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Gene Expression Profiles Predict Sensitivity of Prostate Cancer to Radiotherapy

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DOI: 10.4236/jct.2013.44A003    3,237 Downloads   5,564 Views   Citations


Ionizing radiation (IR) is the most common treatment used to control localized primary prostate cancer (PC). However, for a significant number of patients, radiotherapy fails to adequately control the tumor. Thus, a main clinical problem today is the lack of a specific marker that may be used to predict the treatment outcome and to identify prostate cancer patients who are unlikely to respond to radiation therapy. In this study, we used human PC xenografts with predetermined radioresistant/sensitive phenotypes, and gene expression microarrays, correlated their specific transcripttional profiles with response to radiation. Employing unsupervised two-way hierarchical clustering, we identified four gene clusters displaying different expression patterns. Two clusters showed higher expression levels in the resistant xenografts and the other two clusters showed higher expression levels in the sensitive xenografts. Expression levels of 113 genes differed by at least 3 fold between sensitive and resistant xenografts. These genes represent members of several cellular pathways, some of which are known to be associated with response to radiation. All or several of these genes could serve as predictive tools to determine at biopsy the expected response of a particular tumor to radiotherapy. Indeed, the profiles we identified enabled us to predict the degree of radiosensitivity of a panel of established PC cell lines. Importantly, irradiation of the PC xenografts did not induce any significant changes in gene expression, regardless of their susceptibility phenotype. These data strongly support the first of two models: a: a random effect of irradiation on a homogeneous population of cells, rather than b: of a tumor comprised of a mixture of radioresistant and radiosensitive cell subpopulations. Our findings imply that each of the radio-phenotypes represents different intrinsic characteristics that affect the ability of a tumor to survive radiotherapy.

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The authors declare no conflicts of interest.

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L. Agemy, I. Kela, T. Waks, R. Pfeffer, A. Bar-Shira, A. Orr-Urtreger, E. Domany and Z. Eshhar, "Gene Expression Profiles Predict Sensitivity of Prostate Cancer to Radiotherapy," Journal of Cancer Therapy, Vol. 4 No. 4A, 2013, pp. 11-26. doi: 10.4236/jct.2013.44A003.


[1] T. M. Pisansky, “External-Beam Radiotherapy for Localized Prostate Cancer,” The New England Journal of Medicine, Vol. 355, No. 15, 2006, pp. 1583-1591. doi:10.1056/NEJMct055263
[2] A. Pollack, G. K. Zagars, G. Starkschall, J. A. Antolak, J. J. Lee, E. Huang, A. C. von Eschenbach, D. A. Kuban and I. Rosen, “Prostate Cancer Radiation Dose Response: Results of the M. D. Anderson Phase III Randomized Trial,” International Journal of Radiation Oncology*Biology*Physics, Vol. 53, No. 5, 2002, pp. 1097-1105. doi:10.1016/S0360-3016(02)02829-8
[3] A. R. Snyder and W. F. Morgan, “Gene Expression Profiling after Irradiation: Clues to Understanding Acute and Persistent Responses?” Cancer and Metastasis Reviews, Vol. 23, No. 3-4, 2004, pp. 259-268. doi:10.1023/B:CANC.0000031765.17886.fa
[4] M. H. Bourguignon, P. A. Gisone, M. R. Perez, S. Michelin, D. Dubner, M. D. Giorgio and E. D. Carosella, “Genetic and Epigenetic Features in Radiation Sensitivity Part I: Cell Signalling in Radiation Response,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 32, No. 2, 2005, pp. 229-246. doi:10.1007/s00259-004-1730-7
[5] P. J. Colletier, F. Ashoori, D. Cowen, R. E. Meyn, P. Tofilon, M. E. Meistrich and A. Pollack, “AdenoviralMediated p53 Transgene Expression Sensitizes Both WildType and Null p53 Prostate Cancer Cells in Vitro to Radiation,” International Journal of Radiation Oncology* Biology*Physics, Vol. 48, No. 5, 2000, pp. 1507-1512. doi:10.1016/S0360-3016(00)01409-7
[6] J. M. Lee and A. Bernstein, “p53 Mutations Increase Resistance to Ionizing Radiation,” Proceedings of the National Academy of Sciences of the United States, Vol. 90, No. 12, 1993, pp. 5742-5746. doi:10.1073/pnas.90.12.5742
[7] Z. Fan, P. Chakravarty, A. Alfieri, T. K. Pandita, B. Vikram and C. Guha, “Adenovirus-Mediated Antisense ATM Gene Transfer Sensitizes Prostate Cancer Cells to Radiation,” Cancer Gene Therapy, 7, No. 10, 2000, pp. 1307-1314. doi:10.1038/sj.cgt.0243
[8] C. J. Rosser, M. Tanaka, L. L. Pisters, N. Tanaka, L. B. Levy, D. C. Hoover, H. B. Grossman, T. J. McDonnell, D. A. Kuban and R. E. Meyn, “Adenoviral-Mediated PTEN Transgene Expression Sensitizes Bcl-2-Expressing Prostate Cancer Cells to Radiation,” Cancer Gene Therapy, Vol. 11, No. 4, 2004, pp. 273-279. doi:10.1038/sj.cgt.7700673
[9] G. Bucca, G. Carruba, A. Saetta, P. Muti, L. Castagnetta and C. P. Smith, “Gene Expression Profiling of Human Cancers,” Annals of the New York Academy of Sciences, Vol. 1028, 2004, pp. 28-37. doi:10.1196/annals.1322.003
[10] K. A. Klein, R. E. Reiter, J. Redula, H. Moradi, X. L. Zhu, A. R. Brothman, D. J. Lamb, M. Marcelli, A. Belldegrun, O. N. Witte and C. L. Sawyers, “Progression of Metastatic Human Prostate Cancer to Androgen Independence in Immunodeficient SCID Mice,” Nature Medicine, Vol. 3, No. 4, 1997, pp. 402-408. doi:10.1038/nm0497-402
[11] C. L. Tso, W. H. McBride, J. Sun, B. Patel, K. H. Tsui, S. H. Paik, B. Gitlitz, R. Caliliw, A. van Ophoven, L. Wu, J. deKernion and A. Belldegrun, “Androgen Deprivation Induces Selective Outgrowth of Aggressive Hormone-Refractory Prostate Cancer Clones Expressing Distinct Cellular and Molecular Properties Not Present in Parental Androgen-Dependent Cancer Cells,” The Cancer Journal, Vol. 6, No. 4, 2000, pp. 220-233.
[12] E. Corey, J. E. Quinn, K. R. Buhler, P. S. Nelson, J. A. Macoska, L. D. True and R. L. Vessella, “LuCaP 35: A New Model of Prostate Cancer Progression to Androgen Independence,” Prostate, Vol. 55, No. 4, 2003, pp. 239-246. doi:10.1002/pros.10198
[13] N. Craft, C. Chhor, C. Tran, A. Belldegrun, J. DeKernion, O. N. Witte, J. Said, R. E. Reiter and C. L. Sawyers, “Evidence for Clonal Outgrowth of Androgen-Independent Prostate Cancer Cells from Androgen-Dependent Tumors through a Two-Step Process,” Cancer Research, Vol. 59, No. 19, 1999, pp. 5030-5036.
[14] M. A. Wainstein, F. He, D. Robinson, H. J. Kung, S. Schwartz, J. M. Giaconia, N. L. Edgehouse, T. P. Pretlow, D. R. Bodner, E. D. Kursh, et al., “CWR22: Androgen-Dependent Xenograft Model Derived from a Primary Human Prostatic Carcinoma,” Cancer Research, Vol. 54, No. 23, 1994, pp. 6049-6052.
[15] A. Bar-Shira, J. H. Pinthus, U. Rozovsky, M. Goldstein, W. R. Sellers, Y. Yaron, Z. Eshhar and A. Orr-Urtreger, “Multiple Genes in Human 20q13 Chromosomal Region Are Involved in an Advanced Prostate Cancer Xenograft,” Cancer Research, Vol. 62, No. 23, 2002, pp. 6803-6807.
[16] M. E. Gleave, J. T. Hsieh, H. C. Wu, A. C. von Eschenbach and L. W. Chung, “Serum Prostate Specific Antigen Levels in Mice Bearing Human Prostate LNCaP Tumors Are Determined by Tumor Volume and Endocrine and Growth Factors,” Cancer Research, Vol. 52, No. 6, 1992, pp. 1598-1605.
[17] M. Blatt, S. Wiseman and E. Domany, “Superparamagnetic Clustering of Data,” Physical Review Letters, Vol. 76, No. 18, 1996, pp. 3251-3254.
[18] D. Tsafrir, I. Tsafrir, L. Ein-Dor, O. Zuk, D. A. Notterman and E. Domany, “Sorting Points into Neighborhoods (SPIN): Data Analysis and Visualization by Ordering Distance Matrices,” Bioinformatics, Vol. 21, No. 10, 2005, pp. 2301-2308.
[19] S. E. Langley and R. Laing, “Prostate Brachytherapy Has Come of Age: A Review of the Technique and Results,” BJU International, Vol. 89, No. 3, 2002, pp. 241-249. doi:10.1046/j.1464-4096.2001.01610.x
[20] K. Kannan, N. Amariglio, G. Rechavi, J. Jakob-Hirsch, I. Kela, N. Kaminski, G. Getz, E. Domany and D. Givol, “DNA Microarrays Identification of Primary and Secondary Target Genes Regulated by p53,” Oncogene, Vol. 20, No. 18, 2001, pp. 2225-2234. doi:10.1038/sj.onc.1204319
[21] G. Getz, E. Levine and E. Domany, “Coupled Two-Way Clustering Analysis of Gene Microarray Data,” Proceedings of the National Academy of Sciences of the United States, Vol. 97, No. 22, 2000, pp. 12079-12084. doi:10.1073/pnas.210134797
[22] S. L. Scott, P. H. Gumerlock, L. Beckett, Y. Li and Z. Goldberg, “Survival and Cell Cycle Kinetics of Human Prostate Cancer Cell Lines after Singleand Multifraction Exposures to Ionizing Radiation,” International Journal of Radiation Oncology*Biology*Physics, Vol. 59, No. 1, 2004, pp. 219-227. doi:10.1016/j.ijrobp.2004.01.027
[23] E. H. Chang, K. F. Pirollo and K. B. Bouker, “Tp53 Gene Therapy: A Key to Modulating Resistance to Anticancer Therapies?” Molecular Medicine Today, Vol. 6, No. 9, 2000, pp. 358-364. doi:10.1016/S1357-4310(00)01767-6
[24] O. Kitahara, T. Katagiri, T. Tsunoda, Y. Harima and Y. Nakamura, “Classification of Sensitivity or Resistance of Cervical Cancers to Ionizing Radiation According to Expression Profiles of 62 Genes Selected by cDNA Microarray Analysis,” Neoplasia, Vol. 4, No. 4, 2002, pp. 295-303. doi:10.1038/sj.neo.7900251
[25] L. Vallat, H. Magdelenat, H. Merle-Beral, P. Masdehors, G. P. de Montalk, F. Davi, M. Kruhoffer, L. Sabatier, T. F. Orntoft and J. Delic, “The Resistance of B-CLL Cells to DNA Damage-Induced Apoptosis Defined by DNA Microarrays,” Blood, Vol. 101, No. 11, 2003, pp. 4598-4606. doi:10.1182/blood-2002-06-1743
[26] K. Fukuda, C. Sakakura, K. Miyagawa, Y. Kuriu, S. Kin, Y. Nakase, A. Hagiwara, S. Mitsufuji, Y. Okazaki, Y. Hayashizaki and H. Yamagishi, “Differential Gene Expression Profiles of Radioresistant Oesophageal Cancer Cell Lines Established by Continuous Fractionated Irradiation,” British Journal of Cancer, Vol. 91, No. 8, 2004, pp. 1543-1550. doi:10.1038/sj.bjc.6602187
[27] S. Falt, K. Holmberg, B. Lambert and A. Wennborg, “Long-Term Global Gene Expression Patterns in Irradiated Human Lymphocytes,” Carcinogenesis, Vol. 24, No. 11, 2003, pp. 1837-1845. doi:10.1093/carcin/bgg134
[28] J. J. Kruse, J. A. te Poele, A. Velds, R. M. Kerkhoven, L. J. Boersma, N. S. Russell and F. A. Stewart, “Identification of Differentially Expressed Genes in Mouse Kidney after Irradiation Using Microarray Analysis,” Radiation Research, Vol. 161, No. 1, 2004, pp. 28-38. doi:10.1667/RR3097

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