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Robert A. Sikes, Ph.D.
- BISC 401 - Molecular Biology of the Cell
- BISC 625 - Cancer Biology
The "Lethal Phenotype" of cancer is a direct consequence of cancer spreading to secondary sites, a process called metastasis. Lethal prostate cancer is no exception. The number of men affected by prostate cancer is staggering. In North America, there are approximately 240,000 new cases of prostate cancer in 2011 and around 33,000 deaths. This translates into a 1 in 6 lifetime chance of acquiring prostate cancer if you are an American male. This translates into >27 new cases of prostate cancer diagnosed every hour of every day. These numbers are going to increase as our population ages.
Initially, prostate cancer is sensitive to the levels of male steroid hormones or androgens. Removal of the androgens (Male Sex Hormones), by surgical or chemical castration, is still a gold standard for therapy in cases of advanced prostate cancer. For a time, the cancer responds by regressing under the conditions of androgen deprivation, however, the cancer invariably adapts and continues growing in the absence of androgens or in the presence of reduced levels of androgens. The cancer has now shifted from being androgen dependent or sensitive to an androgen insensitive or castration resistant state. The development of metastases, cancer deposits away from the initial prostate cancer, along with the shift from androgen sensitive to castrate resistance is termed progression.
Research in my laboratory is concerned with the mechanism(s) that contribute to the development of advanced and castrate resistant prostate cancer as defined above. The following areas of research are actively being pursued:
- The role of growth factor presentation and signaling in the development of aggressive, lethal phenotype of prostate cancer and metastasis to bone. Specifically, we are interested in the signaling interplay of TGF beta family members between bone marrow stromal cells and prostate cancer cells.
- We are examining several novel transmembrane proteins for their role in cancer migration and invasion. These include G-protein coupled receptors involved in purinergic/pyrimidinergic signaling as well as the accessory proteins of the voltage sensitive ion channel family, principally beta-2.
- Steps in gland development mimic cancer invasion. We are examining the expression of prostate precursor tissues or Urogenital Sinus (UGS)-for genes involved in shaping tissues and controlling cancer behavior.
- IGF and TGFβ in prostate cancer progression and the colonization of bone - By mediating the mesenchymal transition of prostate cancer cells, TGFβ influences cell adhesion to and extravasation through endothelial cells. The signaling mediating this process is poorly understood. We now believe that these events are mediated in part by Smad independent signaling involving Rho GTPases. IGF1 is a survival factor for prostate cancer and appears o play a critical role in the survival of prostate cancer in the bone. We are examining receptor blockade to interfere with this process.
- Role of novel extracellular adhesion molecules in prostate cancer progression and perineural migration - 85% of prostate cancer has histological evidence of direct association with peripheral nerve bundles. We are examining the molecules hat mediate this association and mediate prostate cancer metastasis.
- Prostate cancer interactions with the bone microenvironment - This project examines factors that mediate prostate cancer cell death and neuroendocrine differentiation of prostate cancer cells through interactions with bone marrow stromal cells.
- Ligand-independent effects of insulin-like growth factor binding protein 2 and androgen in prostate cancer progression - Structural analysis of IGFBP-2 with respect to cell aggressiveness and signaling.
- Madhura Joglekar, Ph.D.-Post-doctoral fellow-Preclinical deveopment of novel anti-androgens
- Anshul Arora, Ph.D.-Post-doctoral fellow- Preclinical development of anti-androgens; bone marrow stromal interactions with prostate cancer
- Jomnarang Lertsuwan, B.S. Graduate Student (B.S., Thailand)-purinergic signaling and breast cancer metastasis, racial disparity
- Kornkamon Nopmonkol, B.S.-Graduate Student (B.S., Thailand)-isolation and purification of toxic bone stromal cell factors
- Senem Kurtoglu, B.S.- Graduate Student (B.S. Turkey)-Mechanisms of TGF beta driven suppression of stromal cell toxicity
- Meghan Kirk- Undergraduate, role of beta 2 in perineural invasion and PCa metastasis.
- Irene Marwa- Undergraduate, solation and purification of toxic bone stromal cell factors
- Stefan Feliciano-Undergraduate, RNA seq analysis of TGF beta effects on one marrow stromal cells
- Erin Moffet-Undergraduate, RNA seq analysis of TGF beta effects on one marrow stromal cells
- John Favate-Undergraduate, role of endoglin in bone marrow stromal cell killing of prostate cancer cells
- Miles F.L. and Sikes R.A., Insidious changes in stromal matrix fuel cancer progression. Mol. Can Res In press 201401
- Dong X., Xu W., Sikes R.A., Wu C., Combination of low dose of genistein and daidzein has synergistic preventive effects on isogenic human prostate cancer cells when compared with individual soy isoflavone, Food Chemistry 141(3):1923-1933, 2013
- Jansson K.H., Lynch J.E., Lepori-Bui N., Czymmek K.J., Duncan R.L., Sikes R.A., Overexpression of the VSSC-associated CAM, beta-2, enhances LNCaP cell metastasis associated behavior. Prostate 72(10):1080-92, 2012. epub 20111201 PMID22127840
- Miles F.L., Tung N.S., Aguiar A.A., Kurtoglu S., Sikes R.A., Increased TGF-b1 mediated suppression of growth and motility in castrate-resistant prostate cancer cells is consistent with smad2/3 signaling., Prostate 72(12): 1339-50, 2012. epub Dec 2011
- Hillyer R.L., Sirinvasin P., Joglekar M., Sikes R.A., van Golen K.L., Nohe A., Differential effects of vitamin D treatment in inflammatory and non-inflammatory breast cancer cell lines. Clin Exp Mets 29(8):971-9, 2012
- Dong X., Wu C, Xu X., Sikes R.A., Apoptotic effects of cooked and in vitro digested soy on human prostate cancer cells, Food Chemistry 135(3):1643-52, 2012
- Dashner E.J., Sikes R.A. and Van Golen K.L., "The Role of the Type I Insulin-like Growth Factor Receptor in Prostate Cancer Skeletal Metastasis." Horizons in Cancer Research. Ed. Hiroto S. Wantanabe. Vol. 47. Hauppauge: NOVA Science, 2012. 235-52
- Kuczmarski J.M., Darocki M.D., Dupont J.J., Sikes R.A., Cooper C.R., Farquhar W.B. and Edwards D.G., Effect of moderate-to-severe chronic kidney disease on flow-mediated dilation and progenitor cells, Exp Biol Med 239(9), 1085-92, 2011
- Zhang C., Soori M., Miles FL, Sikes R.A., Carson DD, Chung LWK, Farach-Carson MC, Paracrine factors produced by bone stromal cells induce apoptosis and neuroendocrine differentiation in prostate cancer cells, Prostate 71(2): p. 157-67, 2011
- Li, Y, Sikes R.A., Malaeb B.S., Yeung F., Law A., Graham S.E., Pei M., Kao C., Nelson J., Koeneman K.S., Chung L.W., Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models, Urol. Oncol. 29(6), 802-09, 2011
- Cooper C.R., Poindexter C., Rohe B. and Sikes R.A., Ph.D. A Scientific update: Thalidomide and its analogs. Biochemical Society 36-39, 2010 (Oct)
- Sikes R.A., Duncan R.L., Lee K., Rajasekaran A.K., Iacocca M., Rabeno B., Catts Z.A.-K., Petrelli N., The Center for Translational Cancer Research: A collaborative effort between the Helen F Graham Cancer Center at Christiana Care, the University of Delaware and Nemours Biomedical Research, Oncology Issues Jan/Feb 2010
- Balian G., Beck G., Madhu V., Sikes R.A., Cui Q., Liang H., Bush J., Peptides from phage display library modukate gene expression in mesenchymal cells and potentiate osteogenesis in unicortical bone defects, JoVE. 46. http://www.jove.com/details.php?id=2362, doi: 10.3791/2362, 2010.
- DeGraff D.J., Aquiar AA, Chen Q, Adams LK, Williams BJ, *Sikes RA, Androgen Mediated Translational and Postranslational Regulation of IGFBP-2 in Androgen-Sensitive LNCaP Human Prostate Cancer Cells, ; Am J Translat Res 2(2):200-208, 2010
- Sheehan S., Muthusamy A., Paul E., Sikes R.A., and Gomes, R.R. Jr., Short-term Intermittent PTH 1-34 Administration Enhances Bone Formation in SCID/Beige Mice. Endocrine Journal 57(5): 373-82, 2010.
- Chen Q., DeGraff D.J., Sikes R.A., The developmental expression profile of PAX2 in the murine prostate. Prostate 70(6):654-665, 2010
- Thalmann G.N., Rhee H., Sikes R.A., Pathak S., Multani A., Zhau H.E., Marshall F.F., Chung L.W.K., Human Prostate Fibroblasts Induce Growth and Confer Castration Resistance and Metastatic Potential in LNCaP Cells., Eur. Urol. 58(1):162-171, 2010.
- Chung S-W, Miles FL, Sikes RA, Cooper CR, Farach-Carson MC, Ogunnaike BA. Quantitative modeling and analysis of the transforming growth factor beta signaling pathway. Biophys J. 2009;96(5):1733–1750.
- DeGraff DJ, Aguiar AA, Sikes RA. Evidence for IGFBP-2 as a key player in prostate cancer progression and development of osteosclerotic lesions. Am J Translational Res. 2009;1(2):115–130.
- Gomes RRJ, Buttke P, Paul EM, Sikes RA. Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation. Clin Exp Metastasis. 2009;26(7):641–651.
- Pritchard C, Mecham B, Dumpit R, et al. Conserved gene expression programs integrate mammalian prostate development and tumorigenesis. Cancer Res. 2009;69(5):1739–1747.
- Cooper CR, Graves B, Pruitt F, et al. Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha. J Cell Biochem. 2008;104(6):2298–2309.
- DeGraff DJ, Miles FL, Gomes RR, Sikes RA. Small animal models for the study of cancer in bone. In: Bronner F, Farach-Carson MC, eds. Topics in Bone Biology, Bone and Cancer. Vol. 5.; 2008:181–204.
- Thorpe LT, Sikes RA, Sequiera L, et al. The expression and contribution of surface hyaluronan to prostate cancer cell adhesion to bone marrow endothelial cells. Clin Exp Metastasis. 2008:in press.
- Deeble PD, Cox ME, Frierson HFJ, et al. Androgen-independent growth and tumorigenesis of prostate cancer cells are enhanced by the presence of PKA-differentiated neuroendocrine cells. Cancer Res. 2007;67(8):3663–3672.
- DeGraff DJ, Malik M, Chen Q, et al. Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model. J Cell Physiol. 2007;213(1):261–268.
- Chen Q, Watson JT, Marengo SR, et al. Gene expression in the LNCaP human prostate cancer progression model: progression associated expression in vitro corresponds to expression changes associated with prostate cancer progression in vivo. Cancer Lett. 2006;244(2):274–288.
- Fiske JL, Fomin VP, Brown ML, Duncan RL, Sikes RA. Voltage-sensitive ion channels and cancer. Cancer Metastasis Rev. 2006;25(3):493–500.
- Tate A, Isotani S, Bradley MJ, et al. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells. BMC Cancer. 2006;6:197.
- Sikes RA, Cooper CR, Beck GL, Pruitt F, Brown ML, Balian G. Bone stromal cells as therapeutics targets in osseous metastasis. In: Meadows GG, ed. Integration/Interaction of Oncologic Growth. Vol. 15. Boston, MA: Kluwer Academic Publishers; 2005:369–386. Cancer Growth and Progression.
- Brennen WN, Cooper CR, Capitosti S, Brown ML, Sikes RA. Thalidomide and analogues: current proposed mechanisms and therapeutic usage. Clin Prostate Cancer. 2004;3(1):54–61.
- Cooper CR, Sikes RA, Nicholson BE, Sun Y-X, Pienta KJ, Taichman RS. Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Cancer Treat Res. 2004;118:291–309.
- Krueckl SL, Sikes RA, Edlund NM, et al. Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Res. 2004;64(23):8620–8629.
- Sikes RA, Nicholson BE, Koeneman KS, et al. Cellular interactions in the tropism of prostate cancer to bone. Int J Cancer. 2004;110(4):497–503.
- Stewart DA, Cooper CR, Sikes RA. Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer. Reprod Biol Endocrinol. 2004;2:2.
- Abbott DE, Pritchard C, Clegg NJ, et al. Expressed sequence tag profiling identifies developmental and anatomic partitioning of gene expression in the mouse prostate. Genome Biol. 2003;4(12):R79.
- Anderson JD, Hansen TP, Lenkowski PW, et al. Voltage-gated sodium channel blockers as cytostatic inhibitors of the androgen-independent prostate cancer cell line PC-3. Mol Cancer Ther. 2003;2(11):1149–1154.
- Guo N, Ye J-J, Liang S-J, et al. The role of insulin-like growth factor-II in cancer growth and progression evidenced by the use of ribozymes and prostate cancer progression models. Growth Horm IGF Res. 2003;13(1):44–53.
- Sikes RA, Walls AM, Brennen WN, et al. Therapeutic approaches targeting prostate cancer progression using novel voltage-gated ion channel blockers. Clin Prostate Cancer. 2003;2(3):181–187.
- Tennant MK, Vessella RL, Sprenger CC, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1/mac 25) is reduced in human prostate cancer and is inversely related to tumor volume and proliferation index in Lucap 23.12 xenografts. Prostate. 2003;56(2):115–122.
Director, Center for Translational Cancer Research
Senior Research Scientist, Helen F. Graham Cancer Center, Christiana Care Health System
Phone: (302) 831-6050
Fax: (302) 831-2281
Office: 326 Wolf Hall
Lab: 333 Wolf Hall
Department of Biological Sciences
326 Wolf Hall
University of Delaware
Newark, DE 19716
- B.A. - University of Colorado
- Ph.D. - University of Texas
- Postdoctoral - University of Texas, Health Science Center
- Postdoctoral - University of Texas, M.D. Anderson Cancer Center