DF/HCC Program Affiliation

Prostate Cancer

Research Abstract

My research centers on understanding mechanisms of genitourinary pathology at the molecular and cellular level. Our current work centers on the role of EGF-like growth factors as soluble and membrane-anchored signaling molecules, on the intracellular signaling systems these factors regulate, and on the physiologic consequences of EGF-like growth factor pathway activation in cell regulation and disease. We have recently determined that one of the high-affinity activating ligands for the EGF receptor/ErbB1 tyrosine kinase, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is a mechanically responsive gene in bladder smooth muscle cells. This finding, and other recently published data from our laboratory, implicate this growth factor in mechanisms of bladder wound healing and hypertrophic bladder growth. We have also recently identified HB-EGF and amphiregulin, an EGF-like growth factor with a similar domain structure to HB-EGF and a similar affinity for heparin, as products of the interstitial smooth muscle cells of the human prostate. We found the HB-EGF and amphiregulin genes to be coordinately expressed in benign and malignant human prostate tissue. These factors likely serve as directional signaling molecules between the fibromuscular stroma and the epithelial compartments of the prostate. The consequences of this directional signaling system in terms of signal transduction pathway activation, mitogenesis and cell survival regulation are under investigation.

Publications

• Maclellan DL, Steen H, Adam RM, Garlick M, Zurakowski D, Gygi SP, Freeman MR, Solomon KR.A quantitative proteomic analysis of growth factor-induced compositional changes in lipid rafts of human smooth muscle cells.Proteomics 2005 Nov 2.
  16267816
• Marcus K, Johnson M, Adam RM, O'Reilly MS, Donovan M, Atala A, Freeman MR, Soker S.Tumor cell-associated neuropilin-1 and vascular endothelial growth factor expression as determinants of tumor growth in neuroblastoma.Neuropathology 2005 Sep;25(3):178-87.
  16193833
• Kim J, Adam RM, Freeman MR.Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress.Cancer Res 2005 Sep 15;65(18):8242-9.
  16166300
• Freeman MR, Cinar B, Lu ML.Membrane rafts as potential sites of nongenomic hormonal signaling in prostate cancer.Trends Endocrinol Metab 2005 Aug;16(6):273-9.
  16002302
• Cinar B, De Benedetti A, Freeman MR.Post-transcriptional regulation of the androgen receptor by Mammalian target of rapamycin.Cancer Res 2005 Apr 1;65(7):2547-53.
  15805247
• Zhuang L, Kim J, Adam RM, Solomon KR, Freeman MR.Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts.J Clin Invest 2005 Apr;115(4):959-68.
  15776112
• Orsola A, Estrada CR, Nguyen HT, Retik AB, Freeman MR, Peters CA, Adam RM.Growth and stretch response of human exstrophy bladder smooth muscle cells: molecular evidence of normal intrinsic function.BJU Int 2005 Jan;95(1):144-8.
  15638913
• Freeman MR.HER2/HER3 heterodimers in prostate cancer: Whither HER1/EGFR?.Cancer Cell 2004 Nov;6(5):427-8.
  15542423
• Stehr M, Estrada CR, Khoury J, Danciu TE, Sullivan MP, Peters CA, Solomon KR, Freeman MR, Adam RM.CAVEOLAE ARE NEGATIVE REGULATORS OF TRANSFORMING GROWTH FACTOR-beta1 SIGNALING IN URETERAL SMOOTH MUSCLE CELLS.J Urol 2004 12;172(6, Part 1 of 2):2451-2455.
  15538289
• Kim J, Lin J, Adam RM, Lamb C, Shively SB, Freeman MR.An oxidative stress mechanism mediates chelerythrine-induced heparin-binding EGF-like growth factor ectodomain shedding.J Cell Biochem 2005 Jan 1;94(1):39-49.
  15490481
• Danciu TE, Gagari E, Adam RM, Damoulis PD, Freeman MR.Mechanical strain delivers anti-apoptotic and proliferative signals to gingival fibroblasts.J Dent Res 2004 Aug;83(8):596-601.
  15271966
• Cinar B, Yeung F, Konaka H, Mayo MW, Freeman MR, Zhau HE, Chung LW.Identification of a negative regulatory cis-element in the enhancer core region of the prostate-specific antigen promoter: implications for intersection of androgen receptor and nuclear fa
  14715080
• Freeman MR, Solomon KR.Cholesterol and prostate cancer.J Cell Biochem 2004 Jan 1;91(1):54-69.
  14689582
• Kim J, Adam RM, Solomon KR, Freeman MR.Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells.Endocrinology 2004 Feb;145(2):613-9.
  14563701
• Kim J, Freeman MR.JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells.Breast Cancer Res Treat 2003 Jun;79(3):321-8.
  12846416
• Adam RM, Roth JA, Cheng HL, Rice DC, Khoury J, Bauer SB, Peters CA, Freeman MR.Signaling through PI3K/Akt mediates stretch and PDGF-BB-dependent DNA synthesis in bladder smooth muscle cells.J Urol 2003 Jun;169(6):2388-93.
  12771803
• Adam RM, Danciu T, McLellan DL, Borer JG, Lin J, Zurakowski D, Weinstein MH, Rajjayabun PH, Mellon JK, Freeman MR.A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carci
  12543806
• Lin J, Freeman MR.Transactivation of ErbB1 and ErbB2 receptors by angiotensin II in normal human prostate stromal cells.Prostate 2003 Jan 1;54(1):1-7.
  12481249
• Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR.Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells.Cancer Res 2002 Apr 15;62(8):2227-31.
  11956073
• Kim J, Adam RM, Freeman MR.Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation.Cancer Res 2002 Mar 1;62(5):1549-54.
  11888934
• Adam RM, Orsola A, Freeman MR.A novel method for implantation of LNCaP prostate tumor cells under the renal capsule.In Vitro Cell Dev Biol Anim 2001 Jun;37(6):360-2.
  11515968
• Soker S, Kaefer M, Johnson M, Klagsbrun M, Atala A, Freeman MR.Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype.Am J Pathol 2001 Aug;159(2):651-9.
  11485923
• Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, Hediger MA, Freeman MR.CaT1 expression correlates with tumor grade in prostate cancer.Biochem Biophys Res Commun 2001 Apr 6;282(3):729-34.
  11401523
• Lin J, Hutchinson L, Gaston SM, Raab G, Freeman MR.BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation.J Biol Chem 2001 Aug 10;276(32):30127-3
  11340068
• Nguyen HT, Adam RM, Bride SH, Park JM, Peters CA, Freeman MR.Cyclic stretch activates p38 SAPK2-, ErbB2-, and AT1-dependent signaling in bladder smooth muscle cells.Am J Physiol Cell Physiol 2000 Oct;279(4):C1155-67.
  11003596
• Nguyen HT, Bride SH, Badawy AB, Adam RM, Lin J, Orsola A, Guthrie PD, Freeman MR, Peters CA.Heparin-binding EGF-like growth factor is up-regulated in the obstructed kidney in a cell- and region-specific manner and acts to inhibit apoptosis.Am J Pathol 200
  10702406
• Borer JG, Park JM, Atala A, Nguyen HT, Adam RM, Retik AB, Freeman MR.Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction.Lab Invest 1999 Nov;79(11):1335-45.
  10576204
• Duque JL, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR.Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer.Urology 1999 Sep;54(3):523-7.
  10475365
• Park JM, Adam RM, Peters CA, Guthrie PD, Sun Z, Klagsbrun M, Freeman MR.AP-1 mediates stretch-induced expression of HB-EGF in bladder smooth muscle cells.Am J Physiol 1999 Aug;277(2 Pt 1):C294-301.
  10444406
• Lin J, Adam RM, Santiestevan E, Freeman MR.The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells.Cancer Res 1999 Jun 15;59(12):2891-7.
  10383151
• Park JM, Yang T, Arend LJ, Schnermann JB, Peters CA, Freeman MR, Briggs JP.Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch.Am J Physiol 1999 Jan;276(1 Pt 2):F129-36.
  9887088
• Freeman MR, Yoo JJ, Raab G, Soker S, Adam RM, Schneck FX, Renshaw AA, Klagsbrun M, Atala A.Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the huma
  9062361