Prostate cancer is a heterogeneous disease with subtypes that are characterized by different molecular profiles as a result of chromosomal rearrangements, epigenetic modifications, and activation of various signaling pathways. The subtype heterogeneity contributes to the challenges with a definitive diagnosis and biomarkers for disease progression. The current diagnostic test based on the detection of prostate specific antigen lacks sensitivity and specificity. Imaging plays an important role in characterizing biomarkers and elucidating the underlying molecular mechanisms . For example, 18 F-fluoro-2-deoxy glucose is commonly used to assess cancer cell metabolism. More recently, magnetic resonance spectroscopic observations of the in vivo dynamic conversion of hyperpolarized 13 C- pyruvate to lactate demonstrate that imaging enables the visualization of molecular processes. Biomarkers have also been developed that reveal aberrant cell growth and proliferation, both hallmarks of cancer. Androgen dependent and independent signaling path- ways underpin prostate cancer pathogenesis as they lead to downstream effect in cell growth, proliferation, survival, and suppression of apoptosis. Molecular imaging with radiolabeled ligands and positron emission tomography/computed tomography has provided quantitative characterization of the interactions between receptors and testosterone or growth factors. These observations, along with data on genetic alterations of the receptor genes, shed light on signal transduction involved in prostate cancer. This review article highlights advances in the understanding of the molecular mechanisms of prostate cancer and the synergy of this knowledge with imaging in characterizing potential biomarkers of the disease.
Imanishi, T., Itoh, T., Suzuki, Y., O’Donovan, C., Fukuchi, S., Koyanagi, K.O., et al. (2004) Integrative annotation of 21,037 human genes validated by full-length cDNA clones. PLoS Biology, 6, e162. doi:10.1371/journal.pbio.0020162
Collins, F.S., Green, E.D., Guttmacher, A.E. and Guyer, M.S. (2003) A vision for the future of genomics research. Nature, 422, 835-847. doi:10.1038/nature01626
Mimeault, M. and Batra, S.K. (2011) Frequent gene pro- ducts and molecular pathways altered in prostate cancer- and metastasis-initiating cells and their progenies and no- vel promising multitargeted therapies. Molecular Medi- cine, 17, 949-964.
Altieri, D.C., Languino, L.R., Lian, J.B., Stein, J.L., Leav, I., van Wijnen, A.J., et al. (2009) Prostate cancer regulatory networks. Journal of Cellular Biochemistry, 107, 845- 852. doi:10.1002/jcb.22162
US Preventive Services Task Force (2012) Screening for prostate cancer. http://www.uspreventiveservicetaskforce.org/prostatecancerscreening/prostatefinalrs.htm
Martin, S.K., Vaughan, T.B., Atkinson, T., Zhu, H. and Kyprianou, N. (2012) Emerging biomarkers of prostate cancer (Review). Oncology Reports, 409-417. doi:10.3892/or.2012.1832
Hessels, D., van Gils, M.P., van Hooij, O., Jannink, S.A., Witjes, J.A., Verhaegh, G.W., et al. (2010) Predictive value of PCA3 in urinary sediments in determining cli- nico-pathological characteristics of prostate cancer. Prostate, 70, 10-16. doi:10.1002/pros.21032
Gu, Z., Thomas, G., Yamashiro, J., Shintaku, I.P., Dorey, F., Raitano, A., et al. (2000) Prostate stem cell antigen (PSCA) expression increases with high gleason score, ad- vanced stage and bone metastasis in prostate cancer. On- cogene, 19, 1288-1296. doi:10.1038/sj.onc.1203426
Warburg, O., Wind, F. and Negelein, E. (1927) Themetabolism of tumors in the body. Journal of General Physiology, 6, 519-530. doi:10.1085/jgp.8.6.519
Warburg, O. (1956) On the origin of cancer cells. Science, 123, 309-314. doi:10.1126/science.123.3191.309
Seth, P., Grant, A., Tang, J., Vinogradov, E., Wang, X., Lenkinski, R., et al. (2011) On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate. Neoplasia, 13, 60-71.
Chen, A.P., Albers, M.J., Cunningham, C.H., Kohler, S.J., Yen, Y.F., Hurd, R.E., et al. (2007) Hyperpolarized C-13 spectroscopic imaging of the TRAMP mouse at 3T-initial experience. Magnetic Resonance in Medicine, 58, 1099- 1106. doi:10.1002/mrm.21256
Chen, A.P., Kurhanewicz, J., Bok, R., Xu, D., Joun, D., Zhang, V., et al. (2008) Feasibility of using hyperpolar- ized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies. Magnetic Resonance Imaging, 26, 721- 726. doi:10.1016/j.mri.2008.01.002
Kurhanewicz, J., Vigneron, D.B., Brindle, K., Chekme- nev, E.Y., Comment, A., Cunningham, C.H., et al. (2011) Analysis of cancer metabolism by imaging hyperpolar- ized nuclei: Prospects for translation to clinical research. Neoplasia, 13, 81-97.
Vallabhajosula, S. (2007) 18F-labeled positron emission tomographic radiopharmaceuticals in oncology: An overview of radiochemistry and mechanisms of tumor local- ization. Seminars in Nuclear Medicine, 37, 400-419. doi:10.1053/j.semnuclmed.2007.08.004
Turcotte, E., Wiens, L.W., Grierson, J.R., Peterson, L.M., Wener, M.H. and Vesselle, H. (2007) Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to pre- viously investigated therapeutic FLT doses. BMC Nu- clear Medicine, 7, 3. doi:10.1186/1471-2385-7-3
Leyton, J., Smith, G., Zhao, Y., Perumal, M., Nguyen, Q.D., Robins, E., et al. (2009) [18F]fluoromethyl-[1,2- 2H4]-choline: A novel radiotracer for imaging choline metabolism in tumors by positron emission tomography. Cancer Research, 69, 7721-7728. doi:10.1158/0008-5472.CAN-09-1419
Jiang, Z., Piao, D., Bartels, K.E., Holyoak, G.R., Ritchey, J.W., Ownby, C.L., et al. (2011) Transrectal ultrasound- integrated spectral optical tomography of hypoxic progression of a regressing tumor in a canine prostate. Technology in Cancer Research and Treatment, 10, 519-531.
Folkman, J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine, 1, 27-31. doi:10.1038/nm0195-27
Risau, W. (1997) Mechanisms of angiogenesis. Nature, 386, 671-674.
Costa, L.J. and Drabkin, H.A. (2007) Renal cell carci- noma: New developments in molecular biology and po- tential for targeted therapies. Oncologist, 12, 1404-1415. doi:10.1634/theoncologist.12-12-1404
Samlowski, W.E., Wong, B. and Vogelzang, N.J. (2008) Management of renal cancer in the tyrosine kinase in- hibitor era: A view from 3 years on. BJU International, 2, 162-165. doi:10.1111/j.1464-410X.2008.07670.x
Lim, E.H., Danthi, N., Bednarski, M. and Li, K.C. (2005) A review: Integrin alphavbeta3-targeted molecular imag- ing and therapy in angiogenesis. Nanomedicine, 1, 110- 114. doi:10.1016/j.nano.2005.03.008
Munshi, H.G. and Stack, M.S. (2006) Reciprocal interactions between adhesion receptor signaling and MMP regulation. Cancer and Metastasis Reviews, 25, 45-56. doi:10.1007/s10555-006-7888-7
Zeisel, S.H. (1993) Choline phospholipids: Signal transduction and carcinogenesis. FASEB Journal, 7, 551-557.
Zeisel, S.H. (1995) Nutrients, signal transduction and carcinogenesis. Advances in Experimental Medicine and Biology, 369, 175-183. doi:10.1007/978-1-4615-1957-7_16
Mena, E., Turkbey, B., Mani, H., Adler, S., Valera, V.A., Bernardo, M., et al. (2012) 11C-Acetate PET/CT in localized prostate cancer: A study with MRI and histopathologic correlation. Journal of Nuclear Medicine, 53, 538- 545. doi:10.2967/jnumed.111.096032
Leung, K. (2004) Quenched indocyanine green-anti-pros- tate-specific membrane antigen antibody J591. Molecular Imaging and Contrast Agent Database (MICAD), Bethesda.
Nanus, D.M., Milowsky, M.I., Kostakoglu, L., Smith-Jones, P.M., Vallabahajosula, S., Goldsmith, S.J., et al. (2003) Clinical use of monoclonal antibody HuJ591 therapy: Targeting prostate specific membrane antigen. Journal of Urology, 170, S84-S88.
Nargund, V., Al Hashmi, D., Kumar, P., Gordon, S., Otitie, U., Ellison, D., et al. (2005) Imaging with radiolabelled monoclonal antibody (MUJ591) to prostate-specific membrane antigen in staging of clinically localized prostatic carcinoma: Comparison with clinical, surgical and histological staging. BJU International, 95, 1232- 1236. doi:10.1111/j.1464-410X.2005.05511.x
Kahn, D., Williams, R.D., Haseman, M.K., Reed, N.L., Miller, S.J. and Gerstbrein, J. (1998) Radioimmunoscintigraphy with In-111-labeled capromabpendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy. Journal of Clinical Oncol- ogy, 20, 284-289.
Kahn, D., Williams, R.D., Manyak, M.J., Haseman, M.K., Seldin, D.W., Libertino, J.A., et al. (1998) 111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. Journal of Urology, 16, 2041-2046.
Holmes, E.H. (2001) PSMA specific antibodies and their diagnostic and therapeutic use. Expert Opinion on Investigational Drugs, 10, 511-519. doi:10.1517/13543784.10.3.511
Wolf, P., Freudenberg, N., Buhler, P., Alt, K., Schultze- Seemann, W., Wetterauer, U., et al. (2010) Three conformational antibodies specific for different PSMA epitopes are promising diagnostic and therapeutic tools for prostate cancer. Prostate, 70, 562-569.
Tomlins, S.A., Aubin, S.M., Siddiqui, J., Lonigro, R.J., Sefton-Miller, L., Miick, S., et al. (2011) Urine TMPRSS2: ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Science Translational Medicine, 3, 72.
Tomlins, S.A., Bjartell, A., Chinnaiyan, A.M., Jenster, G., Nam, R.K., Rubin, M.A., et al. (2009) ETS gene fusions in prostate cancer: From discovery to daily clinical prac- tice. European Urology, 56, 275-286. doi:10.1016/j.eururo.2009.04.036
Stott, S.L., Lee, R.J., Nagrath, S., Yu, M., Miyamoto, D.T., Ulkus, L., et al. (2010) Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Science Translational Medicine, 2, 25-23.
Liu, W., Ewing, C.M., Chang, B.L., Li, T., Sun, J., Tur-ner, A.R., et al. (2007) Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers. Genes Chromosomes Cancer, 46, 972-980. doi:10.1002/gcc.20482
Danila, D.C., Anand, A., Sung, C.C., Heller, G., Leversha, M.A., Cao, L., et al. (2011) TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensi- tivity in castration-resistant prostate cancer patients treated with abiraterone acetate. European Urology, 60, 897- 904. doi:10.1016/j.eururo.2011.07.011
Dahlman, K.B., Parker, J.S., Shamu, T., Hieronymus, H., Chapinski, C., Carver, B., et al. (2012) Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening. PLoS One, 7, e34414. doi:10.1371/journal.pone.0034414
Kaarbo, M., Klokk, T.I. and Saatcioglu, F. (2007) An- drogen signaling and its interactions with other signaling pathways in prostate cancer. BioEssays, 29, 1227-1238. doi:10.1002/bies.20676
Ulmert, D., Evans, M.J., Holland, J.P., Rice, S.L., Wong- vipat, J., Pettersson, K., et al. (2012) Imaging androgen receptor signaling with a radiotracer targeting free prostate-specific antigen. Cancer Discovery, 2, 320-327. doi:10.1158/2159-8290.CD-11-0316
Tomlins, S.A., Mehra, R., Rhodes, D.R., Smith, L.R., Roulston, D., Helgesson, B.E., et al. (2006) TMPRSS2: ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Research, 66, 3396-3400. doi:10.1158/0008-5472.CAN-06-0168
Tomlins, S.A., Rhodes, D.R., Perner, S., Dhanasekaran, S.M., Mehra, R., Sun, X.W., et al. (2006) Recurrent fu- sion of TMPRSS2 and ETS transcription factors in prostate cancer. FASEB Journal, 20, A1327-A1327.
Gupta, S., Iljin, K., Sara, H., Mpindi, J.P., Mirtti, T., Vainio, P., et al. (2010) FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-tomesenchymaltransition in human prostate Cancer Cells. Cancer Research, 70, 6735-6745. doi:10.1158/0008-5472.CAN-10-0244
Iljin, K., Wolf, M., Edgren, H., Gupta, S., Kilpinen, S., Skotheim, R.I., et al. (2006) TMPRSS2 fusions with on- cogenic ETS factors in prostate cancer involve unbal- anced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Re- search, 66, 10242-10246. doi:10.1158/0008-5472.CAN-06-1986
Yu, J.D., Yu, J.J., Mani, R.S., Cao, Q., Brenner, C.J., Cao, X.H., et al. (2010) Anintegrated network of androgen re- ceptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell, 17, 443-454. doi:10.1016/j.ccr.2010.03.018
Zwick, E., Bange, J. and Ullrich, A. (2001) Receptor tyrosine kinase signalling as a target for cancer intervenetion strategies. Endocrine-Related Cancer, 8, 161-173. doi:10.1677/erc.0.0080161
Pawson, T. (1995) Protein modules and signalling networks. Nature, 373, 573-580. doi:10.1038/373573a0
Bublil, E.M. and Yarden, Y. (2007) The EGF receptor family: Spearheading a merger of signaling and therapeutics. Current Opinion in Cell Biology, 19, 124-134.
Johnson, L.N. (2009) Protein kinase inhibitors: Contributions from structure to clinical compounds. Quarterly Reviews of Biophysics, 42, 1-40. doi:10.1017/S0033583508004745
Robinson, D.R., Wu, Y.M. and Lin, S.F. (2000) The protein tyrosine kinase family of the human genome. Oncogene, 19, 5548-5557.