Circulating tumor cells: approaches to isolation and characterization

Circulating tumor cells (CTCs) shed from primary and metastatic cancers are admixed with blood components and are thus rare, making their isolation and characterization a major technological challenge. CTCs hold the key to understanding the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor genotypes during treatment and disease progression. Improvements in technologies to yield purer CTC populations amenable to better cellular and molecular characterization will enable a broad range of clinical applications, including early detection of disease and the discovery of biomarkers to predict treatment responses and disease progression.

[1]  John Calvin Reed,et al.  Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. , 2005, Cancer research.

[2]  S WATANABE,et al.  The metastasizability of tumor cells , 1954, Cancer.

[3]  L. Terstappen,et al.  Characterization of circulating tumor cells by fluorescence in situ hybridization , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[4]  G. T. Budd,et al.  Circulating Tumor Cells at Each Follow-up Time Point during Therapy of Metastatic Breast Cancer Patients Predict Progression-Free and Overall Survival , 2006, Clinical Cancer Research.

[5]  Tanja Fehm,et al.  HER-2 gene amplification can be acquired as breast cancer progresses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  W. Gerald,et al.  Detection of circulating tumor cells in patients with localized and metastatic prostatic carcinoma: clinical implications. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Chalmers,et al.  Application of immunomagnetic cell enrichment in combination with RT‐PCR for the detection of rare circulating head and neck tumor cells in human peripheral blood , 2007, Cytometry. Part B, Clinical cytometry.

[8]  Sabine Kasimir-Bauer,et al.  Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies , 2009, Breast Cancer Research and Treatment.

[9]  Jonathan W. Uhr,et al.  Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but not in Healthy Subjects or Patients With Nonmalignant Diseases , 2004, Clinical Cancer Research.

[10]  A. Chambers,et al.  Detection and quantification of circulating tumor cells in mouse models of human breast cancer using immunomagnetic enrichment and multiparameter flow cytometry , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[11]  Swee Jin Tan,et al.  Microdevice for the isolation and enumeration of cancer cells from blood , 2009, Biomedical microdevices.

[12]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[13]  Siyang Zheng,et al.  Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. , 2007, Journal of chromatography. A.

[14]  Alison Stopeck,et al.  Circulating tumor cells, disease progression, and survival in metastatic breast cancer. , 2004, The New England journal of medicine.

[15]  D. Dearnaley,et al.  Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. , 2009, Cancer research.

[16]  K. Yoon,et al.  Comparison of circulating plasma DNA levels between lung cancer patients and healthy controls. , 2009, The Journal of molecular diagnostics : JMD.

[17]  Tanja Fehm,et al.  Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  Hai Lu,et al.  Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase. , 2004, The Journal of biological chemistry.

[19]  L. Weiner,et al.  Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer. , 2006, Clinical colorectal cancer.

[20]  K. Dardoufas,et al.  Cell‐free DNA and RNA in Plasma as a New Molecular Marker for Prostate and Breast Cancer , 2006, Annals of the New York Academy of Sciences.

[21]  D. Dearnaley,et al.  Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  G. Hu,et al.  Epithelial-mesenchymal transition and cell cooperativity in metastasis. , 2009, Cancer research.

[23]  J. Pierga,et al.  Detection of MUC1-expressing mammary carcinoma cells in the peripheral blood of breast cancer patients by real-time polymerase chain reaction. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  G. Sauter,et al.  Changes in Cytoskeletal Protein Composition Indicative of an Epithelial-Mesenchymal Transition in Human Micrometastatic and Primary Breast Carcinoma Cells , 2005, Clinical Cancer Research.

[25]  Katharina Pachmann,et al.  Standardized quantification of circulating peripheral tumor cells from lung and breast cancer , 2005, Clinical chemistry and laboratory medicine.

[26]  L. Kiesel,et al.  HER2-Positive Circulating Tumor Cells Indicate Poor Clinical Outcome in Stage I to III Breast Cancer Patients , 2006, Clinical Cancer Research.

[27]  M. Tan,et al.  The significance of circulating epithelial cells in Breast Cancer patients by a novel negative selection method , 2008, Breast Cancer Research and Treatment.

[28]  G. Assmann,et al.  Isolation of prostate-derived single cells and cell clusters from human peripheral blood. , 1996, Cancer research.

[29]  N. Brousse,et al.  Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence. , 2000, The Journal of urology.

[30]  M. Golightly,et al.  Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients , 2010, International journal of cancer.

[31]  D. Glaves Correlation between circulating cancer cells and incidence of metastases. , 1983, British Journal of Cancer.

[32]  I. Fidler The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. , 1973, European journal of cancer.

[33]  J. Pierga,et al.  Detection of MUC 1-expressing Mammary Carcinoma Cells in the Peripheral Blood of Breast Cancer Patients by Real-Time Polymerase Chain Reaction 1 , 2000 .

[34]  T. Godfrey,et al.  Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers. , 2007, Clinical chemistry.

[35]  C. Bréchot,et al.  Spontaneous and iatrogenic spreading of liver‐derived cells into peripheral blood of patients with primary liver cancer , 1997, Hepatology.

[36]  K. Pienta,et al.  Apoptosis of circulating tumor cells in prostate cancer patients , 2004, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[37]  L. Liotta,et al.  Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. , 1974, Cancer research.

[38]  Yvonne A. Evrard,et al.  Monitoring Drug-Induced γH2AX as a Pharmacodynamic Biomarker in Individual Circulating Tumor Cells , 2010, Clinical Cancer Research.

[39]  Peter Kuhn,et al.  A rare-cell detector for cancer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Mark M Davis,et al.  Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device , 2009, Proceedings of the National Academy of Sciences.

[41]  J. Chalmers,et al.  Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. , 2009, Molecular pharmaceutics.

[42]  K. Pantel,et al.  Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer , 2009, Clinical Cancer Research.

[43]  G. Hu,et al.  Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. , 2008, Cancer research.

[44]  A. Hart,et al.  Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients , 2003, British Journal of Cancer.

[45]  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.

[46]  E. Higashihara,et al.  Prognostic significance of circulating tumor cells in patients with hormone refractory prostate cancer. , 2009, The Journal of urology.

[47]  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.

[48]  A. Órfão,et al.  Evaluation of multiparameter flow cytometry for the detection of breast cancer tumor cells in blood samples. , 2005, American journal of clinical pathology.

[49]  A. Goldhirsch,et al.  Modeling the relationship between circulating tumour cells number and prognosis of metastatic breast cancer , 2010, Breast Cancer Research and Treatment.

[50]  Thomas Kelly,et al.  In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. , 2009, Nature nanotechnology.

[51]  K. Schütze,et al.  Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulatingtumor cells. , 2000, The American journal of pathology.

[52]  Leon W.M.M. Terstappen,et al.  Circulating Tumor Cells versus Imaging—Predicting Overall Survival in Metastatic Breast Cancer , 2006, Clinical Cancer Research.

[53]  W. Holzgreve,et al.  Positive correlation of cell-free DNA in plasma/serum in patients with malignant and benign breast disease. , 2008, Anticancer research.

[54]  M. Slijper,et al.  Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer , 2009, Breast Cancer Research.

[55]  Hai Lu,et al.  Squamous Cell Carcinoma Cell Aggregates Escape Suspension-induced, p53-mediated Anoikis , 2004, Journal of Biological Chemistry.

[56]  Francisco M. De La Vega,et al.  Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing , 2010, Science Translational Medicine.

[57]  Caroline Dive,et al.  Tumorigenesis and Neoplastic Progression Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy , 2010 .

[58]  K. Pienta,et al.  Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. , 2003, Cancer research.

[59]  J. Uhr,et al.  Circulating tumor cells in breast cancer: fiction or reality? , 2008, Journal of Clinical Oncology.

[60]  Larry Norton,et al.  Tumor Self-Seeding by Circulating Cancer Cells , 2009, Cell.

[61]  C. Sotiriou,et al.  Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[63]  P. Billings,et al.  Circulating tumor cells are transcriptionally similar to the primary tumor in a murine prostate model. , 2009, Cancer research.

[64]  Thomas Rau,et al.  Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity , 2005, Clinical Cancer Research.

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

[66]  J. Nieva,et al.  Case study of the morphologic variation of circulating tumor cells. , 2007, Human pathology.

[67]  Glenn Heller,et al.  Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer , 2007, Clinical Cancer Research.

[68]  L. Liotta,et al.  The significance of hematogenous tumor cell clumps in the metastatic process. , 1976, Cancer research.

[69]  Mehmet Toner,et al.  Isolation and Characterization of Circulating Tumor Cells from Patients with Localized and Metastatic Prostate Cancer , 2010, Science Translational Medicine.

[70]  Mieke Schutte,et al.  Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal-Like Breast Tumor Cells , 2009, Journal of the National Cancer Institute.

[71]  P. Vineis,et al.  Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. , 2007, Mutation research.

[72]  Mehmet Toner,et al.  Detection of mutations in EGFR in circulating lung-cancer cells. , 2008, The New England journal of medicine.

[73]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[74]  James N Turner,et al.  Isolation of tumor cells using size and deformation. , 2009, Journal of chromatography. A.

[75]  P. Hainaut,et al.  Detection of p53 codon 249 mutation in Nigerian patients with hepatocellular carcinoma using a novel evaluation of cell-free DNA. , 2008, Annals of hepatology.

[76]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[77]  J. Chalmers,et al.  Optimization of an enrichment process for circulating tumor cells from the blood of head and neck cancer patients through depletion of normal cells , 2009, Biotechnology and bioengineering.

[78]  S. Digumarthy,et al.  Isolation of rare circulating tumour cells in cancer patients by microchip technology , 2007, Nature.

[79]  Anne Vincent-Salomon,et al.  Circulating Tumor Cell Detection Predicts Early Metastatic Relapse After Neoadjuvant Chemotherapy in Large Operable and Locally Advanced Breast Cancer in a Phase II Randomized Trial , 2008, Clinical Cancer Research.

[80]  Brigitte Rack,et al.  Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System , 2007, Clinical Cancer Research.

[81]  J. Uhr,et al.  Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer. , 2002, International journal of oncology.

[82]  R. Eils,et al.  Systemic spread is an early step in breast cancer. , 2008, Cancer cell.

[83]  K. Isselbacher,et al.  Isolation of circulating tumor cells using a microvortex-generating herringbone-chip , 2010, Proceedings of the National Academy of Sciences.

[84]  Sabine Riethdorf,et al.  Detection and characterization of putative metastatic precursor cells in cancer patients. , 2007, Clinical chemistry.

[85]  G. Kallergi,et al.  Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients , 2008, Breast Cancer Research.

[86]  Jaw-Yuan Wang,et al.  Development of a high‐throughput membrane‐array method for molecular diagnosis of circulating tumor cells in patients with gastric cancers , 2006, International journal of cancer.

[87]  Vladimir P Zharov,et al.  In vivo, noninvasive, label-free detection and eradication of circulating metastatic melanoma cells using two-color photoacoustic flow cytometry with a diode laser. , 2009, Cancer research.

[88]  P. Paterlini-Bréchot,et al.  Circulating tumor cells (CTC) detection: clinical impact and future directions. , 2007, Cancer letters.

[89]  Y. Wong,et al.  Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer , 2008, Clinical & Experimental Metastasis.

[90]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[91]  Robert Rosenberg,et al.  Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. , 2003, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[92]  Emmanuel R. Yera,et al.  Functional phenotyping and genotyping of circulating tumor cells from patients with castration resistant prostate cancer. , 2009, Cancer letters.

[93]  Philip S Low,et al.  In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry , 2007, Proceedings of the National Academy of Sciences.

[94]  Ruud H. Brakenhoff,et al.  Detection, clinical relevance and specific biological properties of disseminating tumour cells , 2008, Nature Reviews Cancer.

[95]  A. Dobrovic,et al.  Molecular detection of blood‐borne epithelial cells in colorectal cancer patients and in patients with benign bowel disease , 2000, International journal of cancer.

[96]  A. Semjonow,et al.  Asynchronous growth of prostate cancer is reflected by circulating tumor cells delivered from distinct, even small foci, harboring loss of heterozygosity of the PTEN gene. , 2006, Cancer research.

[97]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[98]  R. Ghalie,et al.  Detection of tumor cells in the bone marrow, peripheral blood, and apheresis products of breast cancer patients using flow cytometry. , 1995, Experimental hematology.

[99]  Tanja Fehm,et al.  Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients , 2009, Breast Cancer Research.

[100]  Xiaoyu Jia,et al.  Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. , 2009, The Lancet. Oncology.

[101]  F. Becker,et al.  Isolation of rare cells from cell mixtures by dielectrophoresis , 2009, Electrophoresis.

[102]  A W Partin,et al.  Identification and characterization of circulating prostate carcinoma cells , 2000, Cancer.

[103]  John A. Viator,et al.  Detection of circulating melanoma cells in human blood using photoacoustic flowmetry , 2009, 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[104]  K. Pantel,et al.  Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. , 1999, Cancer research.

[105]  G. Assmann,et al.  Isolation of blood‐borne epithelium‐derived c‐erbB‐2 oncoprotein‐positive clustered cells from the peripheral blood of breast cancer patients , 1998, International journal of cancer.

[106]  B. Molnár,et al.  Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[107]  R. Eils,et al.  Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. , 2005, Cancer cell.

[108]  K. Pienta,et al.  Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer , 2008, Clinical Cancer Research.

[109]  T. Utsunomiya,et al.  Detection of occult cancer cells in peripheral blood and bone marrow by quantitative RT-PCR assay for cytokeratin-7 in breast cancer patients. , 2005, International journal of oncology.