Abstract
Cancer dormancy describes a stage in tumor progression where tumor cells survive in a quiescent state. Breast cancer is especially known for prolonged asymptomatic periods (up to 15–20 years) followed by a recurrence. Two main mechanisms of tumor cell dormancy are under discussion: tumor cells cease dividing completely or persist proliferating at a slow rate counterbalanced by apoptosis. In the last decades, major efforts have been made to understand the process of interaction between circulating tumor cells (CTCs) in the bloodstream and their extravasation into distant sites, where CTCs may survive in a dormant state or acquire the ability to build metastases. Despite remarkable progress in this field, factors that determinate the fate of a single tumor cell remain to be clarified.
An important hypothesis explaining the phenomenon of tumor cell dormancy is the stem cell theory. This theory indicates stem cell-like characteristics of at least a fraction of dormant CTCs that allows them to persist in the secondary sites and resist standard chemotherapies. Since dormant tumor cells are considered to cause relapse and metastases after long asymptomatic period, an understanding of their biology may be crucial for development of new therapeutic strategies to eradicate this distinct cell population and prevent recurrence. In this chapter we discuss biological mechanisms and clinical implications of tumor cell dormancy in breast cancer patients.
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Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846
Ashworth TR (1869) A case of cancer in which cells similar to those in tumors were seen in the blood after death. Aust Med J 14:146–149
Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621
Banys M, Krawczyk N, Becker S, Jakubowska J, Staebler A, Wallwiener D, Fehm T, Rothmund R (2012) The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. Breast Cancer Res Treat 132(1):121–129
Barkan D, Kleinman H, Simmons JL, Asmussen H, Kamaraju AK, Hoenorhoff MJ, Liu ZY, Costes SV, Cho EH, Lockett S, Khanna C, Chambers AF, Green JE (2008) Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res 68(15):6241–6250
Becker S, Solomayer E, Becker-Pergola G, Wallwiener D, Fehm T (2007) Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 106(2):239–243
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410
Bozionellou V, Mavroudis D, Perraki M, Papadopoulos S, Apostolaki S, Stathopoulos E, Stathopoulou A, Lianidou E, Georgoulias V (2004) Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clin Cancer Res 10(24):8185–8194
Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802
Cameron MD, Schmidt EE, Kerkvliet N, Nadkarni KV, Morris VL, Groom AC, Chambers AF, MacDonald IC (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 60(9):2541–2546
Clezardin P, Ebetino FH, Fournier PG (2005) Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 65(12):4971–4974
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791
Demicheli R, Abbattista A, Miceli R, Valagussa P, Bonadonna G (1996) Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 41(2):177–185
Fehm T, Krawczyk N, Solomayer EF, Becker-Pergola G, Durr-Storzer S, Neubauer H, Seeger H, Staebler A, Wallwiener D, Becker S (2008a) ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res 10(5):R76
Fehm T, Mueller V, Marches R, Klein G, Gueckel B, Neubauer H, Solomayer E, Becker S (2008b) Tumor cell dormancy: implications for the biology and treatment of breast cancer. APMIS 116(7–8):742–753
Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124(4):619–626
Holen I, Coleman RE (2010) Bisphosphonates as treatment of bone metastases. Curr Pharm Des 16(11):1262–1271
Holen I, Cross SS, Neville-Webbe HL, Cross NA, Balasubramanian SP, Croucher PI, Evans CA, Lippitt JM, Coleman RE, Eaton CL (2005) Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo–a role in tumour cell survival? Breast Cancer Res Treat 92(3):207–215
Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153
Hussein O, Komarova SV (2011) Breast cancer at bone metastatic sites: recent discoveries and treatment targets. J Cell Commun Signal 5(2):85–99. doi:10.1007/s12079-011-0117-3
Indraccolo S, Stievano L, Minuzzo S, Tosello V, Esposito G, Piovan E, Zamarchi R, Chieco-Bianchi L, Amadori A (2006) Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci U S A 103(11):4216–4221
Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K (2005) The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103(5):884–891
Karrison TG, Ferguson DJ, Meier P (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91(1):80–85
Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmuller G (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360(9334):683–689
Krag DN, Ashikaga T, Moss TJ, Kusminsky RE, Feldman S, Carp NZ, Moffat FL, Beitsch PD, Frazier TG, Gaskin TA, Shook JW, Harlow SP, Weaver DL (1999) Breast cancer cells in the blood: a pilot study. Breast J 5(6):354–358
Krawczyk N, Banys M, Neubauer H, Solomayer EF, Gall C, Hahn M, Becker S, Bachmann R, Wallwiener D, Fehm T (2009) HER2 status on persistent disseminated tumor cells after adjuvant therapy may differ from initial HER2 status on primary tumor. Anticancer Res 29(10):4019–4024
Liotta LA, Kleinerman J, Saidel GM (1974) Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34(5):997–1004
Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153(3):865–873
Mehes G, Witt A, Kubista E, Ambros PF (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159(1):17–20
Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004a) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162
Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J (2004b) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101(25):9393–9398
Morgan TM, Lange PH, Porter MP, Lin DW, Ellis WJ, Gallaher IS, Vessella RL (2009) Disseminated tumor cells in prostate cancer patients after radical prostatectomy and without evidence of disease predicts biochemical recurrence. Clin Cancer Res 15(2):677–683
Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, Watnick RS, Straume O, Akslen LA, Folkman J, Almog N (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98(5):316–325
Paget S (1889) Distribution of secondary growths in cancer of the breast. Lancet 1:571
Pawelec G, Heinzel S, Kiessling R, Muller L, Ouyang Q, Zeuthen J (2000) Escape mechanisms in tumor immunity: a year 2000 update. Crit Rev Oncog 11(2):97–133
Rack BK, Schindlbeck C, Andergassen U, Schneeweiss A, Zwingers T, Lichtenegger W, Beckmann M, Sommer HL, Pantel K, Janni W (2010) Use of circulating tumor cells (CTC) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy to predict risk for relapse: the SUCCESS trial. ASCO annual meeting 2010. J Clin Oncol 28:15s (suppl; abstr 1003)
Rack B, Juckstock J, Gunthner-Biller M, Andergassen U, Neugebauer J, Hepp P, Schoberth A, Mayr D, Zwingers T, Schindlbeck C, Friese K, Janni W (2012) Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients. Arch Gynecol Obstet 285(2):485–492
Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260
Solomayer EF, Gebauer G, Hirnle P, Janni W, Luck HJ, Becker S, Huober J, Kramer B, Wackwitz B, Wallwiener D, Fehm T (2012) Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol 23(9):2271–2277
Townson JL, Chambers AF (2006) Dormancy of solitary metastatic cells. Cell Cycle 5(16):1744–1750
Vitetta ES, Tucker TF, Racila E, Huang YW, Marches R, Lane N, Scheuermann RH, Street NE, Watanabe T, Uhr JW (1997) Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established. Blood 89(12):4425–4436
Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massague J (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16(1):67–78
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Krawczyk, N., Banys, M., Neubauer, H., Fehm, T. (2014). Various Factors Contributing to Tumor Dormancy: Therapeutic Implications in Breast Cancer. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Vol. 3. Tumor Dormancy and Cellular Quiescence and Senescence, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9325-4_5
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DOI: https://doi.org/10.1007/978-94-017-9325-4_5
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