Tumor Cell Dormancy—a Hallmark of Metastatic Growth and Disease Recurrence in Bone
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Purpose of Review
Dormant disseminated tumor cells are thought to play a pivotal role in driving tumor growth in bone and are likely responsible for disease recurrence following chemotherapy; however, the mechanisms regulating these processes remain unclear. Herein, we discuss recent advances controlling the mechanisms of tumor cell dormancy in bone and discuss the clinical implications of these findings.
Recent studies have defined gene expression signatures for dormant tumor cells in bone, identifying novel pathways that we can potentially exploit to target these cells. Using intravital imaging and cell fate tracking, bone cells within the bone microenvironment have been shown to play a critical role in regulating tumor cell dormancy and growth, highlighting local bone cell activity as a novel avenue to control tumor cell growth and a role for bone cell niches in supporting dormancy and treatment resistance.
Due to advances in pre-clinical imaging and sequencing tools, we have a greater understanding of the phenomenon of tumor cell dormancy in bone, ultimately opening avenues for novel targeted treatments.
KeywordsTumor dormancy Bone metastases Bone microenvironment Treatment resistance Disease recurrence
Compliance with Ethical Standards
Conflict of Interest
Nancy Haydar and Michelle M. McDonald declare no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 5.•• Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL, Down J, et al. Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun. 2015;6:8983. https://doi.org/10.1038/ncomms9983. This study demonstrates the importance of the endosteal niche in controlling myleoma cell dormancy in bone. The authors show that dormancy is a reversible state which can be switched on through the engagement with bone lining cells/osteoblasts and switched off by osteoclasts remodelling the endosteal niche. CrossRefPubMedPubMedCentralGoogle Scholar
- 6.•• Yumoto K, Eber MR, Wang J, Cackowski FC, Decker AM, Lee E, et al. Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep. 2016;6:36520. https://doi.org/10.1038/srep36520. This study demonstrates the first evidence that AXL is a crucial regulator of prostate cancer dormancy in bone induced by TGF-β signalling. CrossRefPubMedPubMedCentralGoogle Scholar
- 10.• Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer. 2016;16(6):373–86. https://doi.org/10.1038/nrc.2016.44. This review discusses the role of different bone cells in supporting dormancy and reactivation and highlights the therapeutic opportunities they may provide. CrossRefPubMedGoogle Scholar
- 17.•• Lam HM, Vessella RL, Morrissey C. The role of the microenvironment-dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol. 2014;11:41–7. https://doi.org/10.1016/j.ddtec.2014.02.002. This paper describes the important role of cell instrinsic factors and signals from the microenvionment in controlling tumour cell dormancy in bone. CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Zhang XHF, Giuliano M, Trivedi MV, Schiff R, Kent Osborne C. Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19(23). doi: https://doi.org/10.1158/078-0432.CCR-13-838.
- 24.Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, et al. Computational identification of a p38(SAPK) regulated transcription factor network required for tumor cell quiescence. Cancer Res. 2009;69(14):5664–72. https://doi.org/10.1158/0008-5472.CAN-08-3820.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):e1000279. https://doi.org/10.1371/journal.pmed.1000279.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Chery L, Lam HM, Coleman I, Lakely B, Coleman R, Larson S, et al. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget. 2014;5(20):9939–51. https://doi.org/10.18632/oncotarget.2480. CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Guzvic M, Braun B, Ganzer R, Burger M, Nerlich M, Winkler S, et al. Combined genome and transcriptome analysis of single disseminated cancer cells from bone marrow of prostate cancer patients reveals unexpected transcriptomes. Cancer Res. 2014;74(24):7383–94. https://doi.org/10.1158/0008-5472.can-14-0934.CrossRefPubMedGoogle Scholar
- 33.•• Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013;15(7):807–17. https://doi.org/10.1038/ncb2767. This paper illustrates that stable microvasculature (rich in thrombospondin-1) constitutes a dormant niche whereas sprouting neovasculature (enriched with TGF-β1 and periostin) accelerates micrometastatic outgrowth. CrossRefPubMedPubMedCentralGoogle Scholar
- 34.• Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016;8(340):340ra73. https://doi.org/10.1126/scitranslmed.aad4059. This paper provides insights into the mechanisms controlling the movement and anchoring of breast cancer cells in the bone marrow microenvironment. The authors show that breast cancer cells in the bone marrow reside predominantly in E-selectin and stromal cell-derived factor rich perisinusoidal vascular regions. CrossRefPubMedGoogle Scholar
- 38.Bambang IF, Lu D, Li H, Chiu LL, Lau QC, Koay E, et al. Cytokeratin 19 regulates endoplasmic reticulum stress and inhibits ERp29 expression via p38 MAPK/XBP-1 signaling in breast cancer cells. Exp Cell Res. 2009;315(11):1964–74. https://doi.org/10.1016/j.yexcr.2009.02.017.CrossRefPubMedGoogle Scholar
- 41.• Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell. 2011;20(6):701–14. https://doi.org/10.1016/j.ccr.2011.11.002. This study sheds light on the molecular understanding of tumor dormancy by showing that VCAM-1 is an essential protein which reactivates indolent micrometastasis in the bone microenvironment. CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, et al. 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. 2015;6(2):1008–19. https://doi.org/10.18632/oncotarget.2826.CrossRefPubMedGoogle Scholar
- 45.Fremder E, Munster M, Aharon A, Miller V, Gingis-Velitski S, Voloshin T, et al. Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: a process regulated by osteopontin. Int J Cancer. 2014;135(2):270–81. https://doi.org/10.1002/ijc.28678.CrossRefPubMedGoogle Scholar
- 47.•• Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312. https://doi.org/10.1172/jci43414. This study demonstrates the first evidence that disseminated tumor cells can home to compete with HSCs in their niches, thereby supporting their dormant state. CrossRefPubMedPubMedCentralGoogle Scholar
- 49.• Taichman RS, Patel LR, Bedenis R, Wang J, Weidner S, Schumann T, Yumoto K, Berry JE, Shiozawa Y, Pienta KJ GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS One 2013;8(4):e61873. https://doi.org/10.1371/journal.pone.0061873. This study demonstrates a possible association with the expression ratio of AXL and TYRO3 and the ability of prostate cancer cells to switch between dormant and proliferative states.
- 52.• Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol. 2016;18(10):1078–89. https://doi.org/10.1038/ncb3408. This study implicates the LIFR:STAT3:SOCS3 signaling pathway in breast cancer dormancy through the maintenance of STAT3 signaling. CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest. 1996;98(7):1544–9. https://doi.org/10.1172/JCI118947.CrossRefPubMedPubMedCentralGoogle Scholar
- 56.• Ottewell PD, Wang N, Meek J, Fowles CA, Croucher PI, Eaton CL, et al. Castration-induced bone loss triggers growth of disseminated prostate cancer cells in bone. Endocr Relat Cancer. 2014;21(5):769–81. https://doi.org/10.1530/ERC-14-0199. This study was pivotal in revealing the impact of altered bone turnover on tumor growth in bone demonstrating that accelerated bone resorption led to increased bone metastatic tumors and this was blocked with anti-resorptive therapy. CrossRefPubMedGoogle Scholar
- 62.• Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res. 2014;20(11):2922–32. https://doi.org/10.1158/1078-0432.CCR-13-1246. This study provides the first pre-clincal data, in support of clinical data, suggesting that anti-resorptive therapies can suppress tumor growth in bone only in the post-menopausal setting. CrossRefPubMedPubMedCentralGoogle Scholar
- 63.• Holen I, Walker M, Nutter F, Fowles A, Evans CA, Eaton CL, et al. Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo. Clin Exp Metastasis. 2016;33(3):211–24. https://doi.org/10.1007/s10585-015-9770-x. This study provides the first evidence for inhibition of ER − breast cancer metastasis to bone through the suppression of bone turnover. ER + breast cancer cells, on the other hand, grew independently of bone turnover. CrossRefPubMedGoogle Scholar
- 66.• Wang N, Docherty FE, Brown HK, Reeves KJ, Fowles AC, Ottewell PD, et al. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis—evidence from in vivo models. J Bone Min Res the Off J Am Soc Bone Miner Res. 2014;29:2688–96. https://doi.org/10.1002/jbmr.2300. This study highlights a role for osteoblasts supporting engraftment of tumor cells metastasizing to bone. CrossRefGoogle Scholar
- 67.Wang N, Reeves KJ, Brown HK, Fowles AC, Docherty FE, Ottewell PD, et al. The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer. J Exp Clin Cancer Res. 2015;34:124. https://doi.org/10.1186/s13046-015-0240-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Perez EA, Weilbaecher K. Aromatase inhibitors and bone loss. Oncology (Williston Park, NY). 2006;20(9):1029–39. discussion 39–40, 42, 48Google Scholar
- 69.Hadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, et al. Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1–12. https://doi.org/10.1016/j.jbo.2017.03.001. CrossRefPubMedPubMedCentralGoogle Scholar
- 71.Lipton A, Fizazi K, Stopeck AT, Henry DH, Smith MR, Shore N, et al. Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur J Cancer (Oxford, England : 1990). 2016;53:75–83. https://doi.org/10.1016/j.ejca.2015.09.011. CrossRefGoogle Scholar
- 73.Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(11):1143–50. https://doi.org/10.1200/jco.2013.51.6500. CrossRefGoogle Scholar
- 76.Coleman RE. Impact of bone-targeted treatments on skeletal morbidity and survival in breast cancer. Oncology (Williston Park, NY). 2016;30(8):695–702.Google Scholar
- 77.•• Early Breast Cancer Trialists’ Collaborative G. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet (London, England). 2015;386(10001):1353–61. https://doi.org/10.1016/S0140-6736(15)60908-4. This is a seminal study linking our understanding of bone cell regulation of tumor growth with clinical outcomes in patients with early breast cancer treated with anti-resorptives. Disease recurrence was decreased and disease-free survival increased with BP treatment. CrossRefGoogle Scholar
- 78.• Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet (London, England). 2012;379(9810):39–46. https://doi.org/10.1016/s0140-6736(11)61226-9. This study provides data associating anti-resorptive therapy with increases in disease-free survival in men with advanced prostate cancer. CrossRefGoogle Scholar
- 79.Nozawa M, Inagaki T, Nagao K, Nishioka T, Komura T, Esa A, et al. Phase II trial of zoledronic acid combined with androgen-deprivation therapy for treatment-naive prostate cancer with bone metastasis. Int J Clin Oncol. 2014;19(4):693–701. https://doi.org/10.1007/s10147-013-0604-z.CrossRefPubMedGoogle Scholar
- 85.Delgado-Calle J, Anderson J, Cregor MD, Hiasa M, Chirgwin JM, Carlesso N, et al. Bidirectional notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Res. 2016;76(5):1089–100. https://doi.org/10.1158/0008-5472.CAN-15-1703.CrossRefPubMedPubMedCentralGoogle Scholar
- 86.Herroon MK, Rajagurubandara E, Diedrich JD, Heath EI, Podgorski I. Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of heme oxygenase 1 and survivin. Sci Rep. 2018;8(1):40. https://doi.org/10.1038/s41598-017-17800-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D, et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 2013;3(5):578–89. https://doi.org/10.1158/2159-8290.cd-12-0476.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.Niraula S, Templeton AJ, Vera-Badillo F, Dodd A, Nugent Z, Joshua AM, et al. Duration of suppression of bone turnover following treatment with zoledronic acid in men with metastatic castration-resistant prostate cancer. Futur SciOA. 2018;4(1):FSO253. https://doi.org/10.4155/fsoa-2017-0094.CrossRefGoogle Scholar
- 93.Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, Miller K, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol. 2015;67(3):482–91. https://doi.org/10.1016/j.eururo.2014.02.014.CrossRefPubMedGoogle Scholar