches. Finally, we have got an NIH funding to establish a lymphatic specific-fluorescent mouse model. This mouse model will be a valuable tool to study various aspect of lymphatic vessel development.