This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bruchovsky, N. Articles by Lawson, D. Search for Related Content PubMed PubMed Citation Articles by Bruchovsky, N. Articles by Lawson, D.

Effects of Androgen Withdrawal on the Stem Cell Composition of the Shionogi Carcinoma¹

Department of Cancer Endocrinology [N. B., P. S. R., S. L. G., D. L., M. T.], Division of Epidemiology [A. J. C.], Cancer Control Agency of British Columbia, and Division of Urology [P. S. R., S. L. G.], University of British Columbia, Vancouver, BC, V5Z 4E6, Canada

The parent Shionogi mouse mammary carcinoma is androgen dependent but cells that survive hormone withdrawal progress and give rise to an androgen-independent tumor. To determine whether renewed growth might be attributed to the persistence or partial recovery of an androgenic stimulus, we compared the amount of dihydrotestosterone and nuclear androgen receptor in parent and recurrent tumors. The whole tissue concentration of dihydrotestosterone in the parent tumor before castration was 1.40 ± 0.46 (SE) as compared with 0.22 ± 0.10 pmol/mg of DNA in the recurrent tumor. The initial concentration of nuclear androgen receptor in the parent was 0.65 ± 0.12 pmol/mg of DNA; this was reduced to zero within 24 h after castration. Also in keeping with the androgen independence, no receptor was detected in the nuclear fraction of the recurrent carcinoma. In an attempt to relate malignant potential to nonhormonal factors associated with progression, we compared the proportions of androgen-dependent and -independent tumorigenic (stem) cells in parent and recurrent tumors using an in vivo limiting dilution assay. The difference observed, i.e., one stem cell per 4000 tumor cells in the parent versus one stem cell per 200 tumor cells in the recurrent carcinoma, was consistent with a marked enrichment of stem cells in the latter. The proportion of androgen-independent stem cells was also determined by assaying tumor takes in female hosts. The difference, i.e., one stem cell per 370,000 tumor cells in the parent versus one stem cell per 800 tumor cells in the recurrent carcinoma, demonstrated a striking 500-fold increase in androgen-independent stem cells resulting from androgen withdrawal. Unexpectedly, no enrichment of androgen-independent stem cells was evident in regressing parent tumors; rather, the proportion of such cells was very small, i.e., one androgen-independent stem cell per 2,200,000 regressing parent cells. This finding implies that the androgen-independent state of cells which survive androgen withdrawal may result from the ability of a small number of initially androgen-dependent stem cells to adapt to an altered hormone environment.

¹ This research was supported by grants from the National Cancer Institute of Canada and the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Department of Cancer Endocrinology, Cancer Control Agency of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada.

Received 2/ 1/89. Revised 12/12/89.

This article has been cited by other articles:

				T. B. Dorff, C. M. Tangen, E. D. Crawford, D. P. Petrylak, C. S. Higano, D. Raghavan, D. I. Quinn, N. J. Vogelzang, and I. M. Thompson Review: Cooperative group trials -- Southwest Oncology Group (SWOG) innovations in advanced prostate cancer Therapeutic Advances in Medical Oncology, September 1, 2009; 1(2): 69 - 77. [Abstract] [PDF]

				Y. Niu, S. Altuwaijri, S. Yeh, K.-P. Lai, S. Yu, K.-H. Chuang, S.-P. Huang, H. Lardy, and C. Chang Targeting the stromal androgen receptor in primary prostate tumors at earlier stages PNAS, August 26, 2008; 105(34): 12188 - 12193. [Abstract] [Full Text] [PDF]

				L. Y. T. Inoue, M. Neira, C. Nelson, M. Gleave, and R. Etzioni Cluster-based network model for time-course gene expression data Biostat., July 1, 2007; 8(3): 507 - 525. [Abstract] [Full Text] [PDF]

				M. S. Bhandari, J. Crook, and M. Hussain Should Intermittent Androgen Deprivation Be Used in Routine Clinical Practice? J. Clin. Oncol., November 10, 2005; 23(32): 8212 - 8218. [Abstract] [Full Text] [PDF]

				P. Rocchi, A. So, S. Kojima, M. Signaevsky, E. Beraldi, L. Fazli, A. Hurtado-coll, K. Yamanaka, and M. Gleave Heat Shock Protein 27 Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone-Refractory Prostate Cancer Cancer Res., September 15, 2004; 64(18): 6595 - 6602. [Abstract] [Full Text] [PDF]

				A. C. Ferrari, N. Stone, R. Stock, M. Bednar, I. Esseesse, H. Singh, Y. Baldwin, and J. Mandeli 13-cis Retinoic Acid and Complete Androgen Blockade in Advanced Hormone-Naive Prostate Cancer Patients: Report of a Phase II Randomized Study J. Clin. Oncol., January 15, 2002; 20(2): 538 - 544. [Abstract] [Full Text] [PDF]

				G. Auclerc, E. C. Antoine, F. Cajfinger, A. Brunet-Pommeyrol, C. Agazia, and D. Khayat Management of Advanced Prostate Cancer Oncologist, February 1, 2000; 5(1): 36 - 44. [Abstract] [Full Text]

				S. B. Strum, M. C. Scholz, and J. E. McDermed Intermittent Androgen Deprivation in Prostate Cancer Patients: Factors Predictive of Prolonged Time Off Therapy Oncologist, February 1, 2000; 5(1): 45 - 52. [Abstract] [Full Text]

				H. Miayake, A. Tolcher, and M. E. Gleave Chemosensitization and Delayed Androgen-Independent Recurrence of Prostate Cancer With the Use of Antisense Bcl-2 Oligodeoxynucleotides J Natl Cancer Inst, January 5, 2000; 92(1): 34 - 41. [Abstract] [Full Text] [PDF]

				S. Egawa, R. Takashima, K. Matsumoto, H. Mizoguchi, S. Kuwao, and S. Baba A Pilot Study of Intermittent Androgen Ablation in Advanced Prostate Cancer in Japanese Men Jpn. J. Clin. Oncol., January 1, 2000; 30(1): 21 - 26. [Abstract] [Full Text] [PDF]

				H. Miyake, C. Nelson, P. S. Rennie, and M. E. Gleave Testosterone-repressed Prostate Message-2 Is an Antiapoptotic Gene Involved in Progression to Androgen Independence in Prostate Cancer Cancer Res., January 1, 2000; 60(1): 170 - 176. [Abstract] [Full Text]

				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 Res., October 1, 1999; 59(19): 5030 - 5036. [Abstract] [Full Text] [PDF]

				M. Gleave, A. Tolcher, H. Miyake, C. Nelson, B. Brown, E. Beraldi, and J. Goldie Progression to Androgen Independence Is Delayed by Adjuvant Treatment with Antisense Bcl-2 Oligodeoxynucleotides after Castration in the LNCaP Prostate Tumor Model Clin. Cancer Res., October 1, 1999; 5(10): 2891 - 2898. [Abstract] [Full Text] [PDF]

				H. Miyake, A. Tolcher, and M. E. Gleave Antisense Bcl-2 Oligodeoxynucleotides Inhibit Progression to Androgen-Independence after Castration in the Shionogi Tumor Model Cancer Res., August 1, 1999; 59(16): 4030 - 4034. [Abstract] [Full Text] [PDF]

				C. Guo, S. Yu, A. T. Davis, and K. Ahmed Nuclear Matrix Targeting of the Protein Kinase CK2 Signal as a Common Downstream Response to Androgen or Growth Factor Stimulation of Prostate Cancer Cells Cancer Res., March 1, 1999; 59(5): 1146 - 1151. [Abstract] [Full Text] [PDF]

				A. M. Evens, T. M. Lestingi, and J. D. Bitran Intermittent Androgen Suppression as a Treatment for Prostate Cancer: A Review Oncologist, December 1, 1998; 3(6): 419 - 423. [Abstract] [Full Text]

				J. M. Kokontis, N. Hay, and S. Liao Progression of LNCaP Prostate Tumor Cells during Androgen Deprivation: Hormone-Independent Growth, Repression of Proliferation by Androgen, and Role for p27Kip1 in Androgen-Induced Cell Cycle Arrest Mol. Endocrinol., July 1, 1998; 12(7): 941 - 953. [Abstract] [Full Text]