Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment

Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies.

[1]  Simon Kasif,et al.  An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. , 2013, Cell reports.

[2]  Martin J. Aryee,et al.  DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases , 2013, Science Translational Medicine.

[3]  M. Lynch.  Evolution of the mutation rate. , 2010, Trends in genetics : TIG.

[4]  S. Al-Sarraj,et al.  Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. , 2012, Cancer research.

[5]  J. Woźniak,et al.  C‐Kit receptor (CD117) expression on myeloblasts and white blood cell counts in acute myeloid leukemia , 2004, Cytometry. Part B, Clinical cytometry.

[6]  R. Gillies,et al.  Evolutionary dynamics of carcinogenesis and why targeted therapy does not work , 2012, Nature Reviews Cancer.

[7]  Rebecca A Betensky,et al.  Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. , 2011, Cancer cell.

[8]  Y. Maehara,et al.  Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer , 2010, Clinical Cancer Research.

[9]  P. Sorger,et al.  Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis , 2009, Nature.

[10]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[11]  K. Illmensee,et al.  Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Nikkhah,et al.  Stem Cell Biology , 2015, Biomarker insights.

[13]  I. Fidler,et al.  Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. , 2007, The American journal of pathology.

[14]  John G. Albeck,et al.  Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. , 2013, Molecular cell.

[15]  G. Nolan,et al.  K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. , 2007, Blood.

[16]  L. Skoog,et al.  Flow cytometric immunophenotyping including Bcl‐2 detection on fine needle aspirates in the diagnosis of reactive lymphadenopathy and non‐Hodgkin's lymphoma , 2005, Cytometry. Part B, Clinical cytometry.

[17]  Dai Fukumura,et al.  Tumor Microvasculature and Microenvironment: Novel Insights Through Intravital Imaging in Pre‐Clinical Models , 2010, Microcirculation.

[18]  Jonathan M Irish,et al.  Single Cell Profiling of Potentiated Phospho-Protein Networks in Cancer Cells , 2004, Cell.

[19]  A. Feinberg,et al.  Increased methylation variation in epigenetic domains across cancer types , 2011, Nature Genetics.

[20]  R. Weinberg,et al.  Cell plasticity and heterogeneity in cancer. , 2013, Clinical chemistry.

[21]  A. Oudenaarden,et al.  Cellular Decision Making and Biological Noise: From Microbes to Mammals , 2011, Cell.

[22]  Qinghua Zhou,et al.  Detection and Clinical Significance of Intratumoral EGFR Mutational Heterogeneity in Chinese Patients with Advanced Non-Small Cell Lung Cancer , 2013, PloS one.

[23]  M. Gönen,et al.  Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. , 2010, The Journal of clinical investigation.

[24]  L. Ricci-Vitiani,et al.  Identification and expansion of human colon-cancer-initiating cells , 2007, Nature.

[25]  N. McGranahan,et al.  Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. , 2015, Cancer cell.

[26]  Mark J. Ratain,et al.  Tumour heterogeneity in the clinic , 2013, Nature.

[27]  Charles Swanton,et al.  Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine , 2014, Genome Biology.

[28]  Peter W. Laird,et al.  Interplay between the Cancer Genome and Epigenome , 2013, Cell.

[29]  Flow cytometric quantification of cyclin E in human cell lines and hematopoietic malignancies. , 1998, Cytometry.

[30]  C. Zahnow,et al.  The future of epigenetic therapy in solid tumours—lessons from the past , 2013, Nature Reviews Clinical Oncology.

[31]  Sandy L. Klemm,et al.  Single-Cell Expression Analyses during Cellular Reprogramming Reveal an Early Stochastic and a Late Hierarchic Phase , 2012, Cell.

[32]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[33]  Jianguo Wu,et al.  Hypoxia Induces Genomic DNA Demethylation through the Activation of HIF-1α and Transcriptional Upregulation of MAT2A in Hepatoma Cells , 2011, Molecular Cancer Therapeutics.

[34]  A. Harris,et al.  HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. , 2005, Molecular cell.

[35]  M. Brattain,et al.  Selective protein phosphorylation in heterogeneous subpopulations of human colon carcinoma cells. , 1985, Cancer research.

[36]  Kazuhiro Aoki,et al.  Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation. , 2013, Molecular cell.

[37]  R. B. Campbell,et al.  In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy , 2001, Nature Medicine.

[38]  I. Bayazitov,et al.  A perivascular niche for brain tumor stem cells. , 2007, Cancer cell.

[39]  J. Andersen,et al.  Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases , 2007, Breast Cancer Research and Treatment.

[40]  Ash A. Alizadeh,et al.  B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression , 2010, Proceedings of the National Academy of Sciences.

[41]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[42]  S. Quezada,et al.  Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer , 2013, British Journal of Cancer.

[43]  Jeffrey W. Smith,et al.  Stochastic Gene Expression in a Single Cell , 2022 .

[44]  J. Dick,et al.  A human colon cancer cell capable of initiating tumour growth in immunodeficient mice , 2007, Nature.

[45]  M. Stratton,et al.  Clinical and biological implications of driver mutations in myelodysplastic syndromes. , 2013, Blood.

[46]  Scott D. Brown,et al.  Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival , 2014, Genome research.

[47]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[48]  H. Sasaki,et al.  Intra-tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas. , 2015, Experimental and therapeutic medicine.

[49]  N. Reich,et al.  Nuclear trafficking of STAT proteins visualized by live cell imaging. , 2013, Methods in molecular biology.

[50]  T. Mitsudomi,et al.  Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer , 2012, Molecular Cancer Therapeutics.

[51]  B. Huntly,et al.  Recent advances in acute myeloid leukemia stem cell biology , 2012, Haematologica.

[52]  J. Issa,et al.  The epigenome of AML stem and progenitor cells , 2013, Epigenetics.

[53]  A. Børresen-Dale,et al.  The Life History of 21 Breast Cancers , 2012, Cell.

[54]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[55]  Seyed E. Hasnain,et al.  Extensive Intra-tumor Heterogeneity in Primary Human Glial Tumors as a Result of Locus Non-specific Genomic Alterations , 2000, Journal of Neuro-Oncology.

[56]  M. Oyama,et al.  Detection of the Heterogeneous O-Glycosylation Profile of MT1-MMP Expressed in Cancer Cells by a Simple MALDI-MS Method , 2012, PloS one.

[57]  S. Tavaré,et al.  Investigating stem cells in human colon by using methylation patterns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Nikolaus Rajewsky,et al.  Modeling the Initiation and Progression of Human Acute Leukemia in Mice , 2022 .

[59]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[60]  S. Morrison,et al.  Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution , 2009, Cell.

[61]  D. Lipsker,et al.  Single-cell gene expression signatures reveal melanoma cell heterogeneity , 2014, Oncogene.

[62]  J. C. Love,et al.  EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. , 2014, Cancer discovery.

[63]  S. Morrison,et al.  Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. , 2010, Cancer cell.

[64]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[65]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[66]  P. A. Futreal,et al.  Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing , 2014, Nature Genetics.

[67]  Mark Cobbold,et al.  Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study , 2014, PLoS biology.

[68]  H. Moch,et al.  Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. , 2011, Cancer research.

[69]  M. Andreeff,et al.  Cellular ras oncogene expression and cell cycle measured by flow cytometry in hematopoietic cell lines. , 1986, Blood.

[70]  Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. , 1999, Blood.

[71]  Yoshitaka Narita,et al.  Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. , 2010, Genes & development.

[72]  Robin L. Jones,et al.  Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. , 2014, Cell reports.

[73]  E. Mroz,et al.  Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas , 2015, PLoS medicine.

[74]  S. Baylin,et al.  Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. , 2014, Molecular cell.

[75]  M. Elowitz,et al.  Functional Roles of Pulsing in Genetic Circuits , 2013, Science.

[76]  Franziska Michor,et al.  In situ single cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2+ breast cancer , 2015, Nature Genetics.

[77]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[78]  J. Piehler,et al.  Live cell micropatterning reveals the dynamics of signaling complexes at the plasma membrane , 2014, The Journal of cell biology.

[79]  H. O’Hagan,et al.  Chromatin modifications during repair of environmental exposure‐induced DNA damage: A potential mechanism for stable epigenetic alterations , 2014, Environmental and molecular mutagenesis.

[80]  F. Mannello.  Understanding breast cancer stem cell heterogeneity: time to move on to a new research paradigm , 2013, BMC Medicine.

[81]  J. Visvader,et al.  Cancer stem cells in solid tumours: accumulating evidence and unresolved questions , 2008, Nature Reviews Cancer.

[82]  Sabrina L. Spencer,et al.  The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit , 2013, Cell.

[83]  Jacob J. Hughey,et al.  High-Sensitivity Measurements of Multiple Kinase Activities in Live Single Cells , 2014, Cell.

[84]  A. Oudenaarden,et al.  Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences , 2008, Cell.

[85]  R. Bataille,et al.  Phenotypic characterization of the human myeloma cell growth fraction. , 2005, Blood.

[86]  Irving L. Weissman,et al.  Human Melanoma Initiating Cells Express Neural Crest Nerve Growth Factor Receptor CD271 , 2010, Nature.

[87]  Lani F. Wu,et al.  Patterns of basal signaling heterogeneity can distinguish cellular populations with different drug sensitivities , 2010, Molecular systems biology.

[88]  H. Kantarjian,et al.  Acute myeloid leukemia , 2018, Methods in Molecular Biology.

[89]  B. Vogelstein,et al.  Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. , 1986, The New England journal of medicine.

[90]  Dario R Alessi,et al.  Kinase drug discovery--what's next in the field? , 2013, ACS chemical biology.

[91]  B. Al-Lazikani,et al.  Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance , 2012, Clinical pharmacology and therapeutics.

[92]  Corbin E. Meacham,et al.  Tumour heterogeneity and cancer cell plasticity , 2013, Nature.

[93]  Guy S. Salvesen,et al.  SnapShot: Caspases , 2011, Cell.

[94]  M. Thattai,et al.  Attenuation of noise in ultrasensitive signaling cascades. , 2002, Biophysical journal.

[95]  Yu Cao,et al.  Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing , 2014, Science.

[96]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[97]  Andrew Menzies,et al.  Subclonal diversification of primary breast cancer revealed by multiregion sequencing , 2015, Nature Medicine.

[98]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[99]  S. Schnitt,et al.  Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines , 2010, Breast Cancer Research.

[100]  Tobias Meyer,et al.  A polarized Ca2+, diacylglycerol, and STIM1 signaling system regulates directed cell migration , 2014, Nature Cell Biology.

[101]  Z. Szallasi,et al.  Spatial and temporal diversity in genomic instability processes defines lung cancer evolution , 2014, Science.

[102]  A. Harris,et al.  HIF-1α Induces Genetic Instability by Transcriptionally Downregulating MutSα Expression , 2005 .

[103]  Lani F. Wu,et al.  Image-based multivariate profiling of drug responses from single cells , 2007, Nature Methods.

[104]  M. Borowitz,et al.  A clinically relevant population of leukemic CD34(+)CD38(-) cells in acute myeloid leukemia. , 2012, Blood.

[105]  Debyani Chakravarty,et al.  Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response , 2012, Proceedings of the National Academy of Sciences.

[106]  Michael B. Elowitz,et al.  Dynamic Heterogeneity and DNA Methylation in Embryonic Stem Cells , 2014, Molecular cell.

[107]  Stephen S. Taylor,et al.  Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. , 2008, Cancer cell.

[108]  Jonathan M Irish,et al.  Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. , 2008, Cancer cell.

[109]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[110]  K. Cibulskis,et al.  Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. , 2014, Blood.

[111]  A. Gulsvik,et al.  Quantitation of biological tumor markers (p53, c‐myc, Ki‐67 and DNA ploidy) by multiparameter flow cytometry in non‐small‐cell lung cancer , 1992, International journal of cancer.

[112]  Samra Turajlic,et al.  BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells by Reactivating MEK and ERK Signaling , 2014, Science Signaling.