JCT  Vol.5 No.4 , April 2014
The Bone Microenvironmental Effect in the Dormancy of Cancer

Tumors have already threatened human life and health for centuries, especially the recurrent of bone metastases is difficult to cure. Relapse can occur years to decades after resection of primary tumor. This phenomenon is common in many clinical cases and animal experimental studies. The effect of traditional radiotherapy and chemotherapy on relapse is very limited, and the patients’ prognosis is poor. Because the delayed occurrence of metastases, researchers put forward a new concept “dormancy”, including a single dormant tumor cell (growth-arrest) and tumor mass dormancy (equivalence of the proliferation rate and apoptosis rate). It is probable that dormant tumor cells are the resource of relapse and the main reason of chemotherapy resistance. The mechanisms mediated tumor cell dormancy are complex and poorly understood, and bone marrow microenvironment plays an important role in this process. This review focuses on the bone marrow microenvironmental effect in inducing cancer cells to dormancy uncovered by the latest researches.

Cite this paper
Shen, W. , Niu, Y. and Zhang, H. (2014) The Bone Microenvironmental Effect in the Dormancy of Cancer. Journal of Cancer Therapy, 5, 315-322. doi: 10.4236/jct.2014.54038.
[1]   Fidler, I.J. and Hart, I.R. (1982) Biological Diversity in Metastatic Neoplasms: Origins and Implications. Science, 217, 998-1003. http://dx.doi.org/10.1126/science.7112116

[2]   Bernards, R. and Weinberg, R.A. (2002) A Progression Puzzle. Nature, 418, 823.

[3]   Pantel, K. and Brakenhoff, R.H. (2004) Dissecting the Metastatic Cascade. Nature Reviews Cancer, 4, 448-456. http://dx.doi.org/10.1038/nrc1370

[4]   Wimberger, P., Heubner, M., Otterbach, F., Fehm, T., Kimmig, R. and Kasimir-Bauer, S. (2007) Influence of Platinum-Based Chemotherapy on Disseminated Tumor Cells in Blood and Bone Marrow of Patients with Ovarian Cancer. Gynecologic Oncology, 107, 331-338.

[5]   Muller, V., Stahmann, N., Riethdorf, S., Rau, T., Zabel, T., Goetz, A., et al. (2005) Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity. Clinical Cancer Research, 11, 3678-3685.

[6]   Naume, B., Wiedswang, G., Borgen, E., Kvalheim, G., Karesen, R., Qvist, H., et al. (2004) The Prognostic Value of Isolated Tumor Cells in Bone Marrow in Breast Cancer Patients: Evaluation of Morphological Categories and the Number of Clinically Significant Cells. Clinical Cancer Research, 10, 3091-3097. http://dx.doi.org/10.1158/1078-0432.CCR-03-0373

[7]   Wiedswang, G., Borgen, E., Karesen, R., Qvist, H., Janbu, J., Kvalheim, G., et al. (2004) Isolated Tumor Cells in Bone Marrow Three Years after Diagnosis in Disease-Free Breast Cancer Patients Predict Unfavorable Clinical Outcome. Clinical Cancer Research, 10, 5342-5348.

[8]   Janni, W., Rack, B., Schindlbeck, C., Strobl, B., Rjosk, D., Braun, S., et al. (2005) The Persistence of Isolated Tumor Cells in Bone Marrow from Patients with Breast Carcinoma Predicts an Increased Risk for Recurrence. Cancer, 103, 884-891. http://dx.doi.org/10.1002/cncr.20834

[9]   Slade, M.J., Singh, A., Smith, B.M., Tripuraneni, G., Hall, E., Peckitt, C., et al. (2005) Persistence of Bone Marrow Micrometastases in Patients Receiving Adjuvant Therapy for Breast Cancer: Results at 4 Years. International Journal of Cancer, 114, 94-100. http://dx.doi.org/10.1002/ijc.20655

[10]   Naumov, G.N., Macdonald, I.C., Weinmeister, P.M., Kerkvliet, N., Nadkarni, K.V., Wilson, S.M., et al. (2002) Persistence of Solitary Mammary Carcinoma Cells in a Secondary Site: A Possible Contributor to Dormancy. Cancer Research, 62, 2162-2168.

[11]   Townson, J.L. and Chambers, A.F. (2006) Dormancy of Solitary Metastatic Cells. Cell Cycle, 5, 1744-1750. http://dx.doi.org/10.4161/cc.5.16.2864

[12]   Chambers, A.F., Groom, A.C. and Macdonald, I.C. (2002) Dissemination and Growth of Cancer Cells in Metastatic Sites. Nature Reviews Cancer, 2, 563-572. http://dx.doi.org/10.1038/nrc865

[13]   Vessella, R.L., Pantel, K. and Mohla, S. (2007) Tumor Cell Dormancy: An NCI Workshop Report. Cancer Biology & Therapy, 6, 1496-1504. http://dx.doi.org/10.4161/cbt.6.9.4828

[14]   Quesnel, B. (2008) Dormant Tumor Cells as a Therapeutic Target? Cancer Letters, 267, 10-17. http://dx.doi.org/10.1016/j.canlet.2008.02.055

[15]   Aguirre-Ghiso, J.A. (2007) Models, Mechanisms and Clinical Evidence for Cancer Dormancy. Nature Reviews Cancer, 7, 834-846. http://dx.doi.org/10.1038/nrc2256

[16]   Willis, L., Alarcon, T., Elia, G., Jones, J.L., Wright, N.A., Tomlinson, I.P., et al. (2010) Breast Cancer Dormancy Can Be Maintained by Small Numbers of Micrometastases. Cancer Research, 70, 4310-4317. http://dx.doi.org/10.1158/0008-5472.CAN-09-3144

[17]   Hanrahan, E.O., Gonzalez-Angulo, A.M., Giordano, S.H., Rouzier, R., Broglio, K.R., Hortobagyi, G.N., et al. (2007) Overall Survival and Cause-Specific Mortality of Patients with Stage T1a,bN0M0 Breast Carcinoma. Journal of Clinical Oncology, 25, 4952-4960. http://dx.doi.org/10.1200/JCO.2006.08.0499

[18]   Meng, S., Tripathy, D., Frenkel, E.P., Shete, S., Naftalis, E.Z., Huth, J.F., et al. (2004) Circulating Tumor Cells in Patients with Breast Cancer Dormancy. Clinical Cancer Research, 10, 8152-8162.

[19]   Nguyen, D.X., Bos, P.D. and Massague, J. (2009) Metastasis: From Dissemination to Organ-Specific Colonization. Nature Reviews Cancer, 9, 274-284. http://dx.doi.org/10.1038/nrc2622

[20]   Valastyan, S. and Weinberg, R.A. (2011) Tumor Metastasis: Molecular Insights and Evolving Paradigms. Cell, 147, 275-292. http://dx.doi.org/10.1016/j.cell.2011.09.024

[21]   Pantel, K., Brakenhoff, R.H. and Brandt, B. (2008) Detection, Clinical Relevance and Specific Biological Properties of Disseminating Tumour Cells. Nature Reviews Cancer, 8, 329-340.

[22]   Braun, S., Vogl, F.D., Naume, B., Janni, W., Osborne, M.P. and Coombes, R.C., et al. (2005) A Pooled Analysis of Bone Marrow Micrometastasis in Breast Cancer. The New England Journal of Medicine, 353, 793-802. http://dx.doi.org/10.1056/NEJMoa050434

[23]   Pantel, K. and Brakenhoff, R.H. (2004) Dissecting the Metastatic Cascade. Nature Reviews Cancer, 4, 448-456. http://dx.doi.org/10.1038/nrc1370

[24]   Bidard, F.C., Vincent-Salomon, A., Sigal-Zafrani, B., Rodrigues, M., Dieras, V. and Mignot, L., et al. (2008) Time to Metastatic Relapse and Breast Cancer Cells Dissemination in Bone Marrow at Metastatic Relapse. Clinical & Experimental Metastasis, 25, 871-887. http://dx.doi.org/10.1007/ s10585-008-9203-1

[25]   Sosa, M.S., Avivar-Valderas, A., Bragado, P., Wen, H.C. and Aguirre-Ghiso, J.A. (2011) ERK1/2 and p38α/β Signaling in Tumor Cell Quiescence: Opportunities to Control Dormant Residual Disease. Nature Reviews Cancer, 17, 5850-5857.

[26]   Bulavin, D.V., Phillips, C., Nannenga, B., Timofeev, O., Donehower, L.A. and Anderson, C.W., et al. (2004) Inactivation of the Wip1 Phosphatase Inhibits Mammary Tumorigenesis through p38 MAPK-Mediated Activation of the p16Ink4a-p19Arf Pathway. Nature Genetics, 36, 343-350.

[27]   Bulavin, D.V., Demidov, O.N., Saito, S., Kauraniemi, P., Phillips, C. and Amundson, S.A., et al. (2002) Amplification of PPM1D in Human Tumors Abrogates p53 Tumor-Suppressor Activity. Nature Genetics, 31, 210-215. http://dx.doi.org/10.1038/ng894

[28]   Mahnke, Y.D., Schwendemann, J., Beckhove, P. and Schirrmacher, V. (2005) Maintenance of Long-Term Tumour-Specific T-Cell Memory by Residual Dormant Tumour Cells. Immunology, 115, 325-336. http://dx.doi.org/10.1111/j.1365-2567.2005.02163.x.

[29]   Ranganathan, A.C., Adam, A.P., Zhang, L. and Aguirre-Ghiso, J.A. (2006) Tumor Cell Dormancy Induced by p38SAPK and ER-Stress Signaling: An Adaptive Advantage for Metastatic Cells. Cancer Biology & Therapy, 5, 729-735. http://dx.doi.org/10.4161/cbt.5.7.2968

[30]   Horak, C.E., Lee, J.H., Marshall, J.C., Shreeve, S.M. and Steeg, P.S. (2008) The Role of Metastasis Suppressor Genes in Metastatic Dormancy. APMIS, 116, 586-601. http://dx.doi.org/10.1111/j.1600-0463.2008.01027.x

[31]   Aguirre-Ghiso, J.A., Estrada, Y., Liu, D. and Ossowski, L. (2003) ERK (MAPK) Activity as a Determinant of Tumor Growth and Dormancy; Regulation by p38SAPK. Cancer Research, 63, 1684-1695.

[32]   Aguirre-Ghiso, J.A., Liu, D., Mignatti, A., Kovalski, K. and Ossowski, L. (2001) Urokinase Receptor and Fibronectin Regulate the ERKMAPK to p38MAPK Activity Ratios that Determine Carcinoma Cell Proliferation or Dormancy in Vivo. Molecular Biology of the Cell, 12, 863-879.

[33]   Bragado, P., Estrada, Y., Parikh, F., Krause, S., Capobianco, C. and Farina, H.G., et al. (2013) TGF-Beta2 Dictates Disseminated Tumour Cell Fate in Target Organs through TGF-Beta-Riii and p38alpha/beta Signalling. Nature Cell Biology, 15, 1351-1361. http://dx.doi.org/10.1038/ncb2861

[34]   Jung, Y., Shiozawa, Y., Wang, J., Mcgregor, N., Dai, J. and Park, S.I., et al. (2012) Prevalence of Prostate Cancer Metastases after Intravenous Inoculation Provides Clues into the Molecular Basis of Dormancy in the Bone Marrow Microenvironment. Neoplasia, 14, 429-439.

[35]   Shiozawa, Y., Pedersen, E.A., Patel, L.R., Ziegler, A.M., Havens, A.M. and Jung, Y., et al. (2010) GAS6/AXL Axis Regulates Prostate Cancer Invasion, Proliferation, and Survival in the Bone Marrow Niche. Neoplasia, 12, 116-127.

[36]   Marlow, R., Honeth, G., Lombardi, S., Cariati, M., Hessey, S. and Pipili, A., et al. (2013) A Novel Model of Dormancy for Bone Metastatic Breast Cancer Cells. Cancer Research, 73, 6886-6899.

[37]   Shiozawa, Y., Pedersen, E.A., Havens, A.M., Jung, Y., Mishra, A. and Joseph, J., et al. (2011) Human Prostate Cancer Metastases Target the Hematopoietic Stem Cell Niche to Establish Footholds in Mouse Bone Marrow. The Journal of Clinical Investigation, 121, 1298-1312.

[38]   Kim, J.K., Jung, Y., Wang, J., Joseph, J., Mishra, A. and Hill, E.E., et al. (2013) TBK1 Regulates Prostate Cancer Dormancy through mTORC1 Inhibition. Neoplasia, 15, 1064-1074.

[39]   Matsumoto, K., Arao, T., Tanaka, K., Kaneda, H., Kudo, K. and Fujita, Y., et al. (2009) mTORC1 Signal and Hypoxia-Inducible Factor-1 Alpha Regulate CD133 Expression in Cancer Cells. Cancer Research, 69, 7160-7164. http://dx.doi.org/10.1158/0008-5472.CAN-09-1289

[40]   Hoshii, T., Tadokoro, Y., Naka, K., Ooshio, T., Muraguchi, T. and Sugiyama, N., et al. (2012) mTORC1 Is Essential for Leukemia Propagation but Not Stem Cell Self-Renewal. The Journal of Clinical Investigation, 122, 2114-2129. http://dx.doi.org/10.1172/JCI62279

[41]   Kobayashi, A., Okuda, H., Xing, F., Pandey, P.R., Watabe, M. and Hirota, S., et al. (2011) Bone Morphogenetic Protein 7 in Dormancy and Metastasis of Prostate Cancer Stem-Like Cells in Bone. The Journal of Experimental Medicine, 208, 2641-2655. http://dx.doi.org/10.1084/jem.20110840

[42]   Gao, H., Chakraborty, G., Lee-Lim, A.P., Mo, Q., Decker, M. and Vonica, A., et al. (2012) The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites. Cell, 150, 764-779. http://dx.doi.org/10.1016/j.cell.2012.06.035

[43]   Lim, P.K., Bliss, S.A., Patel, S.A., Taborga, M., Dave, M.A. and Gregory, L.A., et al. (2011) Gap Junction-Mediated Import of Microrna from Bone Marrow Stromal Cells Can Elicit Cell Cycle Quiescence in Breast Cancer Cells. Cancer Research, 71, 1550-1560. http://dx.doi.org/10.1158/0008-5472.CAN-10-2372

[44]   Nash, K.T., Phadke, P.A., Navenot, J.M., Hurst, D.R., Accavitti-Loper, M.A. and Sztul, E., et al. (2007) Requirement of KISS1 Secretion for Multiple Organ Metastasis Suppression and Maintenance of Tumor Dormancy. The Journal of the National Cancer Institute, 99, 309-321.

[45]   Shachaf, C.M., Kopelman, A.M., Arvanitis, C., Karlsson, A., Beer, S. and Mandl, S., et al. (2004) MYC Inactivation Uncovers Pluripotent Differentiation and Tumour Dormancy in Hepatocellular Cancer. Nature, 431, 1112-1117. http://dx.doi.org/10.1038/nature03043

[46]   Koebel, C.M., Vermi, W., Swann, J.B., Zerafa, N., Rodig, S.J. and Old, L.J., et al. (2007) Adaptive Immunity Maintains Occult Cancer in an Equilibrium State. Nature, 450, 903-907.

[47]   Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B. and Lagorce-Pages, C., et al. (2006) Type, Density, and Location of Immune Cells within Human Colorectal Tumors Predict Clinical Outcome. Science, 313, 1960-1964. http://dx.doi.org/10.1126/science.1129139

[48]   Demicheli, R., Retsky, M.W., Hrushesky, W.J., Baum, M. and Gukas, I.D. (2008) The Effects of Surgery on Tumor Growth: A Century of Investigations. Annals of Oncology, 19, 1821-1828.

[49]   Retsky, M., Demicheli, R., Hrushesky, W., Baum, M. and Gukas, I. (2010) Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth? Cancers (Basel), 2, 305-337. http://dx.doi.org/10.3390/cancers2020305

[50]   Demicheli, R., Retsky, M.W., Hrushesky, W.J. and Baum, M. (2007) Tumor Dormancy and Surgery-Driven Interruption of Dormancy in Breast Cancer: Learning from Failures. Nature Clinical Practice Oncology, 4, 699-710. http://dx.doi.org/10.1038/ncponc0999

[51]   Steeg, P.S. (2006) Tumor Metastasis: Mechanistic Insights and Clinical Challenges. Nature Medicine, 12, 895-904. http://dx.doi.org/10.1038/nm1469

[52]   Gao, D., Nolan, D.J., Mellick, A.S., Bambino, K., Mcdonnell, K. and Mittal, V. (2008) Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis. Science, 319, 195-198. http://dx.doi.org/10.1126/science.1150224

[53]   Ghajar, C.M., Peinado, H., Mori, H., Matei, I.R., Evason, K.J. and Brazier, H., et al. (2013) The Perivascular Niche Regulates Breast Tumour Dormancy. Nature Cell Biology, 15, 807-817.

[54]   Goldman, J.M., Green, A.R., Holyoake, T., Jamieson, C., Mesa, R. and Mughal, T., et al. (2009) Chronic Myeloproliferative Diseases with and without the Ph Chromosome: Some Unresolved Issues. Leukemia, 23, 1708-1715. http://dx.doi.org/10.1038/leu.2009.142

[55]   Goldman, J.M. (2009) Treatment Strategies for CML. Best Practice & Research Clinical Haematology, 22, 303-313. http://dx.doi.org/10.1016/j.beha.2009.08.001

[56]   Essers, M.A. and Trumpp, A. (2010) Targeting Leukemic Stem Cells by Breaking Their Dormancy. Molecular Oncology, 4, 443-450. http://dx.doi.org/10.1016/j.molonc.2010.06.001

[57]   Azab, A.K., Runnels, J.M., Pitsillides, C., Moreau, A.S., Azab, F. and Leleu. X., et al. (2009) CXCR4 Inhibitor AMD3100 Disrupts the Interaction of Multiple Myeloma Cells with the Bone Marrow Microenvironment and Enhances Their Sensitivity to Therapy. Blood, 113, 4341-4351.

[58]   Weisberg, E., Azab, A.K., Manley, P.W., Kung, A.L., Christie, A.L. and Bronson. R., et al. (2012) Inhibition of CXCR4 in CML Cells Disrupts Their Interaction with the Bone Marrow Microenvironment and Sensitizes Them to Nilotinib. Leukemia, 26, 985-990. http://dx.doi.org/10.1038/leu.2011.360

[59]   Schewe, D.M. and Aguirre-Ghiso, J.A. (2008) ATF6alpha-Rheb-mTOR Signaling Promotes Survival of Dormant Tumor Cells in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 105, 10519-10524. http://dx.doi.org/10.1073/pnas.0800939105

[60]   Ossowski, L. and Aguirre-Ghiso, J.A. (2010) Dormancy of Metastatic Melanoma. Pigment Cell & Melanoma Research, 23, 41-56. http://dx.doi.org/10.1111/j.1755-148X.2009.00647.x