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Benjamin K. Tsang, PhD
Telephone: 613-798-5555, Ext. 16040 (Office)
Telephone: 613-798-5555, Ext. 13713 (Laboratory)
Telephone: 613-798-5555, Ext. 14081/13906 (Res. Admin. Assistant)
Fax: 613-761-4403
btsang@ohri.ca
 Civic Campus
(see Contact page for maps)
 
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Senior Scientist, Chronic Disease, Ottawa Hospital Research Institute
Director, Reproductive Biology Unit, Department of Obstetrics and Gynaecology
Professor, Department of Obstetrics and Gynaecology (Divisions of Reproductive Medicine and Gynaecologic Oncology) and Cellular & Molecular Medicine, University of Ottawa
Biographical Sketch
B.S. (Cum Laude) : Chemistry, Bemidji State University, Minnesota, U.S.A. (1967-1971)
M.S. : Biochemistry, University of Iowa, Iowa, U.S.A. (1971-1973).
Ph.D. : Pharmacology, University of Ottawa, Canada (1973-1976).
Post-Doctoral Studies : Physiology, Obstetrics and Gynaecology, University of Western Ontario, Canada (1976-1978)
Research
Regulation of Ovarian Follicular Development and Atresia
Ovarian follicular development and atresia is the culmination of complex actions and interactions of gonadotropins and intra-ovarian regulators. Although the importance of FSH, thyroid hormone, epidermal growth factors and transforming growth factor beta family members in the regulation of ovarian function is well established, how these ovarian regulators interact at the subcellular levels in determining the fate of granulosa cells (proliferation differentiation vs. apoptosis) and eventually follicle destiny (continual growth vs. atresia) is poorly understood. In this research program, we examine the crosstalk between death and survival signaling pathways in the regulation of ovarian follicular growth and atresia by endocrine, paracrine and autocrine regulators and/or extracellular matrix protein-receptor activation. Our overall hypothesis is that the fate of an ovarian follicle is determined by a balance between actions of cell survival promoters and cell death inducers, which are mediated by the induction and/or activation of granulosa cell intracellular intermediates, which are pro-apoptotic (e.g. prohibitin, caspases), and anti-apoptotic [Inhibitor of Apoptosis Proteins (XIAP and HIAP-2), FLICE-like Inhibitory Proteins (FLIP), focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K)]. Our studies will form the basis for future investigations on the nature and regulation of various ovarian disorders (e.g. polycystic ovarian disease, premature ovarian failure, luteal phase defect and ovarian cancer) and provide important insight into their pathophysiology. (Funded by Canadian Institutes of Health Research).
Human Ovarian Cancer Biology and Chemoresistance
Ovarian cancer (OVCA) is the most lethal gynaecological cancer in the Western world and ranks fifth among the most common female cancers. Despite advances in our understanding of tumour biology, the overall mortality from OVCA remains high. Cisplatin (CDDP) is a first-line chemotherapeutic agent for OVCA but chemoresistance remains a hurdle to successful therapy. Chemoresistance in human OVCA is due in part to defects in drug-induced apoptosis, which is associated with activation of the PI3K/Akt Pathway, stabilization of cell survival intermediate (XIAP and FLIP), p53 gene mutation, suppressed p53 activation and mitochondrial protein release. Our overall objective is to study the molecular and cellular mechanisms of chemoresistance in human OVCA. Specifically, we examine if and how Akt, XIAP, FLIP and p53 interact in the regulation of chemosensitivity of OVCA cells. We hypothesize that p53-induced apoptosis is a determinant of chemosensitivity. We investigate if Akt confers chemoresistance in part by (a) suppressing CDDP-induced p53 phosphorylation and activation, (b) stabilization of Xiap via phosphorylation and inhibition of Xiap ubiquitination and proteasomal degradation induced by CDDP, (c) preventing CDDP-induced mitochondrial release of cytochrome c, Smac/Diablo, Omi and apoptosis inducing factor, and (d) suppressing p53-dependent, proteasomal degradation of FLIP. The proposed studies will provide novel insights into the pathobiology of CDDP resistance and for development of new therapeutic strategies for chemoresistant OVCA (Supported by Canadian Institutes of Health Research and National Cancer Institute of Canada).
Role and Regulation of Placental Apoptosis in Health and Diseases
The understanding of the regulatory mechanisms responsible for placental growth is crucial to further our knowledge of what controls fetal growth. Indeed, placental growth is directly correlated with fetal growth as the placenta is essential to provide adequate nutrient, blood and oxygen supply to ensure adequate fetal growth and development. Despite advances in perinatal care, fetal growth restriction, often seen in pre-eclampsia, remains a leading cause of perinatal morbidity and mortality. Infants from these pregnancies often suffer multiple complications such as asphyxia, respiratory distress syndrome, prematurity and metabolic disturbances. In collaboration with Drs. Andrée Gruslin and Ajoy Basak, we are testing the hypothesis that soluble Fas ligand is involved in the regulation of placental apoptosis and is dependent on expression and/or processing of mFasL as regulated by MMP-7 and its inhibitor, TIMP-3. The processing of mFasL is dysregulated in abnormal placental conditions such as pre-eclampsia and fetal growth restriction, which are characterized by hypoxia. The overall objective of this research program is to examine the role and regulation of soluble Fas ligand in the control of apoptosis in normal and pathological conditions of the human placenta. Specifically, we will: (a) determine the expression of the precursor protein of sFasL (mFasL) throughout placental development and its relationship to placental apoptosis, (b) assess the processing of mFasL and its significance in initiation of placental apoptosis throughout development by examining the expression and activities of MMP-7 and, TIMP-3, (c) examine the influence of hypoxia on mFasL expression and processing and assess the significance of the above mFasL-related changes in pathological placental development, (d) the interaction of EGF and Leptin in the regulation of trophoblast invasion; and (e) the role of proprotein convertase-4 and IGF-II terminal maturation in the pathophysiology of pre-eclampsia and intrauterine growth restriction (support by the Toronto Sick Children Hospital Foundation and Philip Morris Company).
Reproductive and Mammary Tumourigenic Effects of Environmental Toxins
The overall objective of this program is to investigate the influence of environmental toxins on female reproductive function and mammary tumourigenesis. In particular, the effects of physiologically relevant concentrations of organochlorine pollutants, e.g. dioxins and PCBs, on ovarian follicular development and atresia, ovulation and mammary tumour formation are studied (Funded by the Toxic Substances Research Initiative, Health Canada).
Molecular and Cellular Markers for Oocyte Health in Assisted Reproduction
Despite considerable advances made in recent years in improving the outcome of assisted reproductive technologies, a significant hurdle yet to overcome in IVF-ET relates not only in the identification of the determinants for poor oocyte quality and embryo development and mortality, but also to defining strategies to ameliorate these conditions. In collaboration with Drs. M. Mbikay and M.C. Léveillé in The Ottawa Hospital IVF-ET Program, efforts are made to examine cumulus cell biomarkers and apoptosis and to correlate the observed changes with oocyte / cumulus cell morphology and the ability of the oocyte to develop into a viable embryo following fertilization. In addition, this research program should provide a better understanding the molecular and cellular mechanisms of human embryo fragmentation and their significance as determinants in IVF- ET outcome, as well as important insights for the development of diagnostic tests for oocyte quality for IVF-ET (Supported by Canadian Institutes of Health Research).
Honours and Awards
2008 - 2008 Award of Excellence in Reproductive Medicine, Canadian Fertility and Andrology Society, Canada.
2008 - Outstanding Alumnus, Bemidji State University, Minnesota, USA
2005 - J. David Grimes Research Career Achievement Award, Ottawa Health Research Institute
2003 - Japan Society for the Promotion of Science Visiting Professorship, Kobe University School of Medicine, Kobe, Japan
2002 - University of Ottawa Faculty of Medicine Recognition Award for Outstanding Contributions in Medical Education
1996 - Award of Excellence, Faculty of Medicine, University of Ottawa, in recognition of outstanding achievement or contribution to the Faculty in research, scholarship, education, or other contributions to the life of the Faculty.
2005 - Co-Founder and Co-Chair, Sino-Canada Bilateral Program in Reproductive Health Research - "Building a Healthy Family through Scientific Excellence and Innovation: From Bench to Bedside to Community and Back"
2004 - Co-Founder and Co-Chair, Canada-Japan Bilateral Exchange Program in Reproductive Biology and Human Reproduction - "Improving Women's Reproductive Health Through Research and Education: From Bench to Bedside to Community"
2004 - Program Director, CIHR-funded, Strategic Training Initiative in Research in Reproductive Health Sciences
Affiliations
2005 to 2006 President, Canadian Fertility and Andrology Society
2006 to Present Honorary Professor, Nanjing Medical University, China
2004 to Present Honorary Professor, State Key Laboratory in Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
1998 to Present Honorary Professor, Jinan University, Guangzhou, China
1998 to Present Director, Reproductive Biology Unit, Department of Obstetrics and Gynaecology, The Ottawa Hospital (Civic Campus)
1989 to Present Active Scientific Research Staff, The Ottawa Hospital (Civic Campus)
2006 to Present Editorial Board, Reproduction
2006 to Present Editorial Board, Journal of Ovarian Research
2005 to Present Editorial Advisory Board, Journal of Obstetrics and Gynaecology Canada
2001 to 2005 Associate Editor, Journal of Obstetrics and Gynaecology Canada
2002 to 2006 Editorial Board, Biology of Reproduction
1999 to 2003 Associate Chair, Research, Department of Obstetrics & Gynaecology, University of Ottawa
1984 to 1986 Director of Research, Ottawa Civic Hospital
Current Funding
Research Operation Support
2007 - 2012 Canadian Institutes of Health Research for project entitled "Molecular and Cellular Mechanisms of chemoresistance in ovarian cancer" - Operating Grant (with Drs. A. Basak and E. Carmona): $630,615
2000 - 2010 Canadian Institutes of Health Research for project entitled "Regulation of Ovarian Follicular Development and Atresia" - Operating Grant:
2005 - 2010 $702,790
2000 - 2005 $731,376
2008 - 2013 Natural Science and Engineering Research Council for program entitled "The Healthy Embryo Research Network" for Strategic Network Grant (Drs. M-A Sirard et al): $4,895,000.
2007 - 2008 Department of Foreign Affairs and International Trade Canada - Going Global Science & Technology Program for the Fourth Canada-Japan Bilateral Workshop in Human Reproduction and Reproduction. - Contract (with Dr. W. Gibb): $ 10,000.
2006 - 2008 Cancer Research Society for project entitled: "Role and Regulation of FLIP in the Control of Chemosensitivity in Ovarian Cancer" - Operating Grant: $ 104,800
2006 - 2007 Department of Foreign Affairs and International Trade Canada - Going Global Science & Technology Program for "Establishing the Mechanisms of Ovarian Proliferative Disorders and Joint Centres in International Reproductive Health" - Contract: $ 21,219.
2006 - 2009 Canadian Institutes of Health Research and National Natural Science Foundation of China (China-Canada Joint Health Research Initiative) for project entitled "Ovarian Follicular Development: Dysregulation in Polycystic Ovarian Syndrome" - Operating Grant: $ 90,000 + 450,000 RMB
2003 - 2008 Strategic Research Initiative of the Institute of Human Development and Child and Youth Health, Canadian Institutes of Health Research for project entitled "Program on Oocyte Health" - Program Grant: $2,746,575
2002 - 2007 Canadian Institutes of Health Research for project entitled "Role of Xiap and Akt in chemoresistant ovarian cancer" - Operating Grant: $573,129
2005 - 2006 Department of Foreign Affairs and International Trade (Going Global Program) for Sino-Canada Bilateral Workshop in Reproductive Health Research "Building a Healthy Family through Scientific Excellence and Innovations: from Bench to Bedside to Community and Back" - Contract: $ 50,000
2002 - 2005 National Cancer Institute of Canada for project entitled "Role of Xiap and Akt in chemoresistant ovarian cancer" - Operating Grant: $93,212
2002 - 2005 Philip Morris Company for project entitled "Role of PI3K signalling pathway in mediating smoking-induced inhibition of trophoblast invasion" - Operating Grant (with Dr. Andreé Gruslin): $448,600
Research Personnel Support
2006 - 2008 CIHR-STIRRHS Postdoctoral Fellowship for Dr. Mingju Cao: $ 76,000
2008 - 2010 Swedish Research Council Postdoctoral Fellowship for Dr. Patrik Vahlberg: $ 81,384
2006 - 2008 CIHR-STIRRHS Postdoctoral Fellowship for Dr. Noriko Kobayashi: $ 75,000
2007 - 2008 Ontario Graduate Scholarship - Science and Technology for Lihua Wen: $ 15,000
2005 - 2007 NSERC Canada Doctoral Scholarship for Jesse Craig: $ 70,000
2004 - 2006 CIHR Canada Doctoral Scholarship for Michael Fraser: $ 70,000
2002 - 2006 Government of Iran Graduate Scholarship & Tuition for Dr. Mohammad Abedini: $ 124,000
2004 - 2009 Government of Oman Scholarship and Tuition for Ms. Shadia Al Bahlani: $120,000.
Current Research Group Members
Benjamin Tsang, PhD (Senior Scientist)
Andree Gruslin, MD (Associate Scientist)
Qing Qiu, MD (Research Associate)
Mingju Cao, PhD (Postdoctoral Fellow; CIHR-STIRRHS Postdoctoral Fellowship recipient)
Patrik Vahlberg, PhD (Postdoctoral Fellow, Swedish Research Council Postdoctoral Fellowship recipient)
Meirong Du, MD, PhD (Postdoctoral Fellow)
Mohammad Abedini, PharmD (PhD Candidate, funded by Government of Iran)
Shadia Al Bahlani, MSc (PhD Candidate, funded by Government of Oman)
Lihua Wen, MSc (PhD Candidate, OGS-ST studentship recipient)
Cheng Zhang, MSc (PhD Candidate; Graduate Scholarship Recipient, State Scholarship Fund, China Scholarship Council)
Ahmed Ali, MSc (PhD Candidate)
Qi Wang, MSc (PhD Candidate)
Mike Woo, MSc (PhD Candidate)
Maliha Haider, BSc (MSc Candidate)
Publications
Key Selected Publications
Abedini MR, Muller EJ, Brun J, Bergeron R, Gray DA and Tsang, BK. Cisplatin induces p53-dependent FLICE-like inhibitory protein (FLIP) ubiquitination in ovarian cancer cells. Cancer Research 68: 4511-4517 (2008).
Fraser M, Bai T and Tsang, BK. Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Internat. J Cancer. 122:534-546 (2008)
Yang X, Fraser M, Abedini MR, Bai T and Tsang, BK. Regulation of AIF-Mediated, Cisplatin-Induced Apoptosis by Akt. Br. J. Cancer 98: 803-808 (2008).
Yang X, Fraser M, Moll U. Basak A, and Tsang, BK. Akt-mediated Cisplatin resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-dependent Mitochondrial Death Pathway. Cancer Research 66:3126-3136 (2006).
Wang HM, Jiang JY, Zhu C, Peng C and Tsang, BK. Role and Regulation of Nodal/ALK7 Signalling pathway in the control of ovarian follicular development and atresia. Molec. Endocr. 20: 2469-2482 (2006)
Fraser M, Chan SL, Chan SSL, Fiscus RR and. Tsang, BK. Regulation of p53 and suppression of apoptosis by the soluble guanylyl cyclase/cGMP pathway in human ovarian cancer cells. Oncogene 25:2203-2212 (2006).
Orisaka M, Orisaka S, Jiang J-Y, Craig J, Wang Y, Kotsuji F and Tsang, BK. Growth Differentiation Factor-9 is anti-apoptotic during follicular development from preantral to early antral stage. Molec. Endocr. 20: 2456-2468 (2006).
Qiu Q, Yang M, Basak A, Mbikay M, Tsang, BK, Gruslin A. ProIGF-II processing in the human placenta: The expression and role of the proprotein convertase PC4. Proc Nat. Acad. Sci. USA 102: 11047-11052 (2005).
Dan HC, Sun M, Kaneko S, Feldman RI., Nicosia SV, Wang HG, Tsang, BK, Cheng JQ. Akt Phosphorylation and Stabilization of XIAP. J. Biol. Chem. 279: 5405-5412 (2004).
Abedini MR., Qiu Q, Yan X and Tsang, BK. Possible Role of FLICE-Like Inhibitory Protein (FLIP) in Chemoresistant Ovarian Cancer Cells in vitro. Oncogene 24: 6977-7004 (2004).
Wang Y, Rippstein PU and Tsang, BK. Role and gonadotropic regulation of X-linked inhibitor of apoptosis protein expression during ovarian follicular development in vitro. Biol. Reprod. 68: 610-619 (2003).
Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ and Tsang, BK. p53 is a determinant in Xiap/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Research 63: 7081-7088 (2003).
Xiao CW, Asselin E and Tsang, BK. NF6B-mediated induction of FLICE-like inhibitory protein prevents tumour necrosis factor-"-induced apoptosis in rat granulosa cells. Biol. Reprod. 67: 436-441 (2002).
Wang Y, Chan S and Tsang, BK. Involvement of I?B-independent NF?B activation in the gonadotropic regulation of Xiap expression during ovarian follicular development in vitro. Endocrinology 143: 2732-2740 (2002).
Xiao CW, Ash K and Tsang, BK. NF?B-mediated X-linked inhibitor of apoptosis protein expression protects rat granulosa cells from tumour necrosis factor ?-induced apoptosis. Endocrinology 142: 557-563 (2001).
Asselin E, Mills GB and Tsang, BK. Xiap regulates AKT activity and its caspase 3- dependent cleavage during cisplatin-induced apoptosis in human ovarian cancer cells. Cancer Research 61: 1862-1868 (2001).
Sasaki H, Sheng Y, Kotsuji F and Tsang, BK. (2000). Down-regulation of Xiap induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Research 60: 5659-5666.
Recent Publications (2004- Present)
Gregory-Bass RC, Olatinwo M , Xu W, Matthews R, Stiles JK, Thomas K, Liu D, Tsang, BK and Thompson WE. Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis. Internat. J. Cancer 122: 1923-1930 (2008)
Leung LH, Fraser M, Fiscus RR and Tsang, BK. Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: involvement in p53 regulation and cisplatin resistance. Br. J. Cancer 98, 1803 - 1809 (2008)
Wu A, Anupriwan A, Iamsaard S, Chakrabandhu K, Santos DC, Rupar T, Tsang BK, Carmona E and Tanphaichitr N. Sperm Surface Arylsulfatase A Can Disperse the Cumulus Matrix of Cumulus Oocyte Complexes. J. Cell Physiol. 213: 201-211. (2007)
Craig J, Orisaka M, Wang HM, Orisaka S, Thompson W, Zhu C, Kotsuji F and Tsang, BK. Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death. Frontiers in Bioscience 12: 3628-3639 (2007).
Wang HM and Tsang, BK. Nodal signaling and Apoptosis. Reproduction 133: 1-8 (2007).
Qiu Q, Jiang JY, Bell M, Tsang, BK and Gruslin A. Activation of endoproteolytic processing of IGF-II in fetal, early postnatal and pregnant rats and persistence of circulating levels in postnatal life. Endocrinology 148: 4803- 4811 (2007).
Jahani-Asl A, Basak A and Tsang, BK. Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and influence of phosphorylation. FEBB Letters. 581: 2883-2888 (2007).
Bissonette F, Cohen J, Collins J, Cowan L, Dales S, Dills S, Greene C, Gysler M, Hanck B, Hughes E, Leader A, McDonald S, Marrin M, Martin R, Min J, Mortimer D, Mortimer S, Smith J, Tsang, BK, Van Vugt D and Yuzpe A (in alphabetical order). Incidence and complications of multiple gestation in Canada: proceedings of an expert meeting. Reproductive BioMedicine Online. Vol 14, No 6, 773-790 (2007).
Orisaka M, Tajima K, Mizutani T, Miyamoto K, Tsang, BK, Fukuda S, Yoshida Y, and Kotsuji F. Granulosa Cells Promote Differentiation of Cortical Stromal Cells into Theca Cells in the Bovine Ovary. Biol. Reprod. 75: 734 - 740 (2006).
Wang HX, Wang HM, Li QL, Lin HY, Yang Q, Zhang H, Tsang, BK, and Zhu C. Proteasome subunit LMP2 is required for matrix metalloproteinase-2 and-9 expression and activities in human invasive extravillous trophoblast cell line. Journal of Cellular Physiology 206: 616-623 (2006)
Yan XJ, Fraser M, Qiu Q and Tsang, BK. Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecol. Oncology 102: 348-355 (2006).
Lin HY, Yang Q, Wang HM, Qi JG, Zhang H, Wang HX, Tsang, BK and Zhu C. Involvement of Smad4, but not Smad2, in transforming growth factor -beta1-induced trophoblast expression of matrix metalloproteinase-2. Frontiers in Bioscience 11: 637-647 (2005).
Desaulniers D, Xiao G-H, Leingartner K, Chu I, Musicki B, Tsang, BK (2005). Comparison of brain, uterus and liver mRNA expression for cytochrome P450s, DNA methytransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists. Toxicol Sci. 86:175-184.
Qiu Q, Yang M, Tsang, BK and Gruslin A. Fas ligand expression by maternal decidual cells is negatively correlated with the abundance of leukocytes present at the maternal-fetal interface. J. Reproductive Immunology. 65:121-132 (2005).
Xu G, Munir S, Zhong Y, Yang, BB, Tsang, BK, Peng C. Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. J. Clin. Endocr. Metab 89:5523-5534 (2004)
Jiang J-Y and Tsang, BK. Optimal conditions for successful in vitro fertilization in Sprague-Dawley rats. Biol. Reprod. 71:1974-1979 (2004).
Qiu Q, Yang M, Tsang, BK, Gruslin A. Both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling are required in epidermal growth factor-induced human trophoblast migration. Molec Hum Reprod 10: 677-684 (2004)
Chen J, Halappanavar SS, St-Germain JG, Tsang, BK and Li Q. Role of Akt/protein kinase B in the activity of transcriptional coactivator p300. Cell Molec Life Sci 61: 1675-1683(2004).
Desaulniers D, Leingartner K, Musicki B, Cole J, Li M, Charbonneau M, and Tsang, BK. Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the development of methylnitrosourea-induced mammary tumors in Sprague Dawley rats. J. Toxicol Environ. Health 67: 1457-1475 (2004)
Thompson WE, Asselin E, Branch A, Stiles JK, Sutovsky, P., Lai, L., Im, G.S., Prather, R.S., Isom, SK, Rucker, E. III, and Tsang, BK Regulation of Prohibitin Expression during Follicular Development and Atresia in the Mammalian Ovary. Biol. Reprod. 71: 282-290 (2004)
PLEASE REFER TO CURRICULUM VITAE FOR COMPLETE LIST OF PUBLICATIONS
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