Serum Testosterone Plays an Important Role in the Metastatic Ability of Castration Resistant Prostate Cancer

Overview

Journal World J Urol

Specialty Urology

Date 2012 Oct 20

PMID 23080125

Citations 5

Authors

Tim M van der Sluis

Irene V Bijnsdorp

John J L Jacobs

Eric J H Meuleman

Lawrence Rozendaal

Albert A Geldof

R Jeroen A van Moorselaar

Andre N Vis

Affiliations

Soon will be listed here.

Abstract

Purpose: Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings.

Methods: In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily.

Results: Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth.

Conclusions: Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.

Citing Articles

Reporting and ideal testosterone levels in men undergoing androgen deprivation for prostate cancer-time for a rethink?.

Cabarkapa S, Perera M, Sikaris K, OBrien J, Bolton D, Lawrentschuk N Prostate Int. 2018; 6(1):1-6.

PMID: 29556482 PMC: 5857188. DOI: 10.1016/j.prnil.2017.05.003.

Influence of fetal Leydig cells on the development of adult Leydig cell population in rats.

Su D, Feng Y, Wang L, Wu Y, Ge R, Ma X J Reprod Dev. 2018; 64(3):223-231.

PMID: 29515056 PMC: 6021611. DOI: 10.1262/jrd.2017-102.

Antagonizing effects of membrane-acting androgens on the eicosanoid receptor OXER1 in prostate cancer.

Kalyvianaki K, Gebhart V, Peroulis N, Panagiotopoulou C, Kiagiadaki F, Pediaditakis I Sci Rep. 2017; 7:44418.

PMID: 28290516 PMC: 5349529. DOI: 10.1038/srep44418.

Testosterone therapy and prostate cancer--safety concerns are well founded.

Klotz L Nat Rev Urol. 2015; 12(1):48-54.

PMID: 25563848 DOI: 10.1038/nrurol.2014.338.

A comparison of the biological features of prostate cancer with (PSA+, PSMA+) profile according to RKIP.

Ben Jemaa A, Bouraoui Y, Sallami S, Nouira Y, Oueslati R Biomed Res Int. 2013; 2013:409179.

PMID: 23991415 PMC: 3749534. DOI: 10.1155/2013/409179.

References

van der Sluis T, Vis A, Jeroen A van Moorselaar R, Bui H, Blankenstein M, Meuleman E . Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2011; 109(2):176-82. DOI: 10.1111/j.1464-410X.2011.10651.x. View

Isaacs J, Isaacs W, Feitz W, Scheres J . Establishment and characterization of seven Dunning rat prostatic cancer cell lines and their use in developing methods for predicting metastatic abilities of prostatic cancers. Prostate. 1986; 9(3):261-81. DOI: 10.1002/pros.2990090306. View

Saraon P, Jarvi K, Diamandis E . Molecular alterations during progression of prostate cancer to androgen independence. Clin Chem. 2011; 57(10):1366-75. DOI: 10.1373/clinchem.2011.165977. View

Crawford E, Eisenberger M, McLeod D, Spaulding J, Benson R, Dorr F . A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989; 321(7):419-24. DOI: 10.1056/NEJM198908173210702. View

de Bono J, Logothetis C, Molina A, Fizazi K, North S, Chu L . Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364(21):1995-2005. PMC: 3471149. DOI: 10.1056/NEJMoa1014618. View

Isaacs J, Yu G, Coffey D . The characterization of a newly identified, highly metastatic variety of Dunning R 3327 rat prostatic adenocarcinoma system: the MAT LyLu tumor. Invest Urol. 1981; 19(1):20-3. View

Stamey T, Yang N, Hay A, McNeal J, Freiha F, Redwine E . Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987; 317(15):909-16. DOI: 10.1056/NEJM198710083171501. View

Lamont K, Tindall D . Androgen regulation of gene expression. Adv Cancer Res. 2010; 107:137-62. DOI: 10.1016/S0065-230X(10)07005-3. View

Hussain M, Wolf M, Marshall E, Crawford E, Eisenberger M . Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol. 1994; 12(9):1868-75. DOI: 10.1200/JCO.1994.12.9.1868. View

10.

Bijnsdorp I, Capriotti F, Kruyt F, Losekoot N, Fukushima M, Griffioen A . Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors. Br J Cancer. 2011; 104(7):1185-92. PMC: 3068508. DOI: 10.1038/bjc.2011.74. View

11.

Vis A, Schroder F . Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways. BJU Int. 2009; 104(4):438-48. DOI: 10.1111/j.1464-410X.2009.08695.x. View

12.

Gregory C, Hamil K, Kim D, Hall S, Pretlow T, Mohler J . Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Res. 1998; 58(24):5718-24. View

13.

van der Sluis T, Meuleman E, Jeroen A van Moorselaar R, Bui H, Blankenstein M, Heijboer A . Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2011; 109(2):183-8. DOI: 10.1111/j.1464-410X.2011.10652.x. View

14.

Agoulnik I, Weigel N . Androgen receptor action in hormone-dependent and recurrent prostate cancer. J Cell Biochem. 2006; 99(2):362-72. DOI: 10.1002/jcb.20811. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Scher H, Beer T, Higano C, Anand A, Taplin M, Efstathiou E . Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010; 375(9724):1437-46. PMC: 2948179. DOI: 10.1016/S0140-6736(10)60172-9. View

17.

Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin. 2012; 62(1):10-29. DOI: 10.3322/caac.20138. View

18.

Bijnsdorp I, Peters G, Temmink O, Fukushima M, Kruyt F . Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2009; 126(10):2457-68. DOI: 10.1002/ijc.24943. View

19.

van der Sluis T, Bui H, Meuleman E, Heijboer A, Hartman J, van Adrichem N . Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry. J Urol. 2012; 187(5):1601-6. DOI: 10.1016/j.juro.2011.12.063. View

20.

Taylor C, Elson P, Trump D . Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. 1993; 11(11):2167-72. DOI: 10.1200/JCO.1993.11.11.2167. View