Models, mechanisms and clinical evidence for cancer dormancy (original) (raw)

• Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nature Rev. Cancer 4, 448–456 (2004).
  Article CAS 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). First evidence that breast cancer cells can disseminate in a far less progressed genomic state than previously thought. Genomic aberrations that make them metastatic are acquired after this step.
  Article CAS PubMed PubMed Central Google Scholar
• Karrison, T. G., Ferguson, D. J. & Meier, P. Dormancy of mammary carcinoma after mastectomy. J. Natl Cancer Inst. 91, 80–85 (1999).
  Article CAS PubMed Google Scholar
• Pfitzenmaier, J. et al. Telomerase activity in disseminated prostate cancer cells. BJU Int. 97, 1309–1313 (2006).
  Article PubMed Google Scholar
• Weckermann, D. et al. Disseminated cytokeratin positive tumor cells in the bone marrow of patients with prostate cancer: detection and prognostic value. J. Urol. 166, 699–703 (2001).
  Article CAS PubMed Google Scholar
• Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
  Article CAS PubMed Google Scholar
• Talmadge, J. E., Wolman, S. R. & Fidler, I. J. Evidence for the clonal origin of spontaneous metastases. Science 217, 361–363 (1982). First evidence that spontaneous metastases are clonal in origin and that they probably are derived from different progenitor cells.
  Article CAS PubMed 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). This paper genetically characterized disseminated single breast tumour cells and determined that cells with normal karyotypes can disseminate, suggesting that dissemination might occur very early.
  Article CAS PubMed Google Scholar
• Demicheli, R. Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Semin. Cancer Biol. 11, 297–306 (2001).
  Article CAS PubMed Google Scholar
• Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).
  Article CAS 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
• Klein, C. A. & Hölzel, D. Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle 5, 1788–1798 (2006).
  Article CAS PubMed Google Scholar
• Lacroix, M. Significance, detection and markers of disseminated breast cancer cells. Endocr. Relat. Cancer 13, 1033–1067 (2006).
  Article CAS PubMed Google Scholar
• Kovacs, A. F., Ghahremani, M. T., Stefenelli, U. & Bitter, K. Postoperative chemotherapy with cisplatin and 5-fluorouracil in cancer of the oral cavity and the oropharynx--long-term results. J. Chemother. 15, 495–502 (2003).
  CAS PubMed Google Scholar
• Boudreau, N. & Bissell, M. J. Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr. Opin. Cell Biol. 10, 640–646 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Wicha, M. S. Cancer stem cells and metastasis: lethal seeds. Clin. Cancer Res. 12, 5606–5607 (2006).
  Article PubMed Google Scholar
• Kaplan, R. N., Rafii, S. & Lyden, D. Preparing the “soil”: the premetastatic niche. Cancer Res. 66, 11089–11093 (2006).
  Article CAS PubMed PubMed Central 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). Provides evidence that spontaneous or forced downregulation of uPAR induces a state of tumor cell dormancy through decreased ERK signalling and G0–G1 arrest.
  Article CAS PubMed Google Scholar
• Aguirre Ghiso, J. A., Kovalski, K. & Ossowski, L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J. Cell Biol. 147, 89–104 (1999).
  Article CAS PubMed Google Scholar
• White, D. E. et al. Targeted disruption of β1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 6, 159–170 (2004). Provides evidence that mouse mammary epithelial cells transformed with an oncogene require β1 integrin for tumour progression. Absence of this integrin results in a state of tumour cell dormancy.
  Article CAS PubMed Google Scholar
• Weaver, V. M. et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol. 137, 231–245 (1997). Provides evidence that correcting the crosstalk between the tumour cell and the microenvironment can result in loss of malignancy associated with a more differentiated phenotype.
  Article CAS PubMed PubMed Central 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). Shows that loss of uPAR expression causes tumour cell dormancy by impairing EGFR activation by integrins that transduce mitogenic signals from the extracellular matrix molecule fibronectin.
  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
• 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
• Aguirre-Ghiso, J. A., Estrada, Y., Liu, D. & Ossowski, L. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res. 63, 1684–1695 (2003).
  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
• Bulavin, D. V. & Fornace, A. J., Jr. p38 MAP kinase's emerging role as a tumor suppressor. Adv. Cancer Res. 92, 95–118 (2004).
  Article CAS PubMed Google Scholar
• Heiss, M. M. et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nature Med. 1, 1035–1039 (1995). Shows that patients with tumour relapse had an increase or higher number of disseminated tumour cells in bone marrow aspirates, whereas patients without recurrence had negative or low tumour cell counts. uPAR expression on disseminated tumour cells was correlated with increasing tumour cell counts and poor prognosis.
  Article CAS PubMed Google Scholar
• Gattelli, A. et al. Progression of pregnancy-dependent mouse mammary tumors after long dormancy periods. Involvement of Wnt pathway activation. Cancer Res. 64, 5193–5199 (2004).
  Article CAS PubMed Google Scholar
• Gattelli, A., Zimberlin, M. N., Meiss, R. P., Castilla, L. H. & Kordon, E. C. Selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines. J. Virol. 80, 11409–11415 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Naumov, G. N. et al. Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. J. Cell Sci. 112 (Pt 12), 1835–1842 (1999).
  CAS PubMed Google Scholar
• Naumov, G. N. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002). This paper used an experimental model to show that solitary dormant cells that persist in target organs might be the source of dormancy and recurrence.
  CAS PubMed Google Scholar
• Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 (2003).
  Article CAS Google Scholar
• Steeg, P. S., Ouatas, T., Halverson, D., Palmieri, D. & Salerno, M. Metastasis suppressor genes: basic biology and potential clinical use. Clin. Breast Cancer 4, 51–62 (2003).
  Article CAS PubMed Google Scholar
• Mehlen, P. & Puisieux, A. Metastasis: a question of life or death. Nature Rev. Cancer 6, 449–458 (2006).
  Article CAS Google Scholar
• Bandyopadhyay, S. et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Med. 12, 933–938 (2006).
  Article CAS PubMed Google Scholar
• Rinker-Schaeffer, C. W., O'Keefe, J. P., Welch, D. R. & Theodorescu, D. Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin. Cancer Res. 12, 3882–3889 (2006).
  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
• Kauffman, E. C., Robinson, V. L., Stadler, W. M., Sokoloff, M. H. & Rinker-Schaeffer, C. W. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J. Urol. 169, 1122–1133 (2003).
  Article PubMed Google Scholar
• Nash, K. T. et al. Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J. Natl Cancer Inst. 99, 309–321 (2007). First evidence that a metastasis suppressor gene functions though the induction of dormancy.
  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
• Nakayama, K. et al. Homozygous deletion of MKK4 in ovarian serous carcinoma. Cancer Biol. Ther. 5, 630–634 (2006).
  Article CAS PubMed Google Scholar
• Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J. & Greenberg, M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326–1331 (1995).
  Article CAS PubMed Google Scholar
• Ranganathan, A. C., Adam, A. P., Zhang, L. & Aguirre-Ghiso, J. A. Tumor cell dormancy induced by p38(SAPK) and ER-stress signaling: an adaptive advantage for metastatic cells? Cancer Biol. Ther. 5, 729–735 (2006).
  Article CAS PubMed Google Scholar
• Hunter, K. Host genetics influence tumour metastasis. Nature Rev. Cancer 6, 141–146 (2006).
  Article CAS Google Scholar
• Crawford, N. P. et al. Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Breast Cancer Res. 8, R16 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Park, Y. G. et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nature Genet. 37, 1055–1062 (2005). Provides evidence that constitutional genetic polymorphisms in a gene can affect tumour metastasis.
  Article CAS PubMed Google Scholar
• Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).
  Article CAS Google Scholar
• Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).
  Article CAS PubMed Google Scholar
• Naumov, G. N., Akslen, L. A. & Folkman, J. Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle 5, 1779–1787 (2006).
  Article CAS PubMed Google Scholar
• Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nature Rev. Cancer 3, 401–410 (2003).
  Article CAS PubMed Google Scholar
• Naumov, G. N. et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl Cancer Inst. 98, 316–325 (2006).
  Article PubMed Google Scholar
• Watnick, R. S., Cheng, Y. N., Rangarajan, A., Ince, T. A. & Weinberg, R. A. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 3, 219–231 (2003).
  Article CAS PubMed Google Scholar
• Volpert, O. V. & Alani, R. M. Wiring the angiogenic switch: Ras, Myc, and Thrombospondin-1. Cancer Cell 3, 199–200 (2003).
  Article CAS PubMed Google Scholar
• Okajima, E. & Thorgeirsson, U. P. Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells. Biochem. Biophys. Res. Commun. 270, 108–111 (2000).
  Article CAS PubMed Google Scholar
• Guba, M. et al. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res. 61, 5575–5579 (2001).
  CAS PubMed Google Scholar
• Giuriato, S. et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc. Natl Acad. Sci. USA 103, 16266–16271 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Indraccolo, S. et al. Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc. Natl Acad. Sci. USA 103, 4216–4221 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Ruegg, C. & Mutter, N. Anti-angiogenic therapies in cancer: achievements and open questions. Bull. Cancer 94, 753–762 (2007).
  CAS PubMed 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). Shows in a mouse model that the balance between apoptosis and mitosis caused by lack of vascularization can induce angiogenic dormancy.
  Article CAS PubMed Google Scholar
• Al-Mehdi, A. B. et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Med. 6, 100–102 (2000). Shows in a mouse model that disseminated tumour cells can start growing intravascularly into metastases, bypassing any initial need for blood vessels.
  Article CAS PubMed Google Scholar
• Pantel, K. & Otte, M. Disseminated tumor cells: diagnosis, prognostic relevance, and phenotyping. Recent Results Cancer Res. 158, 14–24 (2001).
  Article CAS PubMed Google Scholar
• Finn, O. J. Human tumor antigens, immunosurveillance, and cancer vaccines. Immunol. Res. 36, 73–82 (2006).
  Article CAS PubMed Google Scholar
• Weinhold, K. J., Miller, D. A. & Wheelock, E. F. The tumor dormant state. Comparison of L5178Y cells used to establish dormancy with those that emerge after its termination. J. Exp. Med. 149, 745–757 (1979).
  Article CAS PubMed Google Scholar
• Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005).
  Article CAS Google Scholar
• Weinhold, K. J., Goldstein, L. T. & Wheelock, E. F. The tumor dormant state. Quantitation of L5178Y cells and host immune responses during the establishment and course of dormancy in syngeneic DBA/2 mice. J. Exp. Med. 149, 732–744 (1979).
  Article CAS PubMed Google Scholar
• Matsuzawa, A., Takeda, Y., Narita, M. & Ozawa, H. Survival of leukemic cells in a dormant state following cyclophosphamide-induced cure of strongly immunogenic mouse leukemia (DL811). Int. J. Cancer 49, 303–309 (1991).
  Article CAS PubMed Google Scholar
• Rabinovsky, R., Uhr, J. W., Vitetta, E. S. & Yefenof, E. Cancer dormancy: lessons from a B cell lymphoma and adenocarcinoma of the prostate. Adv. Cancer Res. 97, 189–202 (2007).
  Article CAS PubMed Google Scholar
• Farrar, J. D. et al. Cancer dormancy. VII. A regulatory role for CD8+ T cells and IFN-g in establishing and maintaining the tumor-dormant state. J. Immunol. 162, 2842–2849 (1999).
  CAS PubMed Google Scholar
• Saudemont, A. & Quesnel, B. In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis. Blood 104, 2124–2133 (2004).
  Article CAS PubMed Google Scholar
• Mahnke, Y. D., Schwendemann, J., Beckhove, P. & Schirrmacher, V. Maintenance of long-term tumour-specific T-cell memory by residual dormant tumour cells. Immunology 115, 325–336 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Feuerer, M. et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int. J. Cancer 92, 96–105 (2001).
  Article CAS PubMed Google Scholar
• Muller, M. et al. EblacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells. Cancer Res. 58, 5439–5446 (1998).
  CAS PubMed Google Scholar
• Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005).
  Article CAS PubMed Google Scholar
• Marches, R., Scheuermann, R. H. & Uhr, J. Cancer dormancy from mice to man: a review. Cell Cycle 5, 1772–1778 (2006).
  Article CAS PubMed Google Scholar
• Allgayer, H. et al. Urokinase plasminogen activator receptor (uPA-R.): one potential characteristic of metastatic phenotypes in minimal residual tumor disease. Cancer Res. 57, 1394–1399 (1997).
  CAS PubMed Google Scholar
• Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004). Provides evidence that patients with breast cancer who have been free of disease for 22 years still carry circulating tumour cells in their blood. It is proposed that an occult replicating population is present and sheds cells into the circulation, which eventually die.
  Article PubMed Google Scholar
• Balic, M. et al. 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, 5615–5621 (2006).
  Article CAS PubMed Google Scholar
• Riethmuller, G. & Klein, C. A. Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients. Semin. Cancer Biol. 11, 307–311 (2001).
  Article CAS PubMed Google Scholar
• Heiss, M. M. et al. Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J. Clin. Oncol. 20, 2005–2016 (2002).
  Article CAS PubMed Google Scholar
• Meng, S. et al. uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc. Natl Acad. Sci. USA 103, 17361–17365 (2006). Provides evidence that circulating tumour cells and tumour tissues from patients with cancer display co-amplification of uPAR and ERBB2.
  Article CAS PubMed PubMed Central Google Scholar
• Moody, S. E. et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2, 451–461 (2002).
  Article CAS PubMed Google Scholar
• Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).
  Article CAS PubMed Google Scholar
• Gestl, S. A., Leonard, T. L., Biddle, J. L., Debies, M. T. & Gunther, E. J. Dormant wnt-initiated mammary cancer can participate in reconstituting functional mammary glands. Mol. Cell. Biol. 27, 195–207 (2007).
  Article CAS PubMed Google Scholar
• Chaurasia, P. et al. A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrin and tumor growth. J. Biol. Chem. 281, 14852–14863 (2006).
  Article CAS PubMed Google Scholar
• Hoyer-Hansen, G. et al. Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor. Biochem. J. 358, 673–679 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).
  Article CAS PubMed Google Scholar
• Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).
  Article CAS PubMed Google Scholar
• Pelayo, R. et al. Cell cycle quiescence of early lymphoid progenitors in adult bone marrow. Stem Cells 24, 2703–2713 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Talpaz, M. et al. Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. J. Clin. Invest. 94, 1383–1389 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Kitzis, A. et al. Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission. Leuk. Lymphoma 42, 933–944 (2001).
  Article CAS 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). Provides evidence that solitary non-dividing dormant tumour cells are resistant to chemotherapy.
  Article CAS PubMed Google Scholar
• Schmidt, M. et al. Differential roles of p21(Waf1) and p27(Kip1) in modulating chemosensitivity and their possible application in drug discovery studies. Mol. Pharmacol. 60, 900–906 (2001).
  Article CAS PubMed Google Scholar
• Weaver, V. M. et al. beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2, 205–216 (2002).
  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
• 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
• Pootrakul, L. et al. Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer. Clin. Cancer Res. 12, 5987–5993 (2006).
  Article CAS PubMed Google Scholar
• Scharenberg, C. W., Harkey, M. A. & Torok-Storb, B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 99, 507–512 (2002).
  Article CAS PubMed Google Scholar
• Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nature Rev. Cancer 5, 275–284 (2005).
  Article CAS Google Scholar
• Hirschmann-Jax, C. et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc. Natl Acad. Sci. USA 101, 14228–14233 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Roepman, P. et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nature Genet. 37, 182–186 (2005).
  Article CAS PubMed Google Scholar
• Weinstein, I. B. Cancer. Addiction to oncogenes — the Achilles heal of cancer. Science 297, 63–64 (2002).
  Article CAS PubMed Google Scholar
• Vessella, R. L., Pantel, K. & Mohla, S. Tumor cell dormancy: an NCI workshop report. Cancer Biol. Ther. 6 (2007).
• Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472–476 (2006).
  Article CAS 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
• Sarkisian, C. J. et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biol. 9, 493–505 (2007).
  Article CAS PubMed Google Scholar
• Roninson, I. B. Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705–2715 (2003).
  CAS PubMed Google Scholar
• Zetterberg, A. & Larsson, O. Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proc. Natl Acad. Sci. USA 82, 5365–5369 (1985).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (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). A comprehensive gene-profiling analysis of quiescence programmes induced by three different stimuli.
• Larsson, O., Zetterberg, A. & Engstrom, W. Cell-cycle-specific induction of quiescence achieved by limited inhibition of protein synthesis: counteractive effect of addition of purified growth factors. J. Cell Sci. 73, 375–387 (1985).
  CAS PubMed Google Scholar
• Wang, J. & Kim, S. K. Global analysis of dauer gene expression in Caenorhabditis elegans. Development 130, 1621–1634 (2003).
  Article CAS PubMed Google Scholar
• Koornneef, M., Bentsink, L. & Hilhorst, H. Seed dormancy and germination. Curr. Opin. Plant Biol. 5, 33–36 (2002).
  Article CAS PubMed Google Scholar
• Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313, 971–975 (2006).
  Article CAS PubMed Google Scholar
• Kondo, M. et al. The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei. Mech. Ageing Dev. 126, 642–647 (2005).
  Article CAS PubMed Google Scholar
• Fukuyama, M., Rougvie, A. E. & Rothman, J. H. C. elegans DAF-18/PTEN mediates nutrient-dependent arrest of cell cycle and growth in the germline. Curr. Biol. 16, 773–779 (2006).
  Article CAS PubMed Google Scholar
• Long, X. et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr. Biol. 12, 1448–1461 (2002).
  Article CAS PubMed Google Scholar
• Solomon, A. et al. Caenorhabditis elegans OSR-1 regulates behavioral and physiological responses to hyperosmotic environments. Genetics 167, 161–170 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Merlo, L. M., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nature Rev. Cancer 6, 924–935 (2006).
  Article CAS Google Scholar
• Kitano, H. Cancer as a robust system: implications for anticancer therapy. Nature Rev. Cancer 4, 227–235 (2004). Suggests that inducing genuine dormancy (that is, cellular dormancy) is important to prevent the tumour heterogeneity from increasing and limiting robustness of cancer as a system (that is, the ability to maintain stable functioning despite perturbations, such as therapy).
  Article CAS Google Scholar
• Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615 (2005).
  Article CAS PubMed Google Scholar
• Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).
  Article CAS PubMed Google Scholar
• Naumov, G. N., MacDonald, I. C., Chambers, A. F. & Groom, A. C. Solitary cancer cells as a possible source of tumour dormancy? Semin. Cancer Biol. 11, 271–276 (2001).
  Article CAS PubMed Google Scholar
• Shachaf, C. M. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112–1117 (2004).
  Article CAS PubMed Google Scholar
• Dawson, D. W. et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285, 245–248 (1999).
  Article CAS PubMed Google Scholar
• Kvalheim, G., Naume, B. & Nesland, J. M. Minimal residual disease in breast cancer. Cancer Metastasis Rev. 18, 101–108 (1999).
  Article CAS PubMed Google Scholar
• Merrie, A. E., Yun, K., van Rij, A. M. & McCall, J. L. Detection and significance of minimal residual disease in colorectal cancer. Histol. Histopathol. 14, 561–569 (1999).
  CAS PubMed Google Scholar
• Gath, H. J. & Brakenhoff, R. H. Minimal residual disease in head and neck cancer. Cancer Metastasis Rev. 18, 109–126 (1999).
  Article CAS PubMed Google Scholar
• Cheung, I. Y., Feng, Y., Vickers, A., Gerald, W. & Cheung, N. K. Cyclin D1, a novel molecular marker of minimal residual disease, in metastatic neuroblastoma. J. Mol. Diagn. 9, 237–241 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Roberts, W. M. et al. Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. N. Engl. J. Med. 336, 317–323 (1997).
  Article CAS PubMed Google Scholar
• Bruggemann, M., Pott, C., Ritgen, M. & Kneba, M. Significance of minimal residual disease in lymphoid malignancies. Acta Haematol. 112, 111–119 (2004).
  Article PubMed Google Scholar
• Schwarzenbach, H. et al. Detection of tumor-specific DNA in blood and bone marrow plasma from patients with prostate cancer. Int. J. Cancer 120, 1465–1471 (2007).
  Article CAS PubMed Google Scholar
• Morgan, T. M., Lange, P. H. & Vessella, R. L. Detection and characterization of circulating and disseminated prostate cancer cells. Front. Biosci. 12, 3000–3009 (2007).
  Article CAS PubMed Google Scholar
• Pfitzenmaier, J. et al. The detection and isolation of viable prostate-specific antigen positive epithelial cells by enrichment: a comparison to standard prostate-specific antigen reverse transcriptase polymerase chain reaction and its clinical relevance in prostate cancer. Urol. Oncol. 25, 214–220 (2007).
  Article CAS PubMed Google Scholar
• Kienle, P. & Koch, M. Minimal residual disease in gastrointestinal cancer. Semin. Surg. Oncol. 20, 282–293 (2001).
  Article CAS PubMed Google Scholar
• Max, N. & Keilholz, U. Minimal residual disease in melanoma. Semin. Surg. Oncol. 20, 319–328 (2001).
  Article CAS PubMed Google Scholar
• Blaheta, H. J. et al. Detection of melanoma cells in sentinel lymph nodes, bone marrow and peripheral blood by a reverse transcription-polymerase chain reaction assay in patients with primary cutaneous melanoma: association with Breslow's tumour thickness. Br. J. Dermatol. 145, 195–202 (2001).
  Article CAS PubMed Google Scholar
• Hosch, S. B., Scheunemann, P. & Izbicki, J. R. Minimal residual disease in non-small-cell lung cancer. Semin. Surg. Oncol. 20, 278–281 (2001).
  Article CAS PubMed Google Scholar
• Willeke, F. & Sturm, J. W. Minimal residual disease in soft-tissue sarcomas. Semin. Surg. Oncol. 20, 294–303 (2001).
  Article CAS PubMed Google Scholar