Models, mechanisms and clinical evidence for cancer dormancy

Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.

[1]  P. Kienle,et al.  Minimal residual disease in gastrointestinal cancer. , 2001, Seminars in surgical oncology.

[2]  Xi C. He,et al.  PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention , 2006, Nature.

[3]  S. Gestl,et al.  Dormant Wnt-Initiated Mammary Cancer Can Participate in Reconstituting Functional Mammary Glands , 2006, Molecular and Cellular Biology.

[4]  H. Allgayer,et al.  Individual development and uPA–receptor expression of disseminated tumour cells in bone marrow: A reference to early systemic disease in solid cancer , 1995, Nature Medicine.

[5]  A. Lin,et al.  Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. , 2005, Cancer research.

[6]  O. Liang,et al.  A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with α5β1 Integrin and Tumor Growth* , 2006, Journal of Biological Chemistry.

[7]  P. Steeg,et al.  Metastasis suppressor genes: basic biology and potential clinical use. , 2003, Clinical breast cancer.

[8]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[9]  M. Wicha Cancer Stem Cells and Metastasis: Lethal Seeds , 2006, Clinical Cancer Research.

[10]  K. Bitter,et al.  Postoperative Chemotherapy with Cisplatin and 5-Fluorouracil in Cancer of the Oral Cavity and the Oropharynx - Long-Term Results , 2003, Journal of chemotherapy.

[11]  Mitchell D Schnall,et al.  Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. , 2002, Cancer cell.

[12]  Ruud H. Brakenhoff,et al.  Dissecting the metastatic cascade , 2004, Nature Reviews Cancer.

[13]  U. Weidle,et al.  Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor. , 2001, The Biochemical journal.

[14]  Lars Holmgren,et al.  Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression , 1995, Nature Medicine.

[15]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[16]  B. Naume,et al.  Minimal Residual Disease in Breast Cancer , 2004, Cancer and Metastasis Reviews.

[17]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[18]  O. Volpert,et al.  Wiring the angiogenic switch: Ras, Myc, and Thrombospondin-1. , 2003, Cancer cell.

[19]  J. Ghiso Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo , 2002, Oncogene.

[20]  U. Thorgeirsson,et al.  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. , 2000, Biochemical and biophysical research communications.

[21]  G. Willimsky,et al.  Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance , 2005, Nature.

[22]  J. Aguirre-Ghiso,et al.  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. , 2006, Cancer research.

[23]  Jason L. Townson,et al.  Ineffectiveness of Doxorubicin Treatment on Solitary Dormant Mammary Carcinoma Cells or Late-developing Metastases , 2003, Breast Cancer Research and Treatment.

[24]  J E Talmadge,et al.  Evidence for the clonal origin of spontaneous metastases. , 1982, Science.

[25]  D. Johnston,et al.  Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. , 1997, The New England journal of medicine.

[26]  W. Muller,et al.  Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. , 2004, Cancer cell.

[27]  D. Garigan,et al.  Mutations That Increase the Life Span of C. elegans Inhibit Tumor Growth , 2006, Science.

[28]  R. Eils,et al.  From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Scheuermann,et al.  Cancer dormancy. VII. A regulatory role for CD8+ T cells and IFN-gamma in establishing and maintaining the tumor-dormant state. , 1999, Journal of immunology.

[30]  Carlos Cordon-Cardo,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2007, Nature.

[31]  I. Weinstein Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[32]  Z. Estrov,et al.  Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. , 1994, The Journal of clinical investigation.

[33]  C. Garbe,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 , 2001, The British journal of dermatology.

[34]  A. Zetterberg,et al.  Cell-cycle-specific induction of quiescence achieved by limited inhibition of protein synthesis: counteractive effect of addition of purified growth factors. , 1985, Journal of cell science.

[35]  M. Goodell,et al.  A distinct "side population" of cells with high drug efflux capacity in human tumor cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Avruch,et al.  TOR Deficiency in C. elegans Causes Developmental Arrest and Intestinal Atrophy by Inhibition of mRNA Translation , 2002, Current Biology.

[37]  P. Klatt,et al.  Delayed ageing through damage protection by the Arf/p53 pathway , 2007, Nature.

[38]  A. Giuliano,et al.  Most Early Disseminated Cancer Cells Detected in Bone Marrow of Breast Cancer Patients Have a Putative Breast Cancer Stem Cell Phenotype , 2006, Clinical Cancer Research.

[39]  M. Serrano,et al.  The power and the promise of oncogene-induced senescence markers , 2006, Nature Reviews Cancer.

[40]  W. Gerald,et al.  Cyclin D1, a novel molecular marker of minimal residual disease, in metastatic neuroblastoma. , 2007, The Journal of molecular diagnostics : JMD.

[41]  M. Koornneef,et al.  Seed dormancy and germination. , 2002, Current opinion in plant biology.

[42]  P. Pharoah,et al.  Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1 , 2005, Nature Genetics.

[43]  Kunihiro Matsumoto,et al.  The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei , 2005, Mechanisms of Ageing and Development.

[44]  D. Huo,et al.  The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. , 2006, Cancer research.

[45]  J. Aguirre-Ghiso,et al.  Tumor cell dormancy induced by p38SAPK and ER-stress signaling: An adaptive advantage for metastatic cells? , 2006, Cancer biology & therapy.

[46]  C. Larabell,et al.  Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies , 1997, The Journal of cell biology.

[47]  C. Klein,et al.  Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients. , 2001, Seminars in cancer biology.

[48]  J. Folkman Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[49]  J. Uhr,et al.  Cancer dormancy: lessons from a B cell lymphoma and adenocarcinoma of the prostate. , 2007, Advances in cancer research.

[50]  R. Weinberg,et al.  Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. , 2003, Cancer cell.

[51]  K. Garrett,et al.  Cell Cycle Quiescence of Early Lymphoid Progenitors in Adult Bone Marrow , 2006, Stem cells.

[52]  Michael Dean,et al.  Tumour stem cells and drug resistance , 2005, Nature Reviews Cancer.

[53]  Curzio Ruegg,et al.  Anti-angiogenic therapies in cancer: achievements and open questions. , 2007, Bulletin du cancer.

[54]  R. Brakenhoff,et al.  Minimal Residual Disease in Head and Neck Cancer , 2004, Cancer and Metastasis Reviews.

[55]  L. Castilla,et al.  Selection of Early-Occurring Mutations Dictates Hormone-Independent Progressionin Mouse Mammary TumorLines , 2006, Journal of Virology.

[56]  W. Falk,et al.  A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. , 2001, Cancer research.

[57]  L. Ossowski,et al.  EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. , 2002, Cancer cell.

[58]  Kedar S Vaidya,et al.  Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. , 2007, Journal of the National Cancer Institute.

[59]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[60]  A. Kitzis,et al.  Persistence of Transcriptionally Silent BCR-ABL Rearrangements in Chronic Myeloid Leukemia Patients in Sustained Complete Cytogenetic Remission , 2001, Leukemia & lymphoma.

[61]  W. Ellis,et al.  Telomerase activity in disseminated prostate cancer cells , 2006, BJU international.

[62]  O. Finn Human tumor antigens, immunosurveillance, and cancer vaccines , 2006, Immunologic research.

[63]  Stuart K. Kim,et al.  Global analysis of dauer gene expression in Caenorhabditis elegans , 2003, Development.

[64]  S. Rafii,et al.  Preparing the "soil": the premetastatic niche. , 2006, Cancer research.

[65]  R. Demicheli,et al.  Tumour dormancy: findings and hypotheses from clinical research on breast cancer. , 2001, Seminars in cancer biology.

[66]  C. Klein,et al.  Systemic Cancer Progression and Tumor Dormancy: Mathematical Models Meet Single Cell Genomics , 2006, Cell cycle.

[67]  W. Benedict,et al.  Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. , 1999, Science.

[68]  Christopher H. Contag,et al.  MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer , 2004, Nature.

[69]  James M. Roberts,et al.  A New Description of Cellular Quiescence , 2006, PLoS biology.

[70]  K. Weinhold,et al.  The tumor dormant state. Quantitation of L5178Y cells and host immune responses during the establishment and course of dormancy in syngeneic DBA/2 mice , 1979, The Journal of experimental medicine.

[71]  G. Naumov,et al.  Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. , 1999, Journal of cell science.

[72]  A. Zetterberg,et al.  Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[73]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[74]  G. Esposito,et al.  Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[75]  M. Lacroix,et al.  Significance, detection and markers of disseminated breast cancer cells. , 2006, Endocrine-related cancer.

[76]  R. Vessella,et al.  Tumor cell dormancy: An NCI workshop report , 2007, Cancer biology & therapy.

[77]  W. Ellis,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. , 2007, Urologic oncology.

[78]  Brian K Rutt,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 , 2006, Magnetic resonance in medicine.

[79]  G. Schlimok,et al.  Disseminated cytokeratin positive tumor cells in the bone marrow of patients with prostate cancer: detection and prognostic value. , 2001, The Journal of urology.

[80]  Philip Lijnzaad,et al.  An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas , 2005, Nature Genetics.

[81]  Tanja Fehm,et al.  Circulating Tumor Cells in Patients with Breast Cancer Dormancy , 2004, Clinical Cancer Research.

[82]  N. Crawford,et al.  Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer , 2006, Breast Cancer Research.

[83]  G. Naumov,et al.  Solitary cancer cells as a possible source of tumour dormancy? , 2001, Seminars in cancer biology.

[84]  E. Passegué,et al.  Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch , 2006, Proceedings of the National Academy of Sciences.

[85]  R. Vessella,et al.  Detection and characterization of circulating and disseminated prostate cancer cells. , 2007, Frontiers in bioscience : a journal and virtual library.

[86]  R. Marches,et al.  Cancer Dormancy from Mice to Man: A Review , 2006, Cell cycle.

[87]  H. Allgayer,et al.  Urokinase plasminogen activator receptor (uPA-R): one potential characteristic of metastatic phenotypes in minimal residual tumor disease. , 1997, Cancer research.

[88]  G. Semenza Targeting HIF-1 for cancer therapy , 2003, Nature Reviews Cancer.

[89]  J. McCall,et al.  Detection and significance of minimal residual disease in colorectal cancer. , 1999, Histology and histopathology.

[90]  Masashi Narita,et al.  Reversal of human cellular senescence: roles of the p53 and p16 pathways , 2003, The EMBO journal.

[91]  G. Bastert,et al.  Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients , 2001, International journal of cancer.

[92]  D. Theodorescu,et al.  Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application , 2006, Clinical Cancer Research.

[93]  J. Aguirre-Ghiso,et al.  Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. , 2001, Molecular biology of the cell.

[94]  C. Pott,et al.  Significance of Minimal Residual Disease in Lymphoid Malignancies , 2004, Acta Haematologica.

[95]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[96]  A. Fornace,et al.  p38 MAP kinase's emerging role as a tumor suppressor. , 2004, Advances in cancer research.

[97]  P. Beckhove,et al.  Maintenance of long‐term tumour‐specific T‐cell memory by residual dormant tumour cells , 2005, Immunology.

[98]  I. Roninson,et al.  Tumor cell senescence in cancer treatment. , 2003, Cancer research.

[99]  V. Velculescu,et al.  Homozygous deletion of MKK4 in ovarian serous carcinoma , 2006, Cancer biology & therapy.

[100]  D. Miller,et al.  The tumor dormant state. Comparison of L5178Y cells used to establish dormancy with those that emerge after its termination , 1979, The Journal of experimental medicine.

[101]  D J Ferguson,et al.  Dormancy of mammary carcinoma after mastectomy. , 1999, Journal of the National Cancer Institute.

[102]  K. Miura,et al.  Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression , 2006, Nature Medicine.

[103]  S. Groshen,et al.  GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. , 2006, Cancer research.

[104]  V. Robinson,et al.  Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. , 2003, The Journal of urology.

[105]  J. Aguirre-Ghiso,et al.  ERKMAPK Activity as a Determinant of Tumor Growth and Dormancy; Regulation by p38SAPK , 2003 .

[106]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[107]  Stuart K. Kim,et al.  A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. , 2005, Developmental cell.

[108]  P. Steeg Metastasis suppressors alter the signal transduction of cancer cells , 2003, Nature Reviews Cancer.

[109]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[110]  Sally Temple,et al.  Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells , 2004, Science.

[111]  H. Kitano Cancer as a robust system: implications for anticancer therapy , 2004, Nature Reviews Cancer.

[112]  Lewis A. Chodosh,et al.  Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis , 2007, Nature Cell Biology.

[113]  S. Groshen,et al.  Expression of Stress Response Protein Grp78 Is Associated with the Development of Castration-Resistant Prostate Cancer , 2006, Clinical Cancer Research.

[114]  M. Bissell,et al.  Extracellular matrix signaling: integration of form and function in normal and malignant cells. , 1998, Current opinion in cell biology.

[115]  L. Akslen,et al.  Role of Angiogenesis in Human Tumor Dormancy: Animal Models of the Angiogenic Switch , 2006, Cell cycle.

[116]  F. Gounari,et al.  EblacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells. , 1998, Cancer research.

[117]  A. Al-Mehdi,et al.  Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis , 2000, Nature Medicine.

[118]  A. Rougvie,et al.  C. elegans DAF-18/PTEN Mediates Nutrient-Dependent Arrest of Cell Cycle and Growth in the Germline , 2006, Current Biology.

[119]  K. Pantel,et al.  Disseminated tumor cells: diagnosis, prognostic relevance, and phenotyping. , 2001, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[120]  H. Huland,et al.  Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer , 2007, International journal of cancer.

[121]  E. Fuchs,et al.  Defining the Epithelial Stem Cell Niche in Skin , 2004, Science.

[122]  R. Morimoto,et al.  Caenorhabditis elegans OSR-1 Regulates Behavioral and Physiological Responses to Hyperosmotic Environments , 2004, Genetics.

[123]  Sanjay Shete,et al.  uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues , 2006, Proceedings of the National Academy of Sciences.

[124]  J. Izbicki,et al.  Minimal residual disease in non-small-cell lung cancer. , 2001, Seminars in surgical oncology.

[125]  H. Allgayer,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. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[126]  K. Hunter,et al.  Host genetics influence tumour metastasis , 2006, Nature Reviews Cancer.

[127]  A. Matsuzawa,et al.  Survival of leukemic cells in a dormant state following cyclophosphamide‐induced cure of strongly immunogenic mouse leukemia (DL811) , 1991, International journal of cancer.

[128]  L. Ossowski,et al.  Tumor Dormancy Induced by Downregulation of Urokinase Receptor in Human Carcinoma Involves Integrin and MAPK Signaling , 1999, The Journal of cell biology.

[129]  David Zurakowski,et al.  A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. , 2006, Journal of the National Cancer Institute.

[130]  G. Lozano,et al.  Differential roles of p21(Waf1) and p27(Kip1) in modulating chemosensitivity and their possible application in drug discovery studies. , 2001, Molecular pharmacology.

[131]  G. Naumov,et al.  Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. , 2002, Cancer research.