An illustration of the potential for mapping MRI/MRS parameters with genetic over-expression profiles in human prostate cancer

  • Robert E. Lenkinski
  • B. Nicolas Bloch
  • Fangbing Liu
  • John V. Frangioni
  • Sven Perner
  • Mark A. Rubin
  • Elizabeth M. Genega
  • Neil M. Rofsky
  • Sandra M. Gaston
Research Article



Magnetic resonance imaging (MRI) and MR spectroscopy can probe a variety of physiological (e.g. blood vessel permeability) and metabolic characteristics of prostate cancer. However, little is known about the changes in gene expression that underlie the spectral and imaging features observed in prostate cancer. Tumor induced changes in vascular permeability and angiogenesis are thought to contribute to patterns of dynamic contrast enhanced (DCE) MRI images of prostate cancer even though the genetic basis of tumor vasculogenesis is complex and the specific mechanisms underlying these DCEMRI features have not yet been determined.

Materials and Methods

In order to identify the changes in gene expression that correspond to MRS and DCEMRI patterns in human prostate cancers, we have utilized tissue print micropeel techniques to generate “whole mount” molecular maps of radical prostatectomy specimens that correspond to pre-surgical MRI/MRS studies. These molecular maps include RNA expression profiles from both Affymetrix GeneChip microarrays and quantitative reverse transcriptase PCR (qrt-PCR) analysis, as well as immunohistochemical studies.


Using these methods on patients with prostate cancer, we found robust over-expression of choline kinase a in the majority of primary tumors. We also observed overexpression of neuropeptide Y (NPY), a newly identified angiogenic factor, in a subset of prostate cancers, visualized on DCEMRI.


These studies set the stage for establishing MRI/MRS parameters as validated biomarkers for human prostate cancer.


MRI Prostate Gene expression Prostate cancer 


  1. 1.
    Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55: 10–30PubMedCrossRefGoogle Scholar
  2. 2.
    Andriole G, Djavan B, Fleshner N, Schroder F (2006) The case for prostate cancer screening with prostate-specific antigen. Eur Urol Suppl 5: 737–745CrossRefGoogle Scholar
  3. 3.
    Catalona WJ, Smith DS, Ratliff TL, Basler JW (1993) Detection of organ-confined prostate-cancer is increased through prostate-specific antigen-based screening. Jama-J Am Med Assoc 270: 948–954CrossRefGoogle Scholar
  4. 4.
    Efstathiou JA, Chen MH, Catalona WJ, McLeod DG, Carroll PR, Moul JW, Roehl KA, D’Amico AV (2006) Prostate-specific antigen-based serial screening may decrease prostate cancer-specific mortality. Urology 68: 342–347PubMedCrossRefGoogle Scholar
  5. 5.
    Han M, Partin AW, Piantadosi S, Epstein JI, Walsh PC (2001) Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 166: 416–419PubMedCrossRefGoogle Scholar
  6. 6.
    van der Cruijsen-Koeter IW, van der Kwast TH, Schroder FH (2003) Interval carcinomas in the European randomized study of screening for prostate cancer (ERSPC)-Rotterdam. J Natl Cancer Inst 95: 1462–1466PubMedGoogle Scholar
  7. 7.
    Partin AW, Kattan MW, Subong ENP, Walsh PC, Wojno KJ, Oesterling JE, Scardino PT, Pearson JD (1997) Combination of prostate-specific antigen, clinical stage, and gleason score to predict pathological stage of localized prostate cancer—a multi-institutional update. Jama-J Am Med Assoc 277: 1445–1451CrossRefGoogle Scholar
  8. 8.
    Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD (2001) Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 58: 843–848PubMedCrossRefGoogle Scholar
  9. 9.
    Huzjan R, Sala E, Hricak H (2005) Magnetic resonance imaging and magnetic resonance spectroscopic imaging of prostate cancer. Nat Clin Pract Urol 2: 434–442PubMedCrossRefGoogle Scholar
  10. 10.
    Alonzi R, Padhani AR, Allen C (2007) Dynamic contrast enhanced MRI in prostate cancer. Eur J Radiol 63: 335–350PubMedCrossRefGoogle Scholar
  11. 11.
    Padhani AR, Harvey CJ, Cosgrove DO (2005) Angiogenesis imaging in the management of prostate cancer. Nat Clin Pract Urol 2: 596–607PubMedCrossRefGoogle Scholar
  12. 12.
    Casciani E, Gualdi GF (2006) Prostate cancer: value of magnetic resonance spectroscopy 3D chemical shift imaging. Abdom ImagingGoogle Scholar
  13. 13.
    Dadiani M, Furman-Haran E, Degani H (2006) The application of NMR in tumor angiogenesis research. Prog Nuclear Magn Reson Spectrosc 49: 27–44CrossRefGoogle Scholar
  14. 14.
    Hylton N (2006) Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol 24: 3293–3298PubMedCrossRefGoogle Scholar
  15. 15.
    Rehman S, Jayson GC (2005) Molecular imaging of antiangiogenic agents. Oncologist 10: 92–103PubMedCrossRefGoogle Scholar
  16. 16.
    Oehr P (2006) ‘Omics’-based imaging in cancer detection and therapy. Personal Med 3: 19–32CrossRefGoogle Scholar
  17. 17.
    Negendank W (1992) Studies of human tumors by MRS: a review. NMR Biomed 5: 303–324PubMedGoogle Scholar
  18. 18.
    Segal E, Sirlin CB, Ooi C, Adler AS, Gollub J, Chen X, Chan BK, Matcuk GR, Barry CT, Chang HY, Kuo MD (2007) Decoding global gene expression programs in liver cancer by noninvasive imaging. Nat Biotechnol 25: 675–680PubMedCrossRefGoogle Scholar
  19. 19.
    Gaston SM, Soares MA, Siddiqui MM, Vu D, Lee JM, Goldner DL, Brice MJ, Shih JC, Upton MP, Perides G, Baptista J, Lavin PT, Bloch BN, Genega EM, Rubin MA, Lenkinski RE (2005) Tissue-print and print-phoresis as platform technologies for the molecular analysis of human surgical specimens: mapping tumor invasion of the prostate capsule. Nat Med 11: 95–101PubMedCrossRefGoogle Scholar
  20. 20.
    Rosen Y, Bloch BN, Lenkinski RE, Greenman RL, Marquis RP, Rofsky NM (2007) 3T MR of the prostate: reducing susceptibility gradients by inflating the endorectal coil with a barium sulfate suspension. Magn Reson Med 57: 898–904PubMedCrossRefGoogle Scholar
  21. 21.
    Bloch BN, Rofsky NM, Baroni RH, Marquis RP, Pedrosa I, Lenkinski RE (2004) 3 Tesla magnetic resonance imaging of the prostate with combined pelvic phased-array and endorectal coils; Initial experience (1). Acad Radiol 11: 863–867PubMedGoogle Scholar
  22. 22.
    Cunningham CH, Vigneron DB, Marjanska M, Chen AP, Xu D, Hurd RE, Kurhanewicz J, Garwood M, Pauly JM (2005) Sequence design for magnetic resonance spectroscopic imaging of prostate cancer at 3 T. Magn Reson Med 53: 1033–1039PubMedCrossRefGoogle Scholar
  23. 23.
    Degani H, Gusis V, Weinstein D, Fields S, Strano S (1997) Mapping pathophysiological features of breast tumors by MRI at high spatial resolution. Nat Med 3: 780–782PubMedCrossRefGoogle Scholar
  24. 24.
    Bloch BN, Furman-Haran E, Helbich TH, Lenkinski RE, Degani H, Kratzik C, Susani M, Haitel A, Jaromi S, Ngo L, Rofsky NM (2007) Prostate cancer: accurate determination of extracapsular extension with high-spatial-resolution dynamic contrast-enhanced and T2-weighted MR imaging—initial results. Radiology 245: 176–185PubMedCrossRefGoogle Scholar
  25. 25.
    Furman-Haran E, Degani H (2002) Parametric analysis of breast MRI. J Comput Assist Tomogr 26: 376–386PubMedCrossRefGoogle Scholar
  26. 26.
    Schroeder A, Mueller O, Stocker S, Salowsky R, Leiber M, Gassmann M, Lightfoot S, Menzel W, Granzow M, Ragg T (2006) The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol Biol 7: 3PubMedCrossRefGoogle Scholar
  27. 27.
    Rubin MA, Zerkowski MP, Camp RL, Kuefer R, Hofer MD, Chinnaiyan AM, Rimm DL (2004) Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): a novel paradigm for automated and continuous biomarker measurements. Am J Pathol 164: 831–840PubMedGoogle Scholar
  28. 28.
    Grizzi F, Russo C, Colombo P, Franceschini B, Frezza EE, Cobos E, Chiriva-Internati M (2005) Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension. BMC Cancer 5: 14PubMedCrossRefGoogle Scholar
  29. 29.
    Rajesh A, Coakley FV, Kurhanewicz J (2007) 3D MR spectroscopic imaging in the evaluation of prostate cancer. Clin Radiol 62: 921–929PubMedCrossRefGoogle Scholar
  30. 30.
    Coakley FV, Qayyum A, Kurhanewicz J (2003) Magnetic resonance imaging and spectroscopic imaging of prostate cancer. J Urol 170: S69–S75; discussion S75–S76Google Scholar
  31. 31.
    Zakian KL, Sircar K, Hricak H, Chen HN, Shukla-Dave A, Eberhardt S, Muruganandham M, Ebora L, Kattan MW, Reuter VE, Scardino PT, Koutcher JA (2005) Correlation of proton MR spectroscopic imaging with gleason score based on step-section pathologic analysis after radical prostatectomy. Radiology 234: 804–814PubMedCrossRefGoogle Scholar
  32. 32.
    Haga T (1971) Synthesis and release of (14 C) acetylcholine in synaptosomes. J Neurochem 18: 781–798PubMedCrossRefGoogle Scholar
  33. 33.
    Katz-Brull R, Degani H (1996) Kinetics of choline transport and phosphorylation in human breast cancer cells; NMR application of the zero trans method. Anticancer Res 16: 1375–1380PubMedGoogle Scholar
  34. 34.
    Eliyahu G, Kreizman T, Degani H (2007) Phosphocholine as a biomarker of breast cancer: Molecular and biochemical studies. Int J CancerGoogle Scholar
  35. 35.
    de Molina AR, Rodriguez-Gonzalez A, Gutierrez R, Martinez- Pineiro L, Sanchez JJ, Bonilla F, Rosell R, Lacal JC (2002) Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun 296: 580–583CrossRefGoogle Scholar
  36. 36.
    Glunde K, Jacobs MA, Bhujwalla ZM (2006) Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev Mol Diagnos 6: 821–829CrossRefGoogle Scholar
  37. 37.
    Kwee SA, Coel MN, Lim J, Ko JHP (2005) Prostate cancer localization with (18) fluorine fluorocholine positron emission tomography. J Urol 173: 252–255PubMedGoogle Scholar
  38. 38.
    Kwee SA, Wei H, Sesterhenn I, Yun D, Coel MN (2006) Localization of primary prostate cancer with dual-phase F-18-fluorocholine PET. J Nuclear Med 47: 262–269Google Scholar
  39. 39.
    Reske SN, Blumstein NM, Neumaier B, Gottfried HW, Finsterbusch F, Kocot D, Moller P, Glatting G, Perner S (2006) Imaging prostate cancer with C-11-choline PET/CT. J Nuclear Med 47: 1249–1254Google Scholar
  40. 40.
    Folkman J (2006) Angiogenesis. Annu Rev Med 57: 1–18PubMedCrossRefGoogle Scholar
  41. 41.
    Dome B, Hendrix MJ, Paku S, Tovari J, Timar J (2007) Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol 170: 1–15PubMedCrossRefGoogle Scholar
  42. 42.
    Chaib H, Cockrell EK, Rubin MA, Macoska JA (2001) Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis. Neoplasia 3: 43–52PubMedCrossRefGoogle Scholar
  43. 43.
    El-Gohary YM, Silverman JF, Olson PR, Liu YL, Cohen JK, Miller R, Saad RS (2007) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am J Clin Pathol 127: 572–579PubMedCrossRefGoogle Scholar
  44. 44.
    Soulitzis N, Karyotis I, Delakas D, Spandidos DA (2006) Expression analysis of peptide growth factors VEGF, FGF2, TGFB1, EGF and IGF1 in prostate cancer and benign prostatic hyperplasia. Int J Oncol 29: 305–314PubMedGoogle Scholar
  45. 45.
    Walsh K, Sriprasad S, Hopster D, Codd J, Mulvin D (2002) Distribution of vascular endothelial growth factor (VEGF) in prostate disease. Prostate Cancer Prostat Dis 5: 119–22CrossRefGoogle Scholar
  46. 46.
    Rasiah KK, Kench JG, Gardiner-Garden M, Biankin AV, Golovsky D, Brenner PC, Kooner R, O’Neill G F, Turner JJ, Delprado W, Lee CS, Brown DA, Breit SN, Grygiel JJ, Horvath LG, Stricker PD, Sutherland RL, Henshall SM (2006) Aberrant neuropeptide Y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis. Cancer Epidemiol Biomarkers Prev 15: 711– 716PubMedCrossRefGoogle Scholar
  47. 47.
    Ruscica M, Dozio E, Motta M, Magni P (2007) Modulatory actions of neuropeptide Y on prostate cancer growth: role of MAP kinase/ERK 1/2 activation. Adv Exp Med Biol 604: 96–100PubMedCrossRefGoogle Scholar
  48. 48.
    Ekstrand AJ, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander AC, Hassani H, Hallberg B, Nordlander M, Cao Y (2003) Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci USA 100: 6033–6038PubMedCrossRefGoogle Scholar
  49. 49.
    Lee EW, Grant DS, Movafagh S, Zukowska Z (2003) Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice. Peptides 24: 99–106PubMedCrossRefGoogle Scholar
  50. 50.
    Lee EW, Michalkiewicz M, Kitlinska J, Kalezic I, Switalska H, Yoo P, Sangkharat A, Ji H, Li L, Michalkiewicz T, Ljubisavljevic M, Johansson H, Grant DS, Zukowska Z (2003) Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest 111: 1853–1862PubMedGoogle Scholar
  51. 51.
    Zukowska Z, Grant DS, Lee EW (2003) Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc Med 13: 86–92PubMedCrossRefGoogle Scholar
  52. 52.
    Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H, Yeh Y, Chen WT, Kleinman HK, Grouzmann E, Grant DS (1998) Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83: 187–195PubMedGoogle Scholar
  53. 53.
    Kitlinska J (2007) Neuropeptide Y (NPY) in neuroblastoma: effect on growth and vascularization. Peptides 28: 405–412PubMedCrossRefGoogle Scholar
  54. 54.
    Kitlinska J, Abe K, Kuo L, Pons J, Yu M, Li L, Tilan J, Everhart L, Lee EW, Zukowska Z, Toretsky JA (2005) Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res 65: 1719–1728PubMedCrossRefGoogle Scholar
  55. 55.
    Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, Jayson G, Judson IR, Knopp MV, Maxwell RJ, McIntyre D, Padhani AR, Price P, Rathbone R, Rustin G, Tofts PS, Tozer GM, Vennart W, Waterton JC, Williams SR, Workman P (2003) Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials. Br J Radiol 76: S87–S91PubMedCrossRefGoogle Scholar
  56. 56.
    Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. Jmri-J Magn Reson Imaging 7: 91–101CrossRefGoogle Scholar
  57. 57.
    Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp M, Larsson HBW, Lee TY, Mayr NA, Parker GJM, Port RE, Taylor J, Weisskoff RM (1999) Estimating kinetic parameters from dynamic contrast-enhanced T-1-weighted MRI of a diffusable tracer: Standardized quantities and symbols. Jmri-J Magn Reson Imaging 10: 223–232CrossRefGoogle Scholar
  58. 58.
    Camp RL, Chung GG, Rimm DL (2002) Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 8: 1323–1327PubMedCrossRefGoogle Scholar

Copyright information

© ESMRMB 2008

Authors and Affiliations

  • Robert E. Lenkinski
    • 1
  • B. Nicolas Bloch
    • 1
  • Fangbing Liu
    • 2
  • John V. Frangioni
    • 1
    • 2
  • Sven Perner
    • 3
  • Mark A. Rubin
    • 3
  • Elizabeth M. Genega
    • 4
  • Neil M. Rofsky
    • 1
  • Sandra M. Gaston
    • 5
  1. 1.Department of RadiologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  2. 2.Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  3. 3.Department of PathologyWeill Cornell Medical CenterNew YorkUSA
  4. 4.Department of PathologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  5. 5.Department of SurgeryBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA

Personalised recommendations