Mechanisms of disseminated cancer cell dormancy: an awakening field (original) (raw)

• Klein, C. A. Framework models of tumor dormancy from patient-derived observations. Curr. Opin. Genet. Dev. 21, 42–49 (2010).
  Article PubMed CAS Google Scholar
• Goss, P. E. & Chambers, A. F. Does tumour dormancy offer a therapeutic target? Nature Rev. Cancer 10, 871–877 (2010).
  Article CAS Google Scholar
• Klein, C. A. Selection and adaptation during metastatic cancer progression. Nature 501, 365–372 (2013).
  Article CAS PubMed Google Scholar
• Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nature Rev. Cancer 7, 834–846 (2007).
  Article CAS Google Scholar
• Demicheli, R. et al. Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann. Oncol. 16, 1449–1457 (2005).
  Article CAS PubMed Google Scholar
• Hadfield, G. The dormant cancer cell. Br. Med. J. 2, 607–610 (1954).
  Article CAS PubMed PubMed Central Google Scholar
• Pantel, K., Alix-Panabieres, C. & Riethdorf, S. Cancer micrometastases. Nature Rev. Clin. Oncol. 6, 339–351 (2009).
  Article CAS Google Scholar
• Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nature Rev. Cancer 4, 448–456 (2004).
  Article CAS Google Scholar
• Klein, C. A. Parallel progression of primary tumours and metastases. Nature Rev. Cancer 9, 302–312 (2009).
  Article CAS Google Scholar
• Essers, M. A. & Trumpp, A. Targeting leukemic stem cells by breaking their dormancy. Mol. Oncol. 4, 443–450 (2010).
  Article PubMed PubMed Central Google Scholar
• Sosa, M. S., Avivar-Valderas, A., Bragado, P., Wen, H. C. & Aguirre-Ghiso, J. A. ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin. Cancer Res. 17, 5850–5857 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kang, Y. & Pantel, K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573–581 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Jo, H., Jia, Y., Subramanian, K. K., Hattori, H. & Luo, H. R. Cancer cell-derived clusterin modulates the phosphatidylinositol 3′-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation. Mol. Cell. Biol. 28, 4285–4299 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Humtsoe, J. O. & Kramer, R. H. Differential epidermal growth factor receptor signaling regulates anchorage-independent growth by modulation of the PI3K/AKT pathway. Oncogene 29, 1214–1226 (2010).
  Article CAS PubMed Google Scholar
• Balz, L. M. et al. The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination. J. Pathol. 227, 234–244 (2012).
  Article CAS PubMed Google Scholar
• Schewe, D. M. & Aguirre-Ghiso, J. A. ATF6α-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc. Natl Acad. Sci. USA 105, 10519–10524 (2008). This paper revealed that specific signals can be targeted to kill dormant cells while in quiescence.
  Article CAS PubMed PubMed Central Google Scholar
• Bragado, P. et al. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nature Cell Biol. 15, 1351–1361 (2013). First evidence that the bone marrow is a growth-restrictive 'soil' where TGFβ2 and p38 signalling keep DTCs in a dormant state.
  Article CAS PubMed Google Scholar
• Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011). Demonstrates that VCAM1 on tumour cells instructs osteoclast differentiation to support reactivation of indolent tumour cells and bone metastasis.
  Article CAS PubMed PubMed Central Google Scholar
• Aslakson, C. J. & Miller, F. R. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 52, 1399–1405 (1992).
  CAS PubMed Google Scholar
• Aslakson, C. J., Rak, J. W., Miller, B. E. & Miller, F. R. Differential influence of organ site on three subpopulations of a single mouse mammary tumor at two distinct steps in metastasis. Int. J. Cancer 47, 466–472 (1991).
  Article CAS PubMed Google Scholar
• Avivar-Valderas, A. et al. Regulation of autophagy during ECM detachment is linked to a selective inhibition of mTORC1 by PERK. Oncogene 32, 4932–4940 (2013).
  Article CAS PubMed Google Scholar
• Correa, R. J., Peart, T., Valdes, Y. R., DiMattia, G. E. & Shepherd, T. G. Modulation of AKT activity is associated with reversible dormancy in ascites-derived epithelial ovarian cancer spheroids. Carcinogenesis 33, 49–58 (2012).
  Article CAS PubMed Google Scholar
• Lengyel, E. Ovarian cancer development and metastasis. Am. J. Pathol. 177, 1053–1064 (2010).
  Article PubMed PubMed Central Google Scholar
• Lu, Z. et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J. Clin. Invest. 118, 3917–3929 (2008). This report shows that induction of autophagy by ARHI contributes to induction and survival of dormant ovarian cells.
  CAS PubMed PubMed Central Google Scholar
• Gupta, A. et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc. Natl Acad. Sci. USA 107, 14333–14338 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, I. H. et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336, 225–228 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Avivar-Valderas, A. et al. PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Mol. Cell. Biol. 31, 3616–3629 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Liang, J. et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biol. 9, 218–224 (2007).
  Article CAS PubMed Google Scholar
• Schewe, D. M. & Aguirre-Ghiso, J. A. Inhibition of eIF2α dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res. 69, 1545–1552 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fan, W. et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res. 71, 4494–4505 (2011). This article shows that residual tumour cells left behind after TKR inhibitors remain alive by inducing anti-apoptotic signals. It also suggests that conventional treatments may expose the dormant population that can be targeted by using ABT-737 molecules.
  Article CAS PubMed PubMed Central Google Scholar
• Alvarez, J. V. et al. Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 24, 30–44 (2013). This article shows that PAR4 downregulation is required for relapses after therapy-induced stress and dormancy.
  Article CAS PubMed Google Scholar
• Deng, X., Ewton, D. Z. & Friedman, E. Mirk/Dyrk1B maintains the viability of quiescent pancreatic cancer cells by reducing levels of reactive oxygen species. Cancer Res. 69, 3317–3324 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jin, K., Ewton, D. Z., Park, S., Hu, J. & Friedman, E. Mirk regulates the exit of colon cancer cells from quiescence. J. Biol. Chem. 284, 22916–22925 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ewton, D. Z. et al. Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells. Mol. Cancer Ther. 10, 2104–2114 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Hu, J., Nakhla, H. & Friedman, E. Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. Int. J. Cancer 129, 307–318 (2011). Here the authors demonstrate that DYRK1B regulates the survival and quiescence of ovarian cancer cells.
  Article CAS PubMed Google Scholar
• Jin, K., Park, S., Ewton, D. Z. & Friedman, E. The survival kinase Mirk/Dyrk1B is a downstream effector of oncogenic K-ras in pancreatic cancer. Cancer Res. 67, 7247–7255 (2007).
  Article CAS PubMed Google Scholar
• Litovchick, L., Florens, L. A., Swanson, S. K., Washburn, M. P. & DeCaprio, J. A. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 25, 801–813 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lopez-Maury, L., Marguerat, S. & Bahler, J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nature Rev. Genet. 9, 583–593 (2008).
  Article CAS PubMed Google Scholar
• Chatterjee, M. & van Golen, K. L. Farnesyl transferase inhibitor treatment of breast cancer cells leads to altered RhoA and RhoC GTPase activity and induces a dormant phenotype. Int. J. Cancer 129, 61–69 (2011).
  Article CAS PubMed Google Scholar
• Hickson, J. A. et al. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 66, 2264–2270 (2006).
  Article CAS PubMed Google Scholar
• Vander Griend, D. J. et al. Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 65, 10984–10991 (2005).
  Article CAS PubMed Google Scholar
• Adam, A. P. et al. Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Res. 69, 5664–5672 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hickson, J. A. et al. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 66, 2264–2270 (2006).
  Article CAS PubMed Google Scholar
• El Touny, L. H. et al. Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells. J. Clin. Invest. 124, 156–168 (2014). Provides evidence that pharmacological targeting of MEK and SRC can prevent reactivation and induce dormant DTC killing.
  Article CAS PubMed Google Scholar
• Diehl, N. L. et al. Activation of the p38 mitogen-activated protein kinase pathway arrests cell cycle progression and differentiation of immature thymocytes in vivo. J. Exp. Med. 191, 321–334 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Masiero, M. et al. Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia 25, 588–598 (2011).
  Article CAS PubMed Google Scholar
• Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
  Article CAS PubMed Google Scholar
• Ranganathan, A. C., Zhang, L., Adam, A. P. & Aguirre-Ghiso, J. A. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 66, 1702–1711 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Fu, Y., Li, J. & Lee, A. S. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 67, 3734–3740 (2007).
  Article CAS PubMed Google Scholar
• Bartkowiak, K. et al. Discovery of a novel unfolded protein response phenotype of cancer stem/progenitor cells from the bone marrow of breast cancer patients. J. Proteome Res. 9, 3158–3168 (2010).
  Article CAS PubMed Google Scholar
• Bartkowiak, K. et al. Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/ progenitor cell protein profile. J. Proteome Res. 8, 2004–2014 (2009).
  Article CAS PubMed Google Scholar
• Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Elanchezhian, R. et al. Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells. Cell Death Dis. 3, e301 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Badiola, N. et al. Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis. 2, e149 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, E. et al. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 66, 7849–7853 (2006).
  Article CAS PubMed Google Scholar
• Bambang, I. F. 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. 315, 1964–1974 (2009).
  Article CAS PubMed Google Scholar
• Murrell, D. H., Foster, P. J. & Chambers, A. F. Brain metastases from breast cancer: lessons from experimental magnetic resonance imaging studies and clinical implications. J. Mol. Med. 92, 5–12 (2014).
  Article PubMed Google Scholar
• Heyn, C. et al. In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn. Reson. Med. 56, 1001–1010 (2006).
  Article PubMed Google Scholar
• Naumov, G. N. et al. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res. Treat 82, 199–206 (2003).
  Article CAS PubMed Google Scholar
• Aguirre-Ghiso, J. A., Bragado, P. & Sosa, M. S. Metastasis awakening: targeting dormant cancer. Nature Med. 19, 276–277 (2013).
  Article CAS PubMed Google Scholar
• Bragado, P., Sosa, M. S., Keely, P., Condeelis, J. & Aguirre-Ghiso, J. A. Microenvironments dictating tumor cell dormancy. Recent Results Cancer Res. 195, 25–39 (2012).
  Article PubMed PubMed Central Google Scholar
• Schardt, J. A. et al. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8, 227–239 (2005).
  Article CAS PubMed Google Scholar
• Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008). First evidence that pre-malignant tumour cells can disseminate and remain dormant for long periods only to then give rise to metastasis.
  Article CAS PubMed Google Scholar
• Shiozawa, Y., Havens, A. M., Pienta, K. J. & Taichman, R. S. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22, 941–950 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Shiozawa, Y. et al. Erythropoietin supports the survival of prostate cancer, but not growth and bone metastasis. J. Cell. Biochem. 114, 2471–2478 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Joseph, J. et al. Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype. Mol. Cancer Res.: MCR 10, 282–292 (2012).
  Article CAS PubMed Google Scholar
• Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011). First evidence that DTCs can home and compete with HSCs in their niches, which supports a dormancy-instructive function.
  Article CAS PubMed PubMed Central Google Scholar
• Kobayashi, A. et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 208, 2641–2655 (2011). Provides evidence that one of the TGFβ family members, BMP7, induces dormancy of prostate cancer stem-like cells in the bone through the activation of p38 MAPK, which induces p21 and the tumour metastasis suppressor gene NDRG1.
  Article CAS PubMed PubMed Central Google Scholar
• Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012). Shows in a breast cancer model that COCO-mediated inhibition of BMP4 signalling in the lungs favours breast cancer cell dormancy escape.
  Article CAS PubMed PubMed Central Google Scholar
• Dormady, S. P., Zhang, X. M. & Basch, R. S. Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6). Proc. Natl Acad. Sci. USA 97, 12260–12265 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Shiozawa, Y. et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia 12, 116–127 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Aguirre-Ghiso, J. A., Estrada, Y., Liu, D. & Ossowski, L. ERKMAPK activity as a determinant of tumor growth and dormancy; regulation by p38SAPK. Cancer Res. 63, 1684–1695 (2003).
  CAS PubMed Google Scholar
• Aguirre-Ghiso, J. A., Ossowski, L. & Rosenbaum, S. K. Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res. 64, 7336–7345 (2004).
  Article CAS PubMed Google Scholar
• Liu, W. et al. N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol. Med. 4, 93–108 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Talmadge, J. E. & Fidler, I. J. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Marshall, J. C. et al. Effect of inhibition of the lysophosphatidic Acid receptor 1 on metastasis and metastatic dormancy in breast cancer. J. Natl Cancer Inst. 104, 1306–1319 (2012). Provides evidence that blocking an LPA receptor commonly negatively regulated by the metastasis suppressor NM23 induces dormancy of breast cancer cells.
  Article CAS PubMed PubMed Central Google Scholar
• Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nature Cell Biol. 15, 807–817 (2013). Uses in vitro models to show that endothelial cells can regulate solitary breast cancer tumour cell dormancy and that a sprouting neovasculature niche promotes reactivation.
  Article CAS PubMed Google Scholar
• Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012). Suggests that disseminated tumour cells need to educate stromal cells in secondary niches to induce metastasis. They show that disseminated tumour cells produce TGFβ3 that activates lung fibroblast periostin production, which recruits WNT ligands and activates WNT signalling in breast cancer stem cells.
  Article CAS Google Scholar
• Barkan, D. et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 68, 6241–6250 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, G., Tse, J., Jain, R. K. & Munn, L. L. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells. PLoS ONE 4, e4632 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Liu, D., Aguirre Ghiso, J., Estrada, Y. & Ossowski, L. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1, 445–457 (2002).
  Article CAS PubMed Google Scholar
• Aguirre Ghiso, J. A. Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 21, 2513–2524 (2002).
  Article PubMed Google Scholar
• Shibue, T. & Weinberg, R. A. Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc. Natl Acad. Sci. USA 106, 10290–10295 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Schrader, J. et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53, 1192–1205 (2011).
  Article CAS PubMed Google Scholar
• Barkan, D. et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 70, 5706–5716 (2010). Provides evidence that type I collagen enrichment in lungs activates β1 integrin signalling in dormant D2.0R cells, inducing reactivation.
  Article CAS PubMed PubMed Central Google Scholar
• Swartz, M. A. et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 72, 2473–2480 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Shiao, S. L., Ganesan, A. P., Rugo, H. S. & Coussens, L. M. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 25, 2559–2572 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• MacKie, R. M., Reid, R. & Junor, B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. New Engl. J. Med. 348, 567–568 (2003).
  Article PubMed Google Scholar
• Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010). First evidence that the proliferative switch of early DTCs is regulated by the immune system.
  Article CAS PubMed PubMed Central Google Scholar
• Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).
  Article CAS PubMed Google Scholar
• Muller-Hermelink, N. et al. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008). The authors reported that, depending on microenvironmental signals, CD4+ T cells can promote dormancy or reactivation.
  Article CAS PubMed Google Scholar
• Zhao, X. et al. Vaccines targeting tumor blood vessel antigens promote CD8+ T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. J. Immunol. 188, 1782–1788 (2012).
  Article CAS PubMed Google Scholar
• Braumuller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013).
  Article PubMed CAS Google Scholar
• Holmgren, L., O'Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153 (1995).
  Article CAS PubMed Google Scholar
• Almog, N. et al. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 69, 836–844 (2009).
  Article CAS PubMed Google Scholar
• Almog, N. et al. Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J.: Official Publ. Feder. Am. Societies Exp. Biol. 20, 947–949 (2006).
  Article CAS Google Scholar
• Hsu, S. C. et al. Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer Res. 56, 5684–5691 (1996).
  CAS PubMed Google Scholar
• Weinstat-Saslow, D. L. et al. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res. 54, 6504–6511 (1994).
  CAS PubMed Google Scholar
• Indraccolo, S. et al. Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy. Cancer Res. 69, 1314–1323 (2009).
  Article CAS PubMed Google Scholar
• Panigrahy, D. et al. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J. Clin. Invest. 122, 178–191 (2012).
  Article CAS PubMed Google Scholar
• Pencheva, N. et al. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell 151, 1068–1082 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Magnus, N. et al. Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc. Natl Acad. Sci. USA 111, 3544–3549 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Wells, A., Griffith, L., Wells, J. Z. & Taylor, D. P. The dormancy dilemma: quiescence versus balanced proliferation. Cancer Res. 73, 3811–3816 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Taylor, D. P., Wells, J. Z., Savol, A., Chennubhotla, C. & Wells, A. Modeling boundary conditions for balanced proliferation in metastatic latency. Clin. Cancer Res. 19, 1063–1070 (2013).
  Article PubMed PubMed Central Google Scholar
• Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nature Med. 16, 116–122 (2010).
  Article CAS PubMed Google Scholar
• Taichman, R. S. et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PloS ONE 8, e61873 (2013). Provides evidence that GAS6, an HSC niche regulator, may regulate prostate DTC dormancy.
  Article CAS PubMed PubMed Central Google Scholar
• Tsai, H. C. et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012). Provides evidence that low-dose azacytidine treatment may be amenable for reprogramming tumour cells into a non-proliferative state. This may represent a dormancy-inducing strategy.
  Article CAS PubMed PubMed Central Google Scholar
• Kim, R. S. et al. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PloS ONE 7, e35569 (2012). First evidence that a dormancy gene signature can predict late metastatic relapse in patients.
  Article CAS PubMed PubMed Central Google Scholar
• Dono, M. et al. Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma. Br. J. Cancer 110, 1058–1065 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Landreville, S. et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin. Cancer Res. 18, 408–416 (2012). Provides evidence that HDAC inhibitors may be used to reprogramme cells into a dormancy-like phenotype.
  Article CAS PubMed Google Scholar
• Chen, T. et al. An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration. Nature 485, 104–108 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Kobielak, K., Stokes, N., de la Cruz, J., Polak, L. & Fuchs, E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl Acad. Sci. USA 104, 10063–10068 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Avagyan, S., Glouchkova, L., Choi, J. & Snoeck, H. W. A quantitative trait locus on chromosome 4 affects cycling of hematopoietic stem and progenitor cells through regulation of TGF-β2 responsiveness. J. Immunol. 181, 5904–5911 (2008).
  Article CAS PubMed Google Scholar
• Langer, J. C., Henckaerts, E., Orenstein, J. & Snoeck, H. W. Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function. J. Exp. Med. 199, 5–14 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson, A., Laurenti, E. & Trumpp, A. Balancing dormant and self-renewing hematopoietic stem cells. Curr. Opin. Genet. Dev. 19, 461–468 (2009).
  Article CAS PubMed Google Scholar
• Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).
  Article CAS PubMed Google Scholar
• White, A. C. et al. Stem cell quiescence acts as a tumour suppressor in squamous tumours. Nature Cell Biol. 16, 99–107 (2014). Provides strong evidence that niche signals via the induction of quiescence can antagonize oncogene signalling. This may explain how niche cues may be dominant over oncogenes and thus challenge oncogene addiction.
  Article CAS PubMed Google Scholar
• Onder, T. T. et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature 483, 598–602 (2012). This paper identifies genes found to regulate dormancy as key negative regulators of iPSC reprogramming, arguing that dormancy might involve changes in pluripotency.
  Article CAS PubMed PubMed Central Google Scholar
• Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
  Article CAS PubMed Google Scholar
• Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chaffer, C. L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61–74 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Bragado, P. et al. Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PloS ONE 7, e29974 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Med. 12, 446–451 (2006).
  Article CAS PubMed Google Scholar
• Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Guo, W. et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148, 1015–1028 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cheung, T. H. & Rando, T. A. Molecular regulation of stem cell quiescence. Nature Rev. Mol. Cell Biol. 14, 329–340 (2013).
  Article CAS Google Scholar
• Klein, C. A. et al. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc. Natl Acad. Sci. USA 96, 4494–4499 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Schmidt-Kittler, O. et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc. Natl Acad. Sci. USA 100, 7737–7742 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Smits, B. M. et al. The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation. PLoS Genet. 9, e1003549 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Marino, N. et al. Breast cancer metastasis: issues for the personalization of its prevention and treatment. Am. J. Pathol. 183, 1084–1095 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Steeg, P. S. Perspective: The right trials. Nature 485, S58–59 (2012).
  Article CAS PubMed Google Scholar
• Alix-Panabieres, C., Muller, V. & Pantel, K. Current status in human breast cancer micrometastasis. Curr. Opin. Oncol. 19, 558–563 (2007).
  Article PubMed Google Scholar
• Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. New Engl. J. Med. 353, 793–802 (2005).
  Article CAS PubMed Google Scholar
• Jauch, K. W. et al. Prognostic significance of bone marrow micrometastases in patients with gastric cancer. J. Clin. Oncol. 14, 1810–1817 (1996).
  Article CAS PubMed Google Scholar
• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  Article CAS PubMed Google Scholar
• Kouros-Mehr, H. et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13, 141–152 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Sang, L., Coller, H. A. & Roberts, J. M. Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 321, 1095–1100 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Narita, M. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126, 503–514 (2006).
  Article CAS PubMed Google Scholar
• Coller, H. A., Sang, L. & Roberts, J. M. A new description of cellular quiescence. PLoS Biol. 4, e83 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Sharma, S. V. et al. A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10, 425–435 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Stoecklein, N. H. et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 13, 441–453 (2008).
  Article CAS PubMed Google Scholar
• Marlow, R. et al. A novel model of dormancy for bone metastatic breast cancer cells. Cancer Res. 73, 6886–6899 (2013).
  Article CAS PubMed Google Scholar
• Pardee, A. D. et al. A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor microenvironment. Cancer Res. 70, 9041–9052 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Aguirre-Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K. & Ossowski, L. Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol. Biol. Cell 12, 863–879 (2001).
  Article CAS PubMed PubMed Central Google Scholar