Molecular Pathology Laboratory
- Diagnostic Veterinary Pathology
- Molecular Diagnostic Pathology
- Rodent and Toxicologic Pathology
- Molecular Carcinogenesis of Human and Veterinary Tumors
Ongoing Research Projects
- Molecular Carcinogenesis of Human and Veterinary Tumors
- Characterization of Mesothelial Cancer Stem Cells
- Mesenchymal stem cells
Molecular Carcinogenesis of Human and Veterinary Tumors.
The long-term objective of my research program is to determine the molecular mechanisms of malignant mesothelioma, in order to design better diagnostic and therapeutic strategies. Despite the use of aggressive therapeutic approaches such as surgery, radiotherapy, chemotherapy, and/or their combinations, the overall outcome of malignant mesothelioma remains very poor. New approaches for the treatment of malignant mesotheliomas are urgently needed. We have recently shown that variable signaling pathways are involved in the carcinogenesis of malignant mesotheliomas. Specifically, activation of the insulin-like growth factor 1 (IGF-1) signaling pathway and inactivation of apoptosis are key in the rat malignant mesotheliomas. We are studying the expression of IGF-1 signaling pathway and the effect of IGF-1R kinase inhibitor in human and rat peritoneal mesothelioma cell lines. In addition, we are studying the role of neurofibromatosis type 2 gene function in human malignant mesothelioma cell lines and animal models. In vitro and in vivo systems will be utilized for preclinical evaluation of new therapeutic regimens for malignant mesotheliomas. Another area of interest is the relationship between overproduction of reactive oxygen species (ROS) by mesothelial cells and Epithelial Mesenchymal Transition (EMT). EMT is an important developmental process during which epithelial cells acquire mesenchymal, fibroblast-like properties. Epithelial cell layers lose polarity and cell–cell contact and undergo a dramatic remodeling of the cytoskeleton. EMT also occurs during the progression of epithelial tumors, endowing cancer cells with increased invasive and metastasizing capability. Recent studies have proposed that ROS signaling may contribute to tumor development and metastasis by eliciting a phenotypic EMT conversion resulting in more hardy, resilient cells. The lab is currently examining the role of EMT markers in human malignant mesotheliomas.
Characterization of Mesothelial Cancer Stem Cells.
A long-term objective of research program is to elucidate the pathogenesis of human malignant mesothelioma (HMM), in order to design better diagnostic and therapeutic strategies. Cancer stem cells (CSCs) have been the subject of great interest in recent years because of their unique biological properties and potential therapeutic significance. The CSCs could drive tumor growth, invade into other tissues, and form metastatic tumors. Moreover, tumor recurrence following traditional antiproliferative therapy may be due to untargeted CSC compartment repopulating the tumor. Because CSC-specific cell surface markers are known for only a limited number of tumors, characterization of the putative CSCs in solid and leukemic tumors has largely relied on the separation of side populations (SP) by Hoechst 33342 staining. SP and non-SP of HMM cell lines have been separated using Hoechst 33342 staining method, and the biological properties including proliferation, invasiveness, chemosensitivity and clonogenicity, are being assessed. The tumorigenicity of the SP and NSP was assessed by subcutaneous injection into immunodeficient mice. This study will allow us to determine if SP fraction is truly enriched for CSCs in HMM cell lines, and pave the way to further analyze the mechanisms involved in the maintenance and amplification of potential CSCs of HMMs.
Identification of Side Population in Human Mesothelioma Cell line using Hoechst 33342 dye in the absence (A) or presence (B) of verapamil hydrochloride.
Morphological features of xenografted tumors produced by injecting SP cells into NOD/SCID mice. A: H & E staining, B: Immunohistochemical staining for cytokeratin, C: Immunohistochemical staining for vimentin.
Mesenchymal stem cells.
Tumor-associated stroma is known to play a critical role in the formation and progression of lung tumors. Studies have suggested that bone marrow derived cells migrate to the tumor tissue where they differentiate into tumor-associated stromal cells. Yet, whether or not bone marrow-derived cells are the source of tumor-associated stroma remains controversial, and their role in the carcinogenic process has not been explored. We are interested in examining the role of mesenchymal stem cells in the formation of tumor-associated stroma at the progression stage of lung carcinogenesis. Using a microchimera mouse lung cancer model harboring traceable bone marrow-derived cells, the distribution of stromal cells originating from bone marrow-derived cells in lung tumor-associated stroma at each stage of carcinogenesis will be determined. These studies will provide a novel experimental system that can be used to study mechanisms controlling the formation of the tumor-associated stroma, critical interactions between bone marrow-derived cells and tumor cells and/or resident stromal cells, and treatments that control stromal cells and, thus, tumor growth.
- Susan D'Costa, PhD, Research Specialist (2008 - Current)
- Byung-Il Yoon, DVM, MS, PhD, Visiting Researcher from Korea (2009- 2010)
- Morika Williams, Summer Research Experience for Undergraduate Students (2009)
- Baozhen Hwang, Pack Promise Program (2008-2009)
- Kai Kiyonori, DVM, MS, PhD, Visiting Researcher from Japan (2007- 2008)
- Kwang-Ok Shin, MS, Research Specialist (2006-2008)
- Nancy Brown, BS, Research Assistant (2007)