Education

• Ph.D., Molecular Genetics, Washington University, St. Louis, MO, 1997
  Thesis title: “Molecular Genetic Studies of Prostate Cancer.” Mentor: Helen Donis-Keller, Ph.D.
• M.S., Biology, Loyola University, 1994
  Thesis title: “A Physical Map of the Short Arm / Centromere Region of Human Chromosome 21.” Mentor: Jeffrey Doering, Ph.D.
• B.S., Biology, Rockhurst College, Kansas City, MO, 1990

Interests & Expertise

My research integrates the effects of obesity and dietary fats on angiogenesis, the growth of new blood vessels from the existing vasculature, and prostate cancer. It has evolved around the study of two angiogenesis inhibitors, pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1). Both of these multifunctional glycoproteins are expressed in the normal prostate but are decreased or absent in tissues from prostate cancer (PCa) patients. Angiogenesis is necessary for the progressive growth of tumors, and loss of these inhibitors promotes angiogenesis and tumor progression. Both TSP-1 and PEDF knockout (KO) mouse models develop prostate epithelial hyperplasia, with increased proliferation and increased microvessel density (MVD), a hallmark of angiogenesis. These models demonstrate defects in lipid metabolism with increased abdominal adipose (fat) tissue mass, particularly that surrounding the prostate, and intracellular lipid accumulation in non-adipose tissues. Like tumors, adipose tissue must induce angiogenesis for growth and expansion, and the adipose tissue is one of the few normal adult tissues to retain this ability. These observations suggest that TSP-1 and PEDF negatively regulate adipose tissue expansion and function in regulating intracellular lipid metabolism.

In prostate cancer, a high fat diet and obesity have been consistently associated with more aggressive PCa and increased risk of death from PCa. However, the mechanism(s) of this association remains unknown. The adipose tissue not only serves as a storage depot for excess fats, it also is an active endocrine organ and secretes many types of molecules including growth factors, angiogenic mediators, lipids [triglycerides (TG) and fatty acids (FA)] and pro-inflammatory molecules (see Figure 1). In the setting of obesity, the profile of these secretions is altered. My lab is focused on elucidating the functional mechanism(s) by which obese adipose tissue secretions fuel PCa growth. We are currently investigating the functional contribution of pro-angiogenic and lipid-mediated pathways, with specific focus on delineating PEDF- and TSP-1-mediated pathways. We use a combination of cellular and molecular biology techniques as well as mouse models and human tissue analyses. Related to these studies, we are also examining how PCa cell response changes with different subtypes of fatty acids, such as the omega-3 polyunsaturated fatty acids (PUFA) versus omega-6 PUFA. Understanding the molecular pathways stimulated in PCa cells by obesity and dietary fats will allow the rational design of novel therapies and dietary chemoprevention regimens.

Recent Publications

Scientific Journals

Yu N, JM Kozlowski, II Park, L Chen, Q Zhang, D Xu, JA Doll, SE Crawford, CB Brendler, C Lee.  Over-expression of transforming growth factor β1 in malignant prostate cells is partly caused by a runaway of TGF-β1 auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-β type I receptor. Urology, 76: 1519.e8-1519.e13, 2010.  PMID: 21030067

Fitchev, PP, SM Wcislak, C Lee, A Bergh, CB  Brendler, VM Stellmach, SE Crawford, CD Mavroudis, ML Cornwell, and JA Doll.  Thrombospondin-1 Regulates the Normal Prostate In Vivo Through Angiogenesis and TGF-b Activation.  Lab. Invest., 90: 1078-90, 2010.  PMID: 20458281

Halin, S, SH Rudolfsson, JA Doll, SE Crawford, P Wikstrom, and A Bergh.  Pigment Epithelium-Derived Factor a Prostate Tumor Suppressor with Diverse Biological Effects in the Microenvironment.  Neoplasia, 12(4): 336-45, 2010.  PMID: 20360944

Chung C, C Shugrue, A Nagar, JA Doll, M Cornwell, A Gattu, T Kolodecik, S Pandol, F Gorelick.  Ethanol exposure depletes hepatic pigment epithelium-derived factor (PEDF), a novel lipid regulator in the liver.  Gastroenterology, 136(1): 331-40, 2009.  PMID: 18996124

Plunkett BA, P Fitchev, JA Doll, SE Gerber, M Cornwell, EP Greenstein and SE Crawford. Decreased expression of pigment epithelium derived factor (PEDF), an inhibitor of angiogenesis, in placentas of unexplained stillbirths. Reprod Biol., 8(2):107-20, 2008. PMID: 18677399

Signaevsky M, J Hobbs, J Doll, N Liu and GA Soff. Role of alternatively spliced tissue factor in pancreatic cancer growth and angiogenesis. Semin Thromb Hemost., 34(2):161-9, 2008.                PMID: 18645921

Chung C, JA Doll, A Gattu, C Shugrue, C Cornwell, P Fitchev and SE Crawford. PEDF regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J. Hepatol., 48(3): 471-8, 2008. PMID: 18191271

Chung C, JA Doll, VM Stellmach, J Gonzales, S Surapureddi, M Cornwell, JK Reddy and SE Crawford.  Pigment epithelium-derived factor is an angiogenesis and lipid regulator that activates peroxisome proliferator-activated receptor alpha. Adv Exp Med Biol., 617: 591-7, 2008. PMID: 18497086

Hobbs JE, A Zakarija, DL Cundiff, JA Doll, E Hymen, M Cornwell, SE Crawford and GA Soff. Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model. Thrombosis Res., 120 Suppl 2:S13-21, 2007. PMID: 18023707

Browne M, VM Stellmach, M Cornwell, C Chung, JA Doll, E-J Lee, JL Jameson, M Reynolds, RA Superina, LP Abramson and SE Crawford. Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model. Pediatric Res., 60(3): 282-7, 2006. PMID: 16857775

Wang H, JA Doll, K Jiang, DL Cundiff, JS Czarnecki, M Wilson, K Ridge and GA Soff. Differential binding of plasminogen, plasmin, and angiostatin4.5 to cell surface b-actin: implications for cancer-mediated angiogenesis. Cancer Res., 66(14): 7211-15, 2006. PMID: 16849568

Abramson LP, M Browne, VM Stellmach, J Doll, M Cornwell, M Reynolds, RM Arensman and SE Crawford. Pigment epithelium-derived factor (PEDF) targets endothelial and epithelial cells in Wilms’ tumor. J. Pediatric Surg., 41: 1351-56, 2006. PMID: 16863836

Soff GA, H Wang, DL Cundiff, K Jiang, B Martone, AA Rademaker, JA Doll and TM Kuzel. In vivo generation of angiostatin isoforms by administration of a plasminogen activator and a free-sulfhydryl donor: a phase I study of an angiostatic cocktail of tPA and mesna. Clin. Cancer Res., 11(17): 6218-25, 2005. PMID: 16144924

Halin S, P Wikstrom, SH Rudolfsson, JA Doll, SE Crawford and A Bergh. Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.  Cancer Research, 64: 5664-5671, 2004. PMID: 15313905

Grayhack JT, ND Smith, K Ilio, C Wambi, R Kasjanski, SE Crawford, JA Doll, Z Wang, C Lee and JM Kozlowski. Pigment epithelium-derived factor, a human testis epididymis secretory product, promotes human prostate stromal cell growth in culture. J. Urology, 171: 434-438, 2004. PMID:14665949

Ferbend P, LP Abramson, CL Backer, C Mavroudis, CL Webb, JA Doll, JJ Junewick and SE Crawford. Cardiac plasma cell granulomas: response to oral steroid treatment. Pediatric Cardiol., 25: 406-410, 2004. PMID: 15054564

Doll JA, V Stellmach, N Bouck, A Bergh, C Lee, LP Abramson, M Cornwell, MR Pins, J Borensztajn and SE Crawford. Hormone-sensitive anti-angiogenic pigment epithelium-derived factor regulates the stromal vasculature and epithelium of the prostate and pancreas. Nature Medicine, 9: 774-780, 2003. PMID: 12740569

Abramson LP, V Stellmach, JA Doll, M Cornwell, RM Arensman and SE Crawford. Wilms’ tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model. J. Pediatric Surgery, 38(3): 336-342, 2003. PMID: 12632345

Doll JA, FK Reiher, SE Crawford, MR Pins, SC Campbell and NP Bouck. Thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate. The Prostate, 49(4): 293-305, 2001.  PMID: 11746276

Published Book Chapters

Doll JA and GA Soff. “Angiostatin: Generation, Structure and Function of the Isoforms.” In Cytokines and Cancer, pp. 175-204. L.C. Platanias, Ed.  Cancer Treat. Res. series. Kluwer Academic Publishers, Norwell, MA, 2005.

Doll JA, JE Hobbs and GA Soff. Role of Apoptosis in Anti-angiogenic Cancer Therapies. In Apoptosis and Senescence in Cancer Chemotherapy and Radiotherapy. Humana Press, Inc., Totowa, NJ, 2007. 

Honors & Awards

• 2010: Invited talk at the Prostate Cancer Foundation’s Annual Retreat (Washingtion, D.C., September 15-16, 2010). 
• 2009: Invitation to the NCI Translational Science Meeting (poster presentation with oral summary), Vienna, VA, November 2009.
• 2007: Invitation to the DOD prostate cancer IMPaCT Meeting (poster presentation), Atlanta, GA, September, 2007.
• 2001: Travel Grant Award, AACR: AACR’s “New Discoveries in Prostate Cancer Etiology and Treatment” meeting, Naples, FL, December, 2001.
• 1998: Travel Grant Award, AACR: AACR’s “New Research Approaches in the Prevention and Cure of Prostate Cancer” meeting, Indian Wells, CA, December, 1998.
• 1998: Travel Grant Award, NIH: Biology of Prostate Growth Meeting, Bethesda, MD, March, 1998.
• 1994: Travel Grant Award, AACR: AACR’s “Basic and Clinical Aspects of Prostate Cancer” meeting, Palm Springs, CA, December, 1994.
• 1992: Graduate Research Fellowship, Loyola University
• 1990: Barbara Wynne Outstanding Biology Student Award, Rockhurst College.