Dr. Ran is an associate professor in the Department of Medical Microbiology, Immunology and Cell Biology at SIU School of Medicine and a member of the SIU Simmons Cancer Institute (SCI). Dr. Ran is a member of the American Association of Cancer Research (AACR). She is a coordinator of monthly research seminars in SCI, serves on the organizing committee for the bi-annual SCI Research Symposium as well as on various committees of the School of Medicine.
1991-1992 Postdoctoral training in Cellular Physiology, The Hospital for Sick Children,
1989-1991 Postdoctoral training in Ion Transport, University of Alabama at Birmingham,
1984-1989 Ph.D. in Biochemistry, the Weizmann Institute of Science, Rehovot, Israel
1981-1983 M.S. in Immunology, Ben-Gurion University, Beer Sheva, Israel
1979-1981 B.S. in Biology, Tel Aviv University, Tel Aviv, Israel
Breast cancer ¨ Tumor Physiology ¨ Tumor Angiogenesis & Hematogenous Metastasis ¨Tumor Lymphangiogenesis & Lymphatic Metastasis ¨ Inflammation and Cancer ¨Inflammatory Lymphangiogenesis ¨Tumor Models in vivo ¨ Chemotherapy & Chemoresistance ¨ TLR4 Role in Cancer ¨ VEGF-A & Angiopoietins Families ¨ VEGFRs and Tie-1/-2 Receptors ¨Transcriptional Regulation of Endothelial Receptors
Main Research Focus:
The main goal of my lab is to delineate mechanisms that promote metastasis, that is, tumor dissemination and formation of secondary lesion in organs other than a primary site. Metastases (and not a primary tumor) are the main cause of mortality from cancer. This process begins when malignant cells penetrate the wall of a blood or lymphatic vessel located in the proximity to tumor (i.e., peritumoral) or inside the tumor mass (i.e., intratumoral). The movement of fluid inside the vessels (blood or lymph, respectively) brings tumor cells to lymph nodes located near the tumor or to other secondary sites. Prevention of new vessels around the tumor and inhibition of their activation should be an effective way of inhibiting tumor spread to lymph nodes and distant organs. My laboratory seeks to understand the molecular, cellular and physiological events leading to the formation of the new intratumoral and peritumoral vessels as well as activation of these vessels that might facilitate a metastatic process. We expect that these studies will help to develop new drugs to suppress metastasis in human cancer patients leading to significant extension of patient life-span after diagnosis.
We are currently focusing on the following projects:
Project 1. Mechanisms of tumor-induced lymphangiogenesis and lymphatic metastasis
Dissemination of epithelial tumors typically begins from invasion of intratumoral or peritumoral lymphatic vessels that deliver tumor cells to the proximate lymph nodes. Although lymph node metastases are not life-threatening by themselves, these lesions serve as a reservoir for systemic dissemination leading to formation of distant metastases, which are the well-recognized cause of death in 90% of cancer patients. Most tumors spread first through lymphatic vessels before reaching blood circulation and disseminating systemically. This led us to propose that inhibition of lymphatic metastasis, which is frequently an initial step of the process, might significantly reduce the incidence of secondary tumors in distant organs. The goal of this project is to identify factors that induce new tumor lymphatic vessels (a process known as lymphangiogenesis) and test drugs that potentially can interfere with this process.
Project 2. Mechanisms of tumor resistance to chemotherapy
The goal of this project is to unravel resistance mechanisms of some tumors to commonly used anti-cancer cytotoxic drugs such as paclitaxel. Studies in our laboratory suggest that paclitaxel elicits production of inflammatory cytokines and angiogenic factors that activate tumor cells in an autocrine manner thus diminishing the cytotoxicity and increasing resistance to therapy. The prior studies examined the role of an angiogenic factor, VEGF-A, in development of resistance to chemotherapy (see PMID 18516298). Currently, we are also examining on the role of drug-induced inflammatory mediators in this process. We also explore a new concept that some Toll-like receptors expressed in epithelial malignant cells might contribute to tumor evasion from chemotherapy.
Project 3. Role of Angiopoietin-2 in hematogenous metastasis
The impact of a vascular remodeling factor Angiopoietin-2 (Ang-2) on growth and metastasis of human tumors has long been a matter of debate. Some studies have shown that Ang-2 promotes tumor angiogenesis and metastasis whereas others demonstrated an opposite effects. We recently discovered in the model of highly aggressive human breast cancer, that Ang-2 plays the key role in promotion of hematogenous metastasis. The mechanisms of Ang-2 enhancement of tumor spread through the blood vascular system are currently under investigation.
Project 4. Transcriptional regulation of VEGFR-3 and Prox1 expression in lymphatic and blood vascular endothelial cells
VEGFR-3 is the main receptor in lymphatic endothelial cells that regulates the formation of new lymphatic vessels. The expression of VEGFR-3 is regulated by transcription factor Prox1, and, as we recently discovered (Flister et al, Blood 115:418-429, PMID 19901262), by transcription factors of the NF-kappaB family. However, many other factors and conditions could also regulate VEGFR-3 directly, or indirectly, through controlling the expression of Prox1. Our current interest is to identify these factors and to delineate biochemical mechanisms that lead to up-regulation of VEGFR-3 and Prox1 expression in lymphatic endothelial and other cells.
Selected Publications (2011-2005):
- “Tumor Angiogenesis” published in February 2012 by Open Access InTechOpen publisher, ISBN 978-953-51-0009-6, web address http://www.intechopen.com/books/show/title/tumor-angiogenesis
Recent publications selected from 48 total:
- Rajput, S., Volk-Draper, L.D. and Ran, S. (2013) TLR4 is a novel determinant of the response to paclitaxel in breast cancer. Molecular Cancer Therapeutics, doi:10.1158/1535-7163.MCT-12-1019
- Volk-Draper, L.D., Rajput, S., Hall, K.L., Wilber, A. and Ran, S. (2012) Novel model for triple-negative basaloid breast cancer: behavior in vivo and response to therapy. Neoplasia, 14(10):926-942. PMID 23097627
- Ran, S. and Montgomery, K. E. (2012) Macrophage-Mediated Lymphangiogenesis: The Emerging Role of Macrophages as Lymphatic Endothelial Progenitors. Cancers, 4(3):618-657. PMID 22946011
- Hall, K.L., Volk-Draper, L.D., Flister, M.J. and Ran, S. (2012) New model of macrophage acquisition of the lymphatic endothelial phenotype. PLoS ONE, 7(3): e31794. PMID 22396739
- Yoshioka, S., King, M.L., Ran, S., Okuda, H., MacLean II, J.A., McAsey, M.E., Sugino, N., Watabe, K. and Hayashi, K. (2012) WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Molecular Cancer Research, Epub ahead of print, PMID 22232518
- Mohamedali, K.A., Ran, S., Gomez-Manzano, C., Ramdas, L., Xu, J., Kim, S., Cheung, L. H., Hittelman, W.N., Zhang, W., Waltenberger, J., Thorpe, P.E. and Rosenblum, M.G. (2011) Cytotoxicity of VEGF121/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2. BMC Cancer 11(1):358. PMID 21849059
- Ray, M.A., Trammell, R.A., Verhulst, S., Ran, S., Toth, L.A. (2011) Model development for the assessment of fatigue during chemotherapy in mice. Comparative Medicine, 61:119-130. PMID 21535922
- Volk, L., Flister, M.J., Chihade, D., Desai, N., Trieu, V. and Ran, S. (2011) Synergy of nab-paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and pre-existing metastases. Neoplasia, 13(4):327-38. PMID 21472137
- Flister, M.J., Volk, L. and Ran, S. (2011) Characterization of Prox1 and VEGFR-3 expression and lymphatic phenotype in normal organs of mice lacking p50 subunit of NF-κB. Microcirculation, 18(2):85-101. PMID 21166921
- Hall, K. and Ran, S. (2010) Regulation of tumor angiogenesis by the local environment. Frontiers of Biosciences, 15:195-212. PMID 20036815
- Ran, S., Volk, L., Hall, K., and Flister, M.J. (2010) Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology, 17:229-251. PMID 20036110
- Flister, M.J., Wilber, A., Hall, K., Iwata, C., Miyazono, K., Nisato, R.E., Pepper, M.S., David C. Zawieja, D.C. and Ran, S. (2010) Inflammation induces lymphangiogenesis through upregulation of VEGFR-3 mediated by NF-κB and Prox1. Blood 115 (2):418-429. PMID 19901262
- Cheng, J.M., Volk, L., Janaki, D.K., Vyakaranam S., Ran, S. and Rao, K.A. (2010) Tumor suppressive function of Rab25 in breast cancer. Int. J. Cancer, 126 (12): 2799-812. PMID 19795443
- Ronen, O., Malone, J.P., Kay, P., Bivens, C., Paruchuri, L.P., Hall, K., Mo, Y.Y., Robbins, T.K. and Ran, S. (2009) Expression of a novel marker, Ubc9, in head and neck squamous cell carcinoma. Head and Neck, 31:845-855. PMID 19309722
- Castro-Rivera, E., Ran, S., Brekken, R.A. and Minna, J.D. (2008) Semaphorin 3B inhibits the PI3K/Akt pathway through neuropilin 1 in lung and breast cancer cells. Can. Research, 68 (20): 8295-8303. PMID 18922901
- Volk, L., Flister, M.J., Bivens, C.M., Stutzman, A., Desai, N., Trieu, V. and. Ran, S. (2008) Nab-paclitaxel efficacy in the orthotopic model of human breast cancer is significantly enhanced by concurrent anti-VEGF-A therapy. Neoplasia, 10 (6):613-623. PMID 18516298
- Whitehurst, B., Flister, M.J., Bagaitkar, J., Volk, L., Bivens, C.M., Pickett, B., Castro-Rivera, E., Brekken, R.A., Gerard, R.D. and Ran, S. (2007). Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer, 121(10):2181-2191. PMID 17597103
- Whitehurst, B., Eversgerd, C., Flister, M., Bivens, C.M., Pickett, B., Zawieja, D.C. and Ran, S. (2006). Molecular profile and proliferative responses of rat lymphatic endothelial cells in culture. Lymphatic Research and Biology, 4(3):119-142. PMID 17034293
- Ran, S., Mohamedali, K., Luster, T.A., Thorpe, P.E. and Rosenblum, M.G. (2005) The vasculo-ablative agent VEGF121/rGel inhibits pulmonary metastases of MDA-MB-231 breast tumors. Neoplasia, 7:486-496. PMID 15967101
- Ran, S., He, J., Huang, X., Soares, M., Scothorn, D. and Thorpe, P.E. (2005) Anti-tumor effects in mice of a monoclonal antibody, 3G4, directed against anionic phospholipids. Clin. Cancer Res., 11(4):1551-1562. PMID 15746060