The biology and clinical implications of prostate cancer dormancy and metastasis
- 812 Downloads
Disseminated tumor cells (DTCs) are detected early in the disease process in prostate cancer (PCa) patients and can persist after radical prostatectomy. DTCs can remain dormant in patients with no evidence of disease for a prolonged period of time only to recur 10 or more years later. Recent advances in single-cell genomics and transcriptomics have provided much needed insight into DTC biology and cancer dormancy in patients. With the development of new in vitro and preclinical models, researchers recapitulate the clinical events in patients and therefore allow further elucidation of the molecular mechanisms underlying cancer dormancy and escape. In this review, we explore novel ideas on the detection, heterogeneous transcriptomic profiles, molecular and cellular mechanisms of dormancy, and potential mechanisms underlying dormancy escape by DTCs. As such, there is hope that identifying and targeting novel dormancy-associated pathways in patients with residual disease will have significant clinical implications for the treatment of PCa patients in the future.
KeywordsDisseminated tumor cells Dormancy Microenvironment Bone marrow Prostate cancer Metastasis
The work was supported by NIH PO1 CA85859, the Pacific Northwest Prostate Cancer SPORE NIH P50 CA097186, and the Richard M. LUCAS Foundation. H.M.L. is a recipient of the Young Investigator Award from the Prostate Cancer Foundation, and a Career Development Award from the Pacific Northwest Prostate Cancer SPORE (P50 CA097186). This material is also the result of work supported by resources from the VA Puget Sound Health Care System, Seattle, Washington (R.L.V. is a VA Biomedical Laboratory R&D senior research career scientist and P.H.L. is a staff physician).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 6.Chery L, Lam HM, Coleman I, Lakely B, Coleman R, Larson S, Aguirre-Ghiso JA, Xia J, Gulati R, Nelson PS et al (2014) Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 5:9939–9951CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Todenhofer T, Hennenlotter J, Faber F, Wallwiener D, Schilling D, Kuhs U, Aufderklamm S, Bier S, Mischinger J, Gakis G et al (2015) Significance of apoptotic and non-apoptotic disseminated tumor cells in the bone marrow of patients with clinically localized prostate cancer. Prostate 75:637–645CrossRefPubMedGoogle Scholar
- 11.Pfitzenmaier J, Ellis WJ, Hawley S, Arfman EW, Klein JR, Lange PH, Vessella RL (2007) The detection and isolation of viable prostate-specific antigen positive epithelial cells by enrichment: a comparison to standard prostate-specific antigen reverse transcriptase polymerase chain reaction and its clinical relevance in prostate cancer. Urol Oncol 25:214–220CrossRefPubMedGoogle Scholar
- 15.Guzvic M, Braun B, Ganzer R, Burger M, Nerlich M, Winkler S, Werner-Klein M, Czyz ZT, Polzer B, Klein CA (2014) Combined genome and transcriptome analysis of single disseminated cancer cells from bone marrow of prostate cancer patients reveals unexpected transcriptomes. Cancer Res 74:7383–7394CrossRefPubMedGoogle Scholar
- 22.Mitsiades CS, Lembessis P, Sourla A, Milathianakis C, Tsintavis A, Koutsilieris M (2004) Molecular staging by RT-pCR analysis for PSA and PSMA in peripheral blood and bone marrow samples is an independent predictor of time to biochemical failure following radical prostatectomy for clinically localized prostate cancer. Clin Exp Metastasis 21:495–505CrossRefPubMedGoogle Scholar
- 37.Wang N, Docherty F, Brown HK, Reeves K, Fowles A, Lawson M, Ottewell PD, Holen I, Croucher PI, Eaton CL (2015) Mitotic quiescence, but not unique “stemness,” marks the phenotype of bone metastasis-initiating cells in prostate cancer. FASEB J 29:3141–3150Google Scholar
- 48.Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A, Nakayama H, Hiraki A et al (2015) Intrinsic TGF-beta2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells. Oncotarget 6:1008–1019CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Hartkopf AD, Taran FA, Wallwiener M, Hahn M, Becker S, Solomayer EF, Brucker SY, Fehm TN, Wallwiener D (2014) Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients - results from a large single-centre analysis. Eur J Cancer 50:2550–2559CrossRefPubMedGoogle Scholar
- 58.Banys M, Solomayer EF, Gebauer G, Janni W, Krawczyk N, Lueck HJ, Becker S, Huober J, Kraemer B, Wackwitz B et al (2013) Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 13:480CrossRefPubMedPubMedCentralGoogle Scholar