Abstract
The bone marrow (BM) of cancer patients is considered an essential secondary lymphoid organ with substantial impact on tumor cell dissemination and tumor–immune responses. Recent advances in the understanding of BM/primary tumor crosstalk, homing processes, premetastatic niche formation, tumor cell dormancy, and ultimately, identification of the BM micromilieu cytokines, chemokines, and growth factors may provide the basis for the development of targeted therapeutic strategies potentially rendering primary cancers and cancer bone metastases more susceptible to chemotherapy. The present review aims to dissect the individual components of the BM microenvironment in cancer patients, compare it to the healthy BM, and discuss its impact on interactions between the tumor and the immune system.
Similar content being viewed by others
References
Osmond, D. G. (1994). Production and selection of B lymphocytes in bone marrow: Lymphostromal interactions and apoptosis in normal, mutant and transgenic mice. Advances in Experimental Medicine and Biology, 355, 15–20.
Feuerer, M., Beckhove, P., Garbi, N., Mahnke, Y., Limmer, A., Hommel, M., et al. (2003). Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nature Medicine, 9(9), 1151–1157.
Schirrmacher, V., Feuerer, M., Fournier, P., Ahlert, T., Umansky, V., & Beckhove, P. (2003). T-cell priming in bone marrow: The potential for long-lasting protective anti-tumor immunity. Trends in Molecular Medicine, 9(12), 526–534.
Mazo, I. B., Honczarenko, M., Leung, H., Cavanagh, L. L., Bonasio, R., Weninger, W., et al. (2005). Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity, 22(2), 259–270.
Feuerer, M., Beckhove, P., Mahnke, Y., Hommel, M., Kyewski, B., Hamann, A., et al. (2004). Bone marrow microenvironment facilitating dendritic cell:CD4 T cell interactions and maintenance of CD4 memory. International Journal of Oncology, 25(4), 867–876.
Khazaie, K., Prifti, S., Beckhove, P., Griesbach, A., Russell, S., Collins, M., et al. (1994). Persistence of dormant tumor cells in the bone marrow of tumor cell-vaccinated mice correlates with long-term immunological protection. Proceedings of the National Academy of Sciences of the United States of America, 91(16), 7430–7434.
Schirrmacher, V., Feuerer, M., Beckhove, P., Ahlert, T., & Umansky, V. (2002). T cell memory, anergy and immunotherapy in breast cancer. Journal of Mammary Gland Biology and Neoplasia, 7(2), 201–208.
Müller, M., Gounari, F., Prifti, S., Hacker, H. J., Schirrmacher, V., & Khazaie, K. (1998). EblacZ tumor dormancy in bone marrow and lymph nodes: Active control of proliferating tumor cells by CD8+ immune T cells. Cancer Research, 58(23), 5439–5446.
Beckhove, P., Feuerer, M., Dolenc, M., Schuetz, F., Choi, C., Sommerfeldt, N., et al. (2004). Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. The Journal of Clinical Investigation, 114(1), 67–76.
Choi, C., Witzens, M., Bucur, M., Feuerer, M., Sommerfeldt, N., Trojan, A., et al. (2005). Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. Blood, 105(5), 2132–2134.
Feuerer, M., Beckhove, P., Bai, L., Solomayer, E. F., Bastert, G., Diel, I. J., et al. (2001). Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nature Medicine, 7(4), 452–458.
Nagorsen, D., Scheibenbogen, C., Marincola, F. M., Letsch, A., & Keilholz, U. (2003). Natural T cell immunity against cancer. Clinical Cancer Research, 9(12), 4296–4303.
Domschke, C., Schuetz, F., Ge, Y., Seibel, T., Falk, C., Brors, B., et al. (2009). Intratumoral cytokines and tumor cell biology determine spontaneous breast cancer-specific immune responses and their correlation to prognosis. Cancer Research, 69(21), 8420–8428.
Murao, A., Oka, Y., Tsuboi, A., Elisseeva, O. A., Tanaka-Harada, Y., Fujiki, F., et al. (2010). High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients: An important role of bone marrow as a secondary lymphoid organ. Cancer Science, 101(4), 848–854.
Melenhorst, J. J., Scheinberg, P., Chattopadhyay, P. K., Gostick, E., Ladell, K., Roederer, M., et al. (2009). High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow. Blood, 113(10), 2238–2244.
Schuetz, F., Ehlert, K., Ge, Y., Schneeweiss, A., Rom, J., Inzkirweli, N., et al. (2009). Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: A pilot clinical study. Cancer Immunology, Immunotherapy, 58(6), 887–900.
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., et al. (2004). Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell, 118(2), 149–161.
Mercier, F. E., Ragu, C., & Scadden, D. T. (2012). The bone marrow at the crossroads of blood and immunity. Nature Reviews. Immunology, 12(1), 49–60.
Di Rosa, F., & Pabst, R. (2005). The bone marrow: A nest for migratory memory T cells. Trends in Immunology, 26(7), 360–366.
Zhao, E., Xu, H., Wang, L., Kryczek, I., Wu, K., Hu, Y., et al. (2012). Bone marrow and the control of immunity. Cellular & Molecular Immunology, 9(1), 11–19.
Zou, L., Barnett, B., Safah, H., Larussa, V. F., Evdemon-Hogan, M., Mottram, P., et al. (2004). Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Research, 64(22), 8451–8455.
Ostanin, A. A., Petrovskii, Y. L., Shevela, E. Y., & Chernykh, E. R. (2011). Multiplex analysis of cytokines, chemokines, growth factors, MMP-9 and TIMP-1 produced by human bone marrow, adipose tissue, and placental mesenchymal stromal cells. Bulletin of Experimental Biology and Medicine, 151(1), 133–141.
Omatsu, Y., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno, K., et al. (2010). The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity, 33(3), 387–399.
Tokoyoda, K., Hauser, A. E., Nakayama, T., & Radbruch, A. (2010). Organization of immunological memory by bone marrow stroma. Nature Reviews. Immunology, 10(3), 193–200.
Sugiyama, T., Kohara, H., Noda, M., & Nagasawa, T. (2006). Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity, 25(6), 977–988.
Cassese, G., Arce, S., Hauser, A. E., Lehnert, K., Moewes, B., Mostarac, M., et al. (2003). Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. Journal of Immunology, 171(4), 1684–1690.
Peschon, J. J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Maraskovsky, E., Gliniak, B. C., et al. (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. The Journal of Experimental Medicine, 180(5), 1955–1960.
Tokoyoda, K., Zehentmeier, S., Hegazy, A. N., Albrecht, I., Grün, J. R., Löhning, M., et al. (2009). Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity, 30(5), 721–730.
Benson, M. J., Dillon, S. R., Castigli, E., Geha, R. S., Xu, S., Lam, K. P., et al. (2008). Cutting edge: The dependence of plasma cells and independence of memory B cells on BAFF and APRIL. Journal of Immunology, 180(6), 3655–3659.
Sapoznikov, A., Pewzner-Jung, Y., Kalchenko, V., Krauthgamer, R., Shachar, I., & Jung, S. (2008). Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nature Immunology, 9(4), 388–395.
Chu, V. T., Fröhlich, A., Steinhauser, G., Scheel, T., Roch, T., Fillatreau, S., et al. (2011). Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nature Immunology, 12(2), 151–159.
Winter, O., Moser, K., Mohr, E., Zotos, D., Kaminski, H., Szyska, M., et al. (2010). Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood, 116(11), 1867–1875.
Nie, Y., Waite, J., Brewer, F., Sunshine, M. J., Littman, D. R., & Zou, Y. R. (2004). The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. The Journal of Experimental Medicine, 200(9), 1145–1156.
Fry, T. J., & Mackall, C. L. (2005). The many faces of IL-7: From lymphopoiesis to peripheral T cell maintenance. Journal of Immunology, 174(11), 6571–6576.
Klein, C. A. (2008). Cancer. The metastasis cascade. Science, 321(5897), 1785–1787.
Pantel, K., & Brakenhoff, R. H. (2004). Dissecting the metastatic cascade. Nature Reviews. Cancer, 4(6), 448–456.
Coghlin, C., & Murray, G. I. (2010). Current and emerging concepts in tumour metastasis. The Journal of Pathology, 222(1), 1–15.
Hüsemann, Y., Geigl, J. B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., et al. (2008). Systemic spread is an early step in breast cancer. Cancer Cell, 13(1), 58–68.
Korkaya, H., Liu, S., & Wicha, M. S. (2011). Breast cancer stem cells, cytokine networks, and the tumor microenvironment. The Journal of Clinical Investigation, 121(10), 3804–3809.
Li, X., Lewis, M. T., Huang, J., Gutierrez, C., Osborne, C. K., Wu, M. F., et al. (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute, 100(9), 672–679.
Liu, H., Patel, M. R., Prescher, J. A., Patsialou, A., Qian, D., Lin, J., et al. (2010). Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proceedings of the National Academy of Sciences of the United States of America, 107(42), 18115–18120.
Liu, S., Ginestier, C., Ou, S. J., Clouthier, S. G., Patel, S. H., Monville, F., et al. (2011). Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Research, 71(2), 614–624.
Ginestier, C., Liu, S., Diebel, M. E., Korkaya, H., Luo, M., Brown, M., et al. (2010). CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. The Journal of Clinical Investigation, 120(2), 485–497.
Yang, J., Mani, S. A., & Weinberg, R. A. (2006). Exploring a new twist on tumor metastasis. Cancer Research, 66(9), 4549–4552.
Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R. A., Come, C., et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117(7), 927–939.
Roodman, G. D. (2004). Mechanisms of bone metastasis. The New England Journal of Medicine, 350(16), 1655–1664.
van der Pluijm, G., Sijmons, B., Vloedgraven, H., Deckers, M., Papapoulos, S., & Löwik, C. (2001). Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: Elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. Journal of Bone and Mineral Research, 16(6), 1077–1091.
Terpos, E., & Dimopoulos, M. A. (2011). Interaction between the skeletal and immune systems in cancer: Mechanisms and clinical implications. Cancer Immunology, Immunotherapy, 60(3), 305–317.
Kingsley, L. A., Fournier, P. G., Chirgwin, J. M., & Guise, T. A. (2007). Molecular biology of bone metastasis. Molecular Cancer Therapeutics, 6(10), 2609–2617.
Roodman, G. D. (2003). Role of stromal-derived cytokines and growth factors in bone metastasis. Cancer, 97(3 Suppl), 733–738.
Faccio, R. (2011). Immune regulation of the tumor/bone vicious cycle. Annals of the New York Academy of Sciences, 1237, 71–78.
Kakonen, S. M., & Mundy, G. R. (2003). Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer, 97(3 Suppl), 834–839.
Sterling, J. A., Edwards, J. R., Martin, T. J., & Mundy, G. R. (2011). Advances in the biology of bone metastasis: How the skeleton affects tumor behavior. Bone, 48(1), 6–15.
Henderson, M. A., Danks, J. A., Slavin, J. L., Byrnes, G. B., Choong, P. F., Spillane, J. B., et al. (2006). Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Research, 66(4), 2250–2256.
Canon, J. R., Roudier, M., Bryant, R., Morony, S., Stolina, M., Kostenuik, P. J., et al. (2008). Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clinical & Experimental Metastasis, 25(2), 119–129.
Rose, A. A., & Siegel, P. M. (2010). Emerging therapeutic targets in breast cancer bone metastasis. Future Oncology, 6(1), 55–74.
Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., et al. (1996). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. The Journal of Clinical Investigation, 98(7), 1544–1549.
Gallwitz, W. E., Guise, T. A., & Mundy, G. R. (2002). Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. The Journal of Clinical Investigation, 110(10), 1559–1572.
Suva, L. J., Washam, C., Nicholas, R. W., & Griffin, R. J. (2011). Bone metastasis: Mechanisms and therapeutic opportunities. Nature Reviews. Endocrinology, 7(4), 208–218.
Buijs, J. T., Stayrook, K. R., & Guise, T. A. (2011). TGF-β in the bone microenvironment: Role in breast cancer metastases. Cancer Microenvironment, 4(3), 261–281.
Juárez, P., & Guise, T. A. (2011). TGF-β in cancer and bone: Implications for treatment of bone metastases. Bone, 48(1), 23–29.
Biswas, S., Nyman, J. S., Alvarez, J. A., Chakrabarti, A., Ayres, A., Sterling, J., et al. (2011). Anti-transforming growth factor β antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS One, 6(11), e27090.
Muraoka, R. S., Dumont, N., Ritter, C. A., Dugger, T. C., Brantley, D. M., Chen, J., et al. (2002). Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. Journal of Clinical Investigation, 109(12), 1551–1559.
Mourskaia, A. A., Northey, J. J., & Siegel, P. M. (2007). Targeting aberrant TGF-β signaling in preclinical models of cancer. Anti-Cancer Agents in Medicinal Chemistry, 7(5), 504–514.
Morris, J. C., Shapiro, G. I., Tan, A. R., Lawrence, D. P., Olencki, T. E., Dezube, B. J., et al. (2008). Phase I/II study of GC1008: A human anti-transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC). Journal of Clinical Oncology, 26(Suppl). abstr 9028.
Ehata, S., Hanyn, A., Fujime, M., Katsuno, Y., Fukunaga, E., Goto, K., et al. (2007). Ki26894, a novel transforming growth factor-β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Science, 98(1), 127–133.
Zhang, B., Halder, S. K., Zhang, S., & Datta, P. K. (2009). Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Letters, 277(1), 114–120.
Melisi, D., Ishiyama, S., Sclabas, G. M., Fleming, J. B., Xia, Q., Tortora, G., et al. (2008). LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Molecular Cancer Therapeutics, 7(4), 829–840.
Calvo-Aller, E., Baselga, J., Glatt, S., Cleverly, A., Lahn, M., Arteaga, C. L., et al. (2008). First human dose escalation study in patients with metastatic malignancies to determine safety and pharmacokinetics of LY2157299, a small molecule inhibitor of the transforming growth factor-beta receptor I kinase. Journal of Clinical Oncology, 26(15 Suppl). abstr 14554.
Hau, P., Jachimczak, P., Schlingensiepen, R., Schulmeyer, F., Jauch, T., Steinbrecher, A., et al. (2007). Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: From preclinical to phase I/II studies. Oligonucleotides, 17(2), 201–212.
Bogdahn, U., Hau, P., Stockhammer, G., Venkataramana, N. K., Mahapatra, A. K., Suri, A., et al. (2011). Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: Results of a randomized and controlled phase IIb study. Neuro-Oncology, 13(1), 132–142.
Zhang, K., Kim, S., Cremasco, V., Hirbe, A. C., Collins, L., Piwnica-Worms, D., et al. (2011). CD8+ T cells regulate bone tumor burden independent of osteoclast resorption. Cancer Research, 71(14), 4799–4808.
Koh, B. I., & Kang, Y. (2012). The pro-metastatic role of bone marrow-derived cells: A focus on MSCs and regulatory T cells. EMBO Reports, 13(5), 412–422.
Gallo, M., De Luca, A., Lamura, L., & Normanno, N. (2012). Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: Implications for adjuvant therapy of breast cancer. Annals of Oncology, 23(3), 597–604.
Hamilton, E., Clay, T. M., & Blackwell, K. L. (2011). New perspectives on zoledronic acid in breast cancer: Potential augmentation of anticancer immune response. Cancer Investigation, 29(8), 533–541.
Sanders, J. M., Ghosh, S., Chan, J. M., Meints, G., Wang, H., Raker, A. M., et al. (2004). Quantitative structure–activity relationships for gammadelta T cell activation by bisphosphonates. Journal of Medicinal Chemistry, 47(2), 375–384.
Benzaïd, I., Mönkkönen, H., Stresing, V., Bonnelye, E., Green, J., Mönkkönen, J., et al. (2011). High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Research, 71(13), 4562–4572.
Cabillic, F., Toutirais, O., Lavoué, V., de La Pintière, C. T., Daniel, P., Rioux-Leclerc, N., et al. (2010). Aminobisphosphonate-pretreated dendritic cells trigger successful Vgamma9Vdelta2 T cell amplification for immunotherapy in advanced cancer patients. Cancer Immunology, Immunotherapy, 59(11), 1611–1619.
Santini, D., Martini, F., Fratto, M. E., Galluzzo, S., Vincenzi, B., Agrati, C., et al. (2009). In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunology, Immunotherapy, 58(1), 31–38.
Meraviglia, S., Eberl, M., Vermijlen, D., Todaro, M., Buccheri, S., Cicero, G., et al. (2010). In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clinical and Experimental Immunology, 161(2), 290–297.
Coleman, R. E., Winter, M. C., Cameron, D., Bell, R., Dodwell, D., Keane, M. M., et al. (2010). The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: Exploratory evidence for direct anti-tumour activity in breast cancer. British Journal of Cancer, 102(7), 1099–1105.
Aft, R., Naughton, M., Trinkaus, K., Watson, M., Ylagan, L., Chavez-MacGregor, M., et al. (2010). Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: An open label, randomised, phase 2 trial. The Lancet Oncology, 11(5), 421–428.
Rack, B., Jückstock, J., Genss, E. M., Schoberth, A., Schindlbeck, C., Strobl, B., et al. (2010). Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Research, 30(5), 1807–1813.
Eidtmann, H., de Boer, R., Bundred, N., Llombart-Cussac, A., Davidson, N., Neven, P., et al. (2010). Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Annals of Oncology, 21(11), 2188–2194.
Gnant, M., Mlineritsch, B., Schippinger, W., Luschin-Ebengreuth, G., Pöstlberger, S., Menzel, C., et al. (2009). Endocrine therapy plus zoledronic acid in premenopausal breast cancer. The New England Journal of Medicine, 360(7), 679–691.
Stopeck, A. T., Lipton, A., Body, J. J., Steger, G. G., Tonkin, K., de Boer, R. H., et al. (2010). Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study. Journal of Clinical Oncology, 28(35), 5132–5139.
Lipton, A. (2010). Implications of bone metastases and the benefits of bone-targeted therapy. Seminars in Oncology, 37(Suppl 2), S15–S29.
Suva, L. J., Brander, B. E., & Makhoul, I. (2011). Update on bone-modifying agents in metastatic breast cancer. Nature Reviews Endocrinology, 7(7), 380–381.
Fouque-Aubert, A., & Chapurlat, R. (2008). Influence of RANKL inhibition on immune system in the treatment of bone diseases. Joint, Bone, Spine, 75(1), 5–10.
Roux, S. (2006). RANKL inhibitors: A bright future? Joint, Bone, Spine, 73(2), 129–131.
Fidler, I. J. (2003). The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3(6), 453–458.
Kaplan, R. N., Psaila, B., & Lyden, D. (2006). Bone marrow cells in the ‘pre-metastatic’ niche: Within bone and beyond. Cancer Metastasis Reviews, 25(4), 521–529.
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827.
Kaplan, R. N., Rafii, S., & Lyden, D. (2006). Preparing the ‘soil’: The premetastatic niche. Cancer Research, 66(23), 11089–11093.
Wels, J., Kaplan, R. N., Rafii, S., & Lyden, D. (2008). Migratory neighbors and distant invaders: Tumor-associated niche cells. Genes & Development, 22(5), 559–574.
Miller, K., Wang, M., Gralow, J., Dickler, M., Cobleigh, M., Perez, E. A., et al. (2007). Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. The New England Journal of Medicine, 357(26), 2666–2676.
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., et al. (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. The New England Journal of Medicine, 350(23), 2335–2342.
Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., et al. (2006). Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England Journal of Medicine, 355(24), 2542–2550.
Xu, L., Duda, D. G., di Tomaso, E., Ancukiewicz, M., Chung, D. C., Lauwers, G. Y., et al. (2009). Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Research, 69(20), 7905–7910.
Allen, M., & Jones, L. J. (2011). Jekyll and Hyde: The role of the microenvironment on the progression of cancer. The Journal of Pathology, 223(2), 162–176.
Ellis, L. M., & Hicklin, D. J. (2008). VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nature Reviews. Cancer, 8(8), 579–591.
Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C., Oudard, S., Siebels, M., et al. (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. The New England Journal of Medicine, 356(2), 125–134.
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. The New England Journal of Medicine, 359(4), 378–390.
Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., et al. (2007). Sunitinib versus interferon alpha in metastatic renal-cell carcinoma. The New England Journal of Medicine, 356(2), 115–124.
Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., et al. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1), 35–44.
Kagan, H. M., & Li, W. (2003). Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. Journal of Cellular Biochemistry, 88(4), 660–672.
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–1226.
Barker, H. E., Cox, T. R., & Erler, J. T. (2012). The rationale for targeting the LOX family in cancer. Nature Reviews. Cancer, 12(8), 540–552.
Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.
Shiozawa, Y., Pedersen, E. A., Havens, A. M., Jung, Y., Mishra, A., 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(4), 1298–1312.
Schuettpelz, L. G., & Link, D. C. (2011). Niche competition and cancer metastasis to bone. The Journal of Clinical Investigation, 121(4), 1253–1255.
Liang, Z., Wu, T., Lou, H., Yu, X., Taichman, R. S., Lau, S. K., et al. (2004). Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Research, 64(12), 4302–4308.
Huang, E. H., Singh, B., Cristofanilli, M., Gelovani, J., Wei, C., Vincent, L., et al. (2009). A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. The Journal of Surgical Research, 155(2), 231–236.
Johnson, M. D., Torri, J. A., Lippman, M. E., & Dickson, R. B. (1999). Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness. Experimental Cell Research, 247(1), 105–113.
Roberts, J. D., Smith, M. R., Feldman, E. J., Cragg, L., Millenson, M. M., Roboz, G. J., et al. (2006). Phase I study of bryostatin-1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin’s) lymphoma. Clinical Cancer Research, 12(19), 5809–5816.
Haas, N. B., Smith, M., Lewis, N., Littman, L., Yeslow, G., Joshi, I. D., et al. (2003). Weekly bryostatin-1 in metastatic renal cell carcinoma: A phase II study. Clinical Cancer Research, 9(1), 109–114.
Smith, M. C., Luker, K. E., Garbow, J. R., Prior, J. L., Jackson, E., Piwnica-Worms, D., et al. (2004). CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Research, 64(23), 8604–8612.
Dillmann, F., Veldwijk, M. R., Laufs, S., Sperandio, M., Calandra, G., Wenz, F., et al. (2009). Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to imatinib and nilotinib. Leukemia & Lymphoma, 50(10), 1676–1686.
Kidd, S., Spaeth, E., Watson, K., Burks, J., Lu, H., Klopp, A., et al. (2012). Origins of the tumor microenvironment: Quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One, 7(2), e30563.
Christopher, M. J., Liu, F., Hilton, M. J., Long, F., & Link, D. C. (2009). Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood, 114(7), 1331–1339.
Balkwill, F. (2004). The significance of cancer cell expression of the chemokine receptor CXCR4. Seminars in Cancer Biology, 14(3), 171–179.
Karnoub, A. E., Dash, A. B., Vo, A. P., Sullivan, A., Brooks, M. W., Bell, G. W., et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449(7162), 557–563.
Aggarwal, B. B. (2003). Signalling pathways of the TNF superfamily: A double-edged sword. Nature Reviews. Immunology, 3(9), 745–756.
Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H., & Karin, M. (2004). Inhibition of NF-ĸB in cancer cells converts inflammation-induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression. Cancer Cell, 6(3), 297–305.
Lin, W. W., & Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation, 117(5), 1175–1183.
Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews. Immunology, 3(2), 133–146.
Fakhrai, H., Mantil, J. C., Liu, L., Nicholson, G. L., Murphy-Satter, C. S., Ruppert, J., et al. (2006). Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Therapy, 13(12), 1052–1060.
Bussard, K. M., Venzon, D. J., & Mastro, A. M. (2010). Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. Journal of Cellular Biochemistry, 111(5), 1138–1148.
Herman, S. E., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., et al. (2011). Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 117(23), 6287–6296.
Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., et al. (2008). Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell, 132(5), 794–806.
Tai, Y. T., Chang, B. Y., Kong, S. Y., Fulciniti, M., Yang, G., Calle, Y., et al. (2012). Bruton’s tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood‚ 120(9), 1877-1887. doi:10.1182/blood-2011-12-396853. Epub 11 June 2012.
Reddy, B.Y., Lim, P.K., Silverio, K., Patel, S.A., Won, B.W., Rameshwar, P. (2012). The microenvironmental effect in the progression, metastasis, and dormancy of breast cancer: A model system within bone marrow. International Journal of Breast Cancer, 2012, 721659 (Epub 6 Feb 2012).
Braun, S., Kentenich, C., Janni, W., Hepp, F., de Waal, J., Willgeroth, F., et al. (2000). Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. Journal of Clinical Oncology, 18(1), 80–86.
Rameshwar, P. (2010). Breast cancer cell dormancy in bone marrow: Potential therapeutic targets within the marrow microenvironment. Expert Review of Anticancer Therapy, 10(2), 129–132.
Kiel, M. J., & Morrison, S. J. (2008). Uncertainty in the niches that maintain haematopoietic stem cells. Nat Reviews. Immunology, 8(4), 290–301.
Lim, P. K., Bliss, S. A., Patel, S. A., Taborga, M., Dave, M. A., 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(5), 1550–1560.
Locke, M., Feisst, V., & Dunbar, P. R. (2011). Human adipose-derived stem cells: Separating promise from clinical need. Stem Cells, 29(3), 404–411.
Moharita, A. L., Taborga, M., Corcoran, K. E., Bryan, M., Patel, P. S., & Rameshwar, P. (2006). SDF-1alpha regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis. Blood, 108(10), 3245–3252.
Patel, S. A., Dave, M. A., Murthy, R. G., Helmy, K. Y., & Rameshwar, P. (2011). Metastatic breast cancer cells in the bone marrow microenvironment: Novel insights into oncoprotection. Oncology Reviews, 5(2), 93–102.
Zhang, Q., Shi, S., Liu, Y., Uyanne, J., Shi, Y., Shi, S., et al. (2009). Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. Journal of Immunology, 183(12), 7787–7798.
Davis, M. E., Zuckerman, J. E., Choi, C. H., Seligson, D., Tolcher, A., Alabi, C. A., et al. (2010). Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature, 464(7291), 1067–1070.
Grymula, K., Tarnowski, M., Wysoczynski, M., Drukala, J., Barr, F. G., Ratajczak, J., et al. (2010). Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior in human rhabdomyosarcomas. International Journal of Cancer, 127(11), 2554–2568.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stefanovic, S., Schuetz, F., Sohn, C. et al. Bone marrow microenvironment in cancer patients: immunological aspects and clinical implications. Cancer Metastasis Rev 32, 163–178 (2013). https://doi.org/10.1007/s10555-012-9397-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10555-012-9397-1