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PMID: 22513401 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Intra-tumour heterogeneity: a looking glass for cancer?

Nature reviews. Cancer ·Vol. 12 ·No. 5 ·2012-04-19 ·Pages 323-34

Marusyk A, Almendro V, Polyak K

Abstract

Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance.

MeSH Terms
Animals Epigenesis, Genetic Gene Expression Regulation, Neoplastic Genetic Heterogeneity Humans Neoplasms/diagnosis,genetics,therapy Phenotype
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Marusyk Andriy
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston MA 02215, USA.
Almendro Vanessa
Polyak Kornelia
References (101)
101 references, click to expand
  1. The role of genetic diversity in cancer.
    J Clin Invest. 2010 Feb;120(2):401-3 PMID: 20101092
  2. Problems in histological grading of malignancy and its clinical significance in patients with operable breast cancer.
    Breast Cancer. 2006;13(3):249-253 PMID: 16929117
  3. Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
    Nature. 2010 Oct 28;467(7319):1114-7 PMID: 20981102
  4. Non-genetic cell-to-cell variability and the consequences for pharmacology.
    Curr Opin Chem Biol. 2009 Dec;13(5-6):556-61 PMID: 19833543
  5. Single-cell dissection of transcriptional heterogeneity in human colon tumors.
    Nat Biotechnol. 2011 Nov 13;29(12):1120-7 PMID: 22081019
  6. Tumors as organs: complex tissues that interface with the entire organism.
    Dev Cell. 2010 Jun 15;18(6):884-901 PMID: 20627072
  7. Functional roles for noise in genetic circuits.
    Nature. 2010 Sep 9;467(7312):167-73 PMID: 20829787
  8. HSP90 and the chaperoning of cancer.
    Nat Rev Cancer. 2005 Oct;5(10):761-72 PMID: 16175177
  9. Breast tumor heterogeneity: cancer stem cells or clonal evolution?
    Cell Cycle. 2007 Oct 1;6(19):2332-8 PMID: 17786053
  10. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.
    Cancer Cell. 2011 Dec 13;20(6):810-7 PMID: 22137795
  11. Efficient tumour formation by single human melanoma cells.
    Nature. 2008 Dec 4;456(7222):593-8 PMID: 19052619
  12. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer.
    Cancer Res. 2005 Oct 15;65(20):9155-8 PMID: 16230372
  13. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
    Cancer Cell. 2009 Mar 3;15(3):232-9 PMID: 19249681
  14. Cancer genomics identifies determinants of tumor biology.
    Genome Biol. 2010;11(5):211 PMID: 20441611
  15. Insight into the heterogeneity of breast cancer through next-generation sequencing.
    J Clin Invest. 2011 Oct;121(10):3810-8 PMID: 21965338
  16. Tumor stroma and regulation of cancer development.
    Annu Rev Pathol. 2006;1:119-50 PMID: 18039110
  17. Cancer as an evolutionary and ecological process.
    Nat Rev Cancer. 2006 Dec;6(12):924-35 PMID: 17109012
  18. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.
    Cell. 2006 Dec 1;127(5):905-15 PMID: 17129778
  19. Dynamic proteomics of individual cancer cells in response to a drug.
    Science. 2008 Dec 5;322(5907):1511-6 PMID: 19023046
  20. Heterogeneity maintenance in glioblastoma: a social network.
    Cancer Res. 2011 Jun 15;71(12):4055-60 PMID: 21628493
  21. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma.
    Nat Rev Cancer. 2003 Jun;3(6):411-21 PMID: 12778131
  22. Cellular decision making and biological noise: from microbes to mammals.
    Cell. 2011 Mar 18;144(6):910-25 PMID: 21414483
  23. Tumor heterogeneity: causes and consequences.
    Biochim Biophys Acta. 2010 Jan;1805(1):105-17 PMID: 19931353
  24. A molecular signature of metastasis in primary solid tumors.
    Nat Genet. 2003 Jan;33(1):49-54 PMID: 12469122
  25. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia.
    Science. 2008 Nov 28;322(5906):1377-80 PMID: 19039135
  26. Parallel progression of primary tumours and metastases.
    Nat Rev Cancer. 2009 Apr;9(4):302-12 PMID: 19308069
  27. Cellular heterogeneity: do differences make a difference?
    Cell. 2010 May 14;141(4):559-63 PMID: 20478246
  28. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus.
    Gut. 2008 Aug;57(8):1041-8 PMID: 18305067
  29. Genetic clonal diversity predicts progression to esophageal adenocarcinoma.
    Nat Genet. 2006 Apr;38(4):468-73 PMID: 16565718
  30. Normalization of the vasculature for treatment of cancer and other diseases.
    Physiol Rev. 2011 Jul;91(3):1071-121 PMID: 21742796
  31. Genetic variegation of clonal architecture and propagating cells in leukaemia.
    Nature. 2011 Jan 20;469(7330):356-61 PMID: 21160474
  32. Molecular characterization of the tumor microenvironment in breast cancer.
    Cancer Cell. 2004 Jul;6(1):17-32 PMID: 15261139
  33. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.
    Nature. 2010 Dec 16;468(7326):973-7 PMID: 21107323
  34. Non-genetic heterogeneity of cells in development: more than just noise.
    Development. 2009 Dec;136(23):3853-62 PMID: 19906852
  35. Evolutionary theory of cancer.
    Ann N Y Acad Sci. 2009 Jun;1168:23-51 PMID: 19566702
  36. Genome remodelling in a basal-like breast cancer metastasis and xenograft.
    Nature. 2010 Apr 15;464(7291):999-1005 PMID: 20393555
  37. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype.
    J Clin Invest. 2010 Feb;120(2):636-44 PMID: 20101094
  38. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer.
    Clin Cancer Res. 2010 Feb 1;16(3):876-87 PMID: 20103682
  39. Stromal gene expression predicts clinical outcome in breast cancer.
    Nat Med. 2008 May;14(5):518-27 PMID: 18438415
  40. Cancer genes and the pathways they control.
    Nat Med. 2004 Aug;10(8):789-99 PMID: 15286780
  41. Tumor self-seeding by circulating cancer cells.
    Cell. 2009 Dec 24;139(7):1315-26 PMID: 20064377
  42. Molecular definition of breast tumor heterogeneity.
    Cancer Cell. 2007 Mar;11(3):259-73 PMID: 17349583
  43. Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis.
    Int J Cancer. 2010 Feb 1;126(3):589-98 PMID: 19795462
  44. The increasing complexity of the cancer stem cell paradigm.
    Science. 2009 Jun 26;324(5935):1670-3 PMID: 19556499
  45. Species- and cell type-specific requirements for cellular transformation.
    Cancer Cell. 2004 Aug;6(2):171-83 PMID: 15324700
  46. Histone deacetylase inhibitors: discovery and development as anticancer agents.
    Expert Opin Investig Drugs. 2005 Dec;14(12):1497-511 PMID: 16307490
  47. Principles of cancer therapy: oncogene and non-oncogene addiction.
    Cell. 2009 Mar 6;136(5):823-37 PMID: 19269363
  48. The cancer stem cell: premises, promises and challenges.
    Nat Med. 2011 Mar;17(3):313-9 PMID: 21386835
  49. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
    Cancer Cell. 2009 Mar 3;15(3):220-31 PMID: 19249680
  50. Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution.
    Clin Cancer Res. 2008 Jan 15;14(2):370-8 PMID: 18223211
  51. A genetic model for colorectal tumorigenesis.
    Cell. 1990 Jun 1;61(5):759-67 PMID: 2188735
  52. Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes.
    Cold Spring Harb Symp Quant Biol. 2005;70:343-56 PMID: 16869771
  53. The epigenomics of cancer.
    Cell. 2007 Feb 23;128(4):683-92 PMID: 17320506
  54. Genetic interactions in cancer progression and treatment.
    Cell. 2011 Apr 1;145(1):30-8 PMID: 21458666
  55. Advancing a clinically relevant perspective of the clonal nature of cancer.
    Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12054-9 PMID: 21730190
  56. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells.
    Nature. 2011 Jan 20;469(7330):362-7 PMID: 21248843
  57. A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma.
    Cancer Prev Res (Phila). 2010 Nov;3(11):1388-97 PMID: 20947487
  58. Non-genetic heterogeneity--a mutation-independent driving force for the somatic evolution of tumours.
    Nat Rev Genet. 2009 May;10(5):336-42 PMID: 19337290
  59. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.
    Nat Med. 2009 Jan;15(1):68-74 PMID: 19122658
  60. Tumor subpopulation interactions affecting melphalan sensitivity in palpable mouse mammary tumors.
    Cancer Res. 1991 Aug 15;51(16):4378-87 PMID: 1868461
  61. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.
    Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5 PMID: 21498687
  62. Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm.
    Cell. 2012 Mar 2;148(5):873-85 PMID: 22385957
  63. A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia.
    N Engl J Med. 2003 May 29;348(22):2265-6 PMID: 12773665
  64. Inferring tumor progression from genomic heterogeneity.
    Genome Res. 2010 Jan;20(1):68-80 PMID: 19903760
  65. Colorectal adenoma and cancer divergence. Evidence of multilineage progression.
    Am J Pathol. 1999 Jun;154(6):1815-24 PMID: 10362806
  66. Tumor heterogeneity and the biology of cancer invasion and metastasis.
    Cancer Res. 1978 Sep;38(9):2651-60 PMID: 354778
  67. Matrix metalloproteinase-induced genomic instability.
    Curr Opin Genet Dev. 2006 Feb;16(1):45-50 PMID: 16377172
  68. Clinical implementation of the intrinsic subtypes of breast cancer.
    Lancet Oncol. 2010 Aug;11(8):718-9; author reply 720-1 PMID: 20688274
  69. The clonal evolution of tumor cell populations.
    Science. 1976 Oct 1;194(4260):23-8 PMID: 959840
  70. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer.
    Cancer Cell. 2011 Feb 15;19(2):244-56 PMID: 21316603
  71. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis.
    Nature. 2009 May 21;459(7245):428-32 PMID: 19363473
  72. Chromatin modifiers and carcinogenesis.
    Trends Cell Biol. 2004 Dec;14(12):695-702 PMID: 15564046
  73. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.
    Nat Med. 2011 Mar;17(3):320-9 PMID: 21383745
  74. Epigenetics as a mechanism driving polygenic clinical drug resistance.
    Br J Cancer. 2006 Apr 24;94(8):1087-92 PMID: 16495912
  75. Nature, nurture, or chance: stochastic gene expression and its consequences.
    Cell. 2008 Oct 17;135(2):216-26 PMID: 18957198
  76. Tumour evolution inferred by single-cell sequencing.
    Nature. 2011 Apr 7;472(7341):90-4 PMID: 21399628
  77. Environment-mediated drug resistance: a major contributor to minimal residual disease.
    Nat Rev Cancer. 2009 Sep;9(9):665-74 PMID: 19693095
  78. Resistance to therapy caused by intragenic deletion in BRCA2.
    Nature. 2008 Feb 28;451(7182):1111-5 PMID: 18264088
  79. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
    Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 PMID: 11553815
  80. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor.
    Cell. 2012 Mar 2;148(5):886-95 PMID: 22385958
  81. Cancer cell societies and tumor progression.
    Stem Cells. 1993 May;11(3):199-203 PMID: 8318906
  82. Heterogeneity in cancer: cancer stem cells versus clonal evolution.
    Cell. 2009 Sep 4;138(5):822-9 PMID: 19737509
  83. The speed of evolution and maintenance of variation in asexual populations.
    Curr Biol. 2007 Mar 6;17(5):385-94 PMID: 17331728
  84. Genome-wide mutational diversity in an evolving population of Escherichia coli.
    Cold Spring Harb Symp Quant Biol. 2009;74:119-29 PMID: 19776167
  85. Functional discovery via a compendium of expression profiles.
    Cell. 2000 Jul 7;102(1):109-26 PMID: 10929718
  86. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.
    Nature. 2008 Feb 28;451(7182):1116-20 PMID: 18264087
  87. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
    Science. 2007 May 18;316(5827):1039-43 PMID: 17463250
  88. Solving the puzzle of metastasis: the evolution of cell migration in neoplasms.
    PLoS One. 2011 Apr 27;6(4):e17933 PMID: 21556134
  89. Resistance to imatinib: mechanisms and management.
    J Natl Compr Canc Netw. 2005 Nov;3(6):757-68 PMID: 16316612
  90. Accumulation of driver and passenger mutations during tumor progression.
    Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18545-50 PMID: 20876136
  91. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits.
    Nat Rev Cancer. 2009 Apr;9(4):265-73 PMID: 19262571
  92. Breast cancer - one term, many entities?
    J Clin Invest. 2011 Oct;121(10):3789-96 PMID: 21965335
  93. Evolved tumor suppression: why are we so good at not getting cancer?
    Cancer Res. 2011 Jun 1;71(11):3739-44 PMID: 21610109
  94. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors.
    Nat Rev Drug Discov. 2009 Sep;8(9):709-23 PMID: 19629074
  95. Filtering transcriptional noise during development: concepts and mechanisms.
    Nat Rev Genet. 2006 Jan;7(1):34-44 PMID: 16369570
  96. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.
    Nature. 2009 Oct 8;461(7265):809-13 PMID: 19812674
  97. Metapopulation dynamics and spatial heterogeneity in cancer.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13085-9 PMID: 12351679
  98. Cellular identity and lineage choice.
    Nat Rev Immunol. 2002 Dec;2(12):977-82 PMID: 12461570
  99. Clonal evolution in cancer.
    Nature. 2012 Jan 18;481(7381):306-13 PMID: 22258609
  100. Molecular pathobiology of gastrointestinal stromal sarcomas.
    Annu Rev Pathol. 2008;3:557-86 PMID: 18039140
  101. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.
    Nature. 2012 Jan 11;481(7382):506-10 PMID: 22237025
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc3261
Published
2012-04-19
Epub
2012-00-19
Pages
323-34
Language
English
Region
England
NLM ID
101124168
Subset
IM
Grants
NCI NIH HHS · P01 CA80111 · United States
External Links
PubMed source DOI: 10.1038/nrc3261 View journal details
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