Associate Professor of Medicine
Program Manager, Program in Immunology
Shelby Building, Room 415
1825 University Boulevard
BS, Tel Aviv University, Tel Aviv, Israel
MSc, Tel Aviv University, Tel Aviv, Israel
PhD, Wezimann Institute of Science, Rehovoth, Israel
Fogarty Visting Fellow, Laboratory of Membrane Biology, NIH
Fogarty Fellowship, NIH, 1979-1981
American Lung Association, Career Investigator Award, 1987-1992
My main recent scientific interests are in the biology of the genitourinary tract. Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic inflammatory disease of the bladder wall. More than 100 years after first being described, the diagnosis of BPS/IC is still associated with controversy. Given the difficulties associated with the diagnosis of BPS/IC, it is not surprising that the etiology of this syndrome is poorly understood. Several theories for the etiology of BPS/IC have been proposed over the years including infection, immunological etiology, leaky urothelium resulting from a deficiency of its surface coat of glycosaminoglycans, activated mast cells and neural changes.
In vitro studies in my laboratory have been consistent with the possibility that BPS/IC may develop in response to noxious stimuli in the bladder lumen1,8,17,18. Thus, lipoteichoic acid (LT-2), a cell wall component of the gram-positive bacterium Streptococcus faecalis, stimulated the proliferation rate of a subpopulation of basal uroepithelial cells with high proliferative potential (possibly stem cells)15. their progeny differentiated at a higher rate and displayed abnormal expression and cellular distribution of β1 integrins14,16, and LT-2 required activation of iNOS13 and NFκB10. Moreover, our studies provided evidence for altered proliferative ability of progenitors of urothelial cells in cell cultures isolated from patients with BPS/IC12. These studies raised a number of questions: What are the mechanisms by which noxious stimuli in the bladder lumen may trigger abnormal function of the muscle and nerve tissue underlying the uroepithelium, causing pain and persistent urge to void? In addition, how is it possible that chronic symptoms similar to those characteristic of bacterial cystitis persist for years in patients with BPS/IC in whom no infectious agent is detected at the time of diagnosis? Based on emerging data from several laboratories, I postulated in a recent review1 that epigenetic reprogramming mechanisms in the bladder may provide an explanation for uroepithelial, mast cells and nerve cell abnormalities in BPS/IC, as well as propagation of this altered state in the absence of the signal that may have triggered it. Data supporting this hypothesis would provide a rationale for new diagnostic, treatment and dietary intervention options for BPS/IC.
My second scientific interest is dietary prevention of prostate cancer (PC). PC is the most commonly diagnosed cancer in North American men. Findings of latent or clinically insignificant PC occurs in a large proportion, and at equal rates, in autopsy studies among men from Asian countries and the United States. In contrast, the incidence of clinically significant PC is an order of magnitude higher in the United States. Epidemiological studies suggest that this might be attributable to differences in environmental factors and life style, including nutrition. Aggressive PC is less prevalent among Asian men where the intake of soy products is very high. However, with Westernization and loss of traditional eating habits, the pattern of disease incidence is also changing in Asian men. On the basis of these findings, it has been postulated that phytoestrogens, including genistein, may have a preventive role in PC. Studies in my laboratory in a transgenic mouse model of prostate cancer (TRAMP mice), supported this hypothesis9.
Prostate cancer fatalities are rarely due to primary tumors, but rather to widespread metastatic disease. The preferential colonization of bone by prostatic adenocarcinomas has been attributed to the passage of prostate epithelial cells from the prostate to the spine via paravertebral blood vessels. However, molecular mechanisms that facilitate retention of metastatic cells in bone and, their subsequent unrestricted proliferation, are poorly understood. In my laboratory, in vitro studies in cell cultures isolated from the human prostate11 and in vivo studies in the transgenic mouse model of prostate cancer6 focused on cell adhesion-mediated molecular mechanisms that: (i) May underlie progression of slow growing prostate tumors to metastatic growth; and that (ii) May be the target of preventive strategies that delay progression of indolent prostate tumors to metastatic growth.
More recent collaborative studies with Gabriel A. Elgavish are focused on developing an MRI method for early noninvasive detection of developing PC2.
1. Elgavish, A. Epigenetic reprogramming: a possible etiological factor in bladder pain syndrome/interstitial Cystitis? J Urology 181: 980-984, 2009. PMID: 19150095
2. Kiss, P, Eltoum IE, Suranyi P, Zeng H, Simor T, Elgavish, A, Elgavish GA. Virtual in vivo biopsy map of early prostate neoplasm in TRAMP mice by MRI. Prostate. 69: 449-458, 2009. PMID: 19107856
3. Saldanha, SN, Nandakumar, V, Elgavish, A, and Tollefsbol, TO. Dietary and environmental influences on histone modifications in cancer. In Cancer Epigenetics, Taylor & Francis Group, 2008.
4. Huffman, D., Johnson M., Watts, A., Elgavish, A, Eltoum, I.E., Nagy, T. Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake. Cancer Research, 67: 417-424, 2007. PMID: 17185379
5. Hira Lal Goel, Jianzhong Zhang, Ishita Das, Sadie Aznavoorian-Cheshire, Norman M. Greenberg, Elgavish, A., and Lucia R. Languino. Aberrant cross-talk and expression of β1 integrins and type 1 insulin-like growth factor receptor during prostate cancer progression. Cancer Research 65: 6692-6700, 2005. PMID: 16061650
6. Mentor-Marcel, R., Lamartiniere, C.A., Eltoum, I-E, Greenberg, N.M., and Elgavish, A Dietary genistein improves survival and downregulates mRNA levels of osteopontin in advanced prostate cancer in TRAMP mice. Journal of Nutrition 135: 989-95, 2005. PMID: 15867270
7. Elgavish, A, Philip A. Wood, Carl A. Pinkert, Todd Cartee, John Wilbanks, Roycelynn Mentor-Marcel, Liqun Tian and Samuel Scroggins. A transgenic mouse model with human mutant p53 expression in the prostate epithelium The Prostate. 61:26-34, 2004. PMID: 15287091
8. Elgavish, A. A hypothesis for the etiology of interstitial cystitis. In: Bladder Disease: Research Concepts and Clinical Applications (Atala, A., and Slade, D., Eds), Kluwer Academic/Plenum Publishers, New York, NY, January 2004. PMID: 15176319
9. Mentor-Marcel, R., Lamartiniere, C., Greenberg, N., and Elgavish, A. Genistein in the diet reduces the incidence of prostate tumors in transgenic mice (TRAMP). Cancer Research, 61:6777-6782, 2001. PMID: 11559550
10. Elgavish, A. NF-kB activation mediates the response of a subpopulation of basal uroepithelial cells to a cell wall component of Enterococcus faecalis. J. Cell. Physiol. 182: 232-238, 2000. PMID: 10623887
11. Elgavish, A., Prince, C., Chang, P.-L., Lloyd, K., Lindsey, R., and Reed, R. Osteopontin stimulates proliferation of a population of quiescent progenitors of human prostate epithelial cells: Studies in vitro. The Prostate, 35: 83-94, 1998. PMID: 9568671
12. Elgavish, A., Pattanaik, A., Lloyd, K., and Reed, R. Evidence for altered proliferative ability of progenitors of urothelial cells in interstitial cystitis. J. Urol., 158: 248-252, 1997. PMID: 9186369
13. Elgavish, A., Robert, B., Lloyd, K., Lindsey, R., and Reed, R. III. Nitric oxide mediates the action of lipoteichoic acid on the function of urothelial cells. J. Cell. Physiol., 169: 66-77, 1996. PMID: 8841423
14. Elgavish, A., Pattanaik, A., Couchman, J., Woods, A., Lloyd, K., Lindsey, R., and Reed, R. II. Long term treatment with lipoteichoic acid from Streptococcus faecalis affects differentiation, and expression and cellular distribution of β1 integrins in human urothelial cells. J. Cell. Physiol., 169: 52-65, 1996. PMID: 8841422
15. Elgavish, A., Lloyd, K., and Reed, R. I. A subpopulation of human urothelial cells is stimulated to proliferate by treatment in vitro with lipoteichoic acid, a cell wall component of Streptococcus faecalis. J. Cell. Physiol., 169: 42-51, 1996. PMID: 8841421
16. Elgavish, A., Pattanaik, A., Lloyd, K., and Reed, R. Integrin-mediated adhesive properties of human uroepithelial cells are inhibited by treatment with bacterial toxins. Amer. J. Physiol., 266: C1552-C1559, 1994. PMID: 8023887
17. Elgavish, A. Effects of Escherichia coli and E. coli lipopolysaccharides on the function of human ureteral epithelial cells cultured in serum-free medium. Infection and Immunity, 61: 3304-3312, 1993. PMID: 8101508
18. Wille, J.J., Park, J., and Elgavish, A. Effect of growth factors, hormones, bacterial lipopolysaccharides and lipoteichoic acids on the clonal growth of normal ureteral epithelial cells in serum-free culture. J. Cell. Physiol. 150: 52-58, 1992. PMID: 1730786