Detecting Circulating Tumor Cells: Current Challenges and New Trends

Circulating tumor cells (CTCs) in the blood stream play a critical role in establishing metastases. The clinical value of CTCs as a biomarker for early cancer detection, diagnosis, prognosis, prediction, stratification, and pharmacodynamics have been widely explored in recent years. However, the clinical utility of current CTC tests is limited mainly due to methodological constraints. In this review, the pros and cons of the reported CTC assays are comprehensively discussed. In addition, the potential of tumor cell-derived materials as new targets for CTC detection, including circulating tumor microemboli, cell fragments, and circulating DNA, is evaluated. Finally, emerging approaches for CTC detection, including telomerase-based or aptamer-based assays and cell functional analysis, are also assessed. Expectantly, a thorough review of the current knowledge and technology of CTC detection will assist the scientific community in the development of more efficient CTC assay systems.

[1]  Mo Chao Huang,et al.  Microsieve lab-chip device for rapid enumeration and fluorescence in situ hybridization of circulating tumor cells. , 2012, Lab on a chip.

[2]  Chao Liu,et al.  Double spiral microchannel for label-free tumor cell separation and enrichment. , 2012, Lab on a chip.

[3]  Charles A Enke,et al.  Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[4]  Massimo Cristofanilli,et al.  Considerations in the development of circulating tumor cell technology for clinical use , 2012, Journal of Translational Medicine.

[5]  Daniel T Chiu,et al.  Sensitive and high-throughput isolation of rare cells from peripheral blood with ensemble-decision aliquot ranking. , 2012, Angewandte Chemie.

[6]  Paraskevi Giannakakou,et al.  Functional Characterization of Circulating Tumor Cells with a Prostate-Cancer-Specific Microfluidic Device , 2012, PloS one.

[7]  Yu Sun,et al.  Microfluidic approaches for cancer cell detection, characterization, and separation. , 2012, Lab on a chip.

[8]  Caroline Dive,et al.  Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Joshua M. Kunken,et al.  Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers , 2012, Physical biology.

[10]  N. Saijo.  Critical comments for roles of biomarkers in the diagnosis and treatment of cancer. , 2012, Cancer treatment reviews.

[11]  L. Ellis,et al.  A novel platform for detection of CK+ and CK- CTCs. , 2011, Cancer discovery.

[12]  J. Schellens,et al.  Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials. , 2011, Cancer treatment reviews.

[13]  Leon W. M. M. Terstappen,et al.  Unbiased and Automated Identification of a Circulating Tumour Cell Definition That Associates with Overall Survival , 2011, PloS one.

[14]  J. Feczko,et al.  Metastatic breast cancer detection and therapy monitoring using folate-targeting flow cytometry. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Jia Fan,et al.  Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance , 2011, Journal of Cancer Research and Clinical Oncology.

[16]  Han Wei Hou,et al.  Pinched flow coupled shear-modulated inertial microfluidics for high-throughput rare blood cell separation. , 2011, Lab on a chip.

[17]  Klaus Pantel,et al.  Cell-free nucleic acids as biomarkers in cancer patients , 2011, Nature Reviews Cancer.

[18]  J. Celestino,et al.  Clinical relevance of cytokeratin-negative circulating tumor cells. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  B. Ramaswamy,et al.  EpCAM-negative cancer-associated circulating cells (CACS) in blood samples of women with triple-negative breast cancer (TNBC). , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  R. Ghadially.  The role of stem and circulating cells in cancer metastasis , 2011, Journal of surgical oncology.

[21]  Massimo Cristofanilli,et al.  Circulating tumor cells in breast cancer: A tool whose time has come of age , 2011, BMC medicine.

[22]  Max S Wicha,et al.  Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  H. Tseng,et al.  Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. , 2011, Angewandte Chemie.

[24]  S. Sleijfer,et al.  External quality assurance of circulating tumor cell enumeration using the CellSearch® system: A feasibility study , 2011, Cytometry. Part B, Clinical cytometry.

[25]  Dieter Falkenhagen,et al.  Enrichment of circulating tumor cells from a large blood volume using leukapheresis and elutriation: Proof of concept , 2011, Cytometry. Part B, Clinical cytometry.

[26]  Caroline Dive,et al.  Circulating tumor cells as a window on metastasis biology in lung cancer. , 2011, The American journal of pathology.

[27]  Mehmet Toner,et al.  Circulating tumor cells: approaches to isolation and characterization , 2011, The Journal of cell biology.

[28]  Bo Lu,et al.  3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood , 2011, Biomedical microdevices.

[29]  M. Takao,et al.  Enumeration, characterization, and collection of intact circulating tumor cells by cross contamination‐free flow cytometry , 2011, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[30]  Gerhardt Attard,et al.  Utilizing circulating tumor cells: challenges and pitfalls. , 2011, Current opinion in genetics & development.

[31]  Luigi Mansi,et al.  AJCC Cancer Staging Handbook: from the AJCC Cancer Staging Manual (7th edition) , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[32]  Erkang Wang,et al.  Review: Aptamers in microfluidic chips. , 2010, Analytica chimica acta.

[33]  Chwee Teck Lim,et al.  Versatile label free biochip for the detection of circulating tumor cells from peripheral blood in cancer patients. , 2010, Biosensors & bioelectronics.

[34]  K. Jung,et al.  Cell-free DNA in the blood as a solid tumor biomarker--a critical appraisal of the literature. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[35]  S. Indraccolo,et al.  M30 Neoepitope Expression in Epithelial Cancer: Quantification of Apoptosis in Circulating Tumor Cells by CellSearch Analysis , 2010, Clinical Cancer Research.

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

[37]  L. Cerchia,et al.  Targeting cancer cells with nucleic acid aptamers. , 2010, Trends in biotechnology.

[38]  S. Groshen,et al.  Portable Filter-Based Microdevice for Detection and Characterization of Circulating Tumor Cells , 2010, Clinical Cancer Research.

[39]  J. Bono,et al.  All circulating EpCAM+CK+CD45- objects predict overall survival in castration-resistant prostate cancer. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  S. Agelaki,et al.  What's new on circulating tumor cells? A meeting report , 2010, Breast Cancer Research.

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

[42]  S. Sleijfer,et al.  Circulating tumor cells and sample size: the more, the better. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  J. Abraham,et al.  Circulating tumor cells in the management of breast cancer. , 2010, Clinical breast cancer.

[44]  T. Ward,et al.  Circulating Tumor Cells, Enumeration and Beyond , 2010, Cancers.

[45]  M. Loda,et al.  Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer , 2010, British Journal of Cancer.

[46]  M. Alunni-Fabbroni,et al.  Circulating tumour cells in clinical practice: Methods of detection and possible characterization. , 2010, Methods.

[47]  Jocelyn Kaiser,et al.  Medicine. Cancer's circulation problem. , 2010, Science.

[48]  J. Kaiser.  Medicine. Keeping tabs on tumor DNA. , 2010, Science.

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

[50]  G. Kallergi,et al.  Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. , 2010, Cancer letters.

[51]  D. Haber,et al.  Circulating tumor cells: a window into cancer biology and metastasis. , 2010, Current opinion in genetics & development.

[52]  Jason P. Gleghorn,et al.  Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. , 2010, Lab on a chip.

[53]  S. Jeffrey,et al.  Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype , 2010, British Journal of Cancer.

[54]  M. Keeney,et al.  Circulating Tumor Cell Analysis: Technical and Statistical Considerations for Application to the Clinic , 2009, Journal of oncology.

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

[56]  N. Tsubota,et al.  Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer , 2009, Clinical Cancer Research.

[57]  Neal J Meropol,et al.  Circulating tumor cells: evolving evidence and future challenges. , 2009, The oncologist.

[58]  J. A. van der Laak,et al.  Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma , 2009, The Journal of pathology.

[59]  A. Fischer.  Circulating tumor cells: seeing is believing. , 2009, Archives of pathology & laboratory medicine.

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

[61]  Paul I. Okagbare,et al.  Highly efficient capture and enumeration of low abundance prostate cancer cells using prostate‐specific membrane antigen aptamers immobilized to a polymeric microfluidic device , 2009, Electrophoresis.

[62]  Stefan Sleijfer,et al.  Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. , 2009, Cancer treatment reviews.

[63]  Weihong Tan,et al.  Aptamer-based microfluidic device for enrichment, sorting, and detection of multiple cancer cells. , 2009, Analytical chemistry.

[64]  G. Hortobagyi,et al.  Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  P. Carli,et al.  Circulating and Disseminated Tumor Cells in the Clinical Management of Breast Cancer Patients: Unanswered Questions , 2009, Oncology.

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

[67]  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.

[68]  W. Tan,et al.  Enrichment of cancer cells using aptamers immobilized on a microfluidic channel. , 2009, Analytical chemistry.

[69]  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.

[70]  Sabine Riethdorf,et al.  Circulating Tumor Cells and Bone Marrow Micrometastasis , 2008, Clinical Cancer Research.

[71]  M. Ali,et al.  Rolling circle amplification: applications in nanotechnology and biodetection with functional nucleic acids. , 2008, Angewandte Chemie.

[72]  D. Krag,et al.  Enrichment with anti-cytokeratin alone or combined with anti-EpCAM antibodies significantly increases the sensitivity for circulating tumor cell detection in metastatic breast cancer patients , 2008, Breast Cancer Research.

[73]  L. Fass.  Imaging and cancer: A review , 2008, Molecular oncology.

[74]  Michael Morse,et al.  Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  Paul I. Okagbare,et al.  Highly efficient circulating tumor cell isolation from whole blood and label-free enumeration using polymer-based microfluidics with an integrated conductivity sensor. , 2008, Journal of the American Chemical Society.

[76]  Daniel F. Hayes,et al.  Is There a Role for Circulating Tumor Cells in the Management of Breast Cancer? , 2008, Clinical Cancer Research.

[77]  J. Abraham,et al.  Role of tumor markers and circulating tumors cells in the management of breast cancer. , 2008, Oncology.

[78]  A. Goldhirsch,et al.  Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[79]  E. D. de Vries,et al.  Prognostic versus predictive value of biomarkers in oncology. , 2008, European journal of cancer.

[80]  T. Kroll,et al.  Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[82]  J. Vorhies,et al.  Nucleic acid aptamers for targeting of shRNA-based cancer therapeutics , 2007, Biologics : targets & therapy.

[83]  R. Bast,et al.  American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. , 2007, Journal of oncology practice.

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

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

[86]  Leon W M M Terstappen,et al.  Statistical considerations for enumeration of circulating tumor cells , 2007, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[87]  K. Pantel,et al.  Detection and characterization of putative metastatic precursor cells in cancer patients. , 2007, Clinical chemistry.

[88]  R. Beveridge.  Circulating tumor cells in the management of metastatic breast cancer patients , 2007 .

[89]  R. Crevoisier,et al.  High detection rate of circulating tumor cells in blood of patients with prostate cancer using telomerase activity. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

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

[91]  A. Rajasekaran,et al.  Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. , 2006, Cancer research.

[92]  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.

[93]  E. Dellambra,et al.  Inactivation of p16INK4a (inhibitor of cyclin‐dependent kinase 4A) immortalizes primary human keratinocytes by maintaining cells in the stem cell compartment , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[94]  Mario Pazzagli,et al.  Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer: correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection. , 2006, Human pathology.

[95]  A. DeCaprio,et al.  Introduction to Toxicologic Biomarkers , 2006 .

[96]  Peter Kuhn,et al.  High speed detection of circulating tumor cells. , 2006, Biosensors & bioelectronics.

[97]  Liying Zhang,et al.  Prognostic significance of circulating tumour cells enumerated after filtration enrichment in early and metastatic breast cancer patients , 2006, Breast Cancer Research and Treatment.

[98]  Douglas G Altman,et al.  Dichotomizing continuous predictors in multiple regression: a bad idea , 2006, Statistics in medicine.

[99]  Frank Diehl,et al.  Detection and quantification of mutations in the plasma of patients with colorectal tumors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[100]  H. B. Halsall,et al.  Microfluidic immunosensor systems. , 2005, Biosensors & bioelectronics.

[101]  N. Lane,et al.  Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells. , 2005, Cytotherapy.

[102]  Thierry Maudelonde,et al.  Characterization and enumeration of cells secreting tumor markers in the peripheral blood of breast cancer patients. , 2005, Journal of immunological methods.

[103]  Katharina Pachmann,et al.  Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC® is a predictor for relapse: A preliminary report , 2005, World journal of surgical oncology.

[104]  J. Imura,et al.  Evaluation of Tumor Cell Dissociation as a Predictive Marker of Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma , 2005, Diseases of the colon and rectum.

[105]  Alison Stopeck,et al.  Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[106]  C Hollmann,et al.  DETECTION OF DISSEMINATED TUMOR CELLS IN PERIPHERAL BLOOD , 2005, Critical reviews in clinical laboratory sciences.

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

[108]  M. Daidone,et al.  Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. , 2004, European journal of cancer.

[109]  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.

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

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

[112]  Peter C Austin,et al.  Inflation of the type I error rate when a continuous confounding variable is categorized in logistic regression analyses , 2004, Statistics in medicine.

[113]  Bernard Lacour,et al.  Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer , 2004, Hepatology.

[114]  P. Friedl,et al.  Tumour-cell invasion and migration: diversity and escape mechanisms , 2003, Nature Reviews Cancer.

[115]  J R Siewert,et al.  Comparison of two density gradient centrifugation systems for the enrichment of disseminated tumor cells in blood. , 2002, Cytometry.

[116]  R. Stahel,et al.  Circulating DNA: a new diagnostic gold mine? , 2002, Cancer treatment reviews.

[117]  D. S. Coffey,et al.  Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. , 2002, Cancer research.

[118]  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.

[119]  E. Diamandis,et al.  Tumor Markers: Physiology, Pathobiology, Technology, and Clinical Applications , 2002 .

[120]  James N Ingle,et al.  Detection of circulating cytokeratin-positive cells in the blood of breast cancer patients using immunomagnetic enrichment and digital microscopy. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[121]  T. Rutherford,et al.  Detection of telomerase-positive circulating epithelial cells in ovarian cancer patients. , 2002, Cancer detection and prevention.

[122]  James F. Leary,et al.  Rare‐Event Detection and Sorting of Rare Cells , 2002 .

[123]  D. Soligo,et al.  Detection of micrometastatic cells in breast cancer by RT-pCR for the mammaglobin gene. , 2002, Cancer detection and prevention.

[124]  J André Knottnerus,et al.  Evaluation of diagnostic procedures , 2002, BMJ : British Medical Journal.

[125]  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.

[126]  G. Doyle,et al.  Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status. , 2001, Urology.

[127]  N. Drenck,et al.  Point of care testing in Critical Care Medicine: the clinician's view. , 2001, Clinica chimica acta; international journal of clinical chemistry.

[128]  P. Balaram,et al.  Cadherins as Predictive Markers of Nodal Metastasis in Breast Cancer , 2001, Modern Pathology.

[129]  E. Raymond,et al.  Detection of circulating carcinoma cells by telomerase activity , 2001, British Journal of Cancer.

[130]  M. Gion.  Serum tumour markers: from quality control to total quality management. , 2000, Breast.

[131]  E. Blackburn,et al.  Telomere states and cell fates , 2000, Nature.

[132]  G. Kost,et al.  Point-of-Care Testing: Millennium Technology for Critical Care , 2000 .

[133]  E. Raymond,et al.  Molecular detection of telomerase-positive circulating epithelial cells in metastatic breast cancer patients. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[134]  S J Steindel,et al.  Evaluating stat testing options in an academic health center: therapeutic turnaround time and staff satisfaction. , 1998, Clinical chemistry.

[135]  A. Weiss,et al.  Detection and characterization of carcinoma cells in the blood. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[136]  J A Hokanson,et al.  Theoretical basis for sampling statistics useful for detecting and isolating rare cells using flow cytometry and cell sorting. , 1997, Cytometry.

[137]  R. Simon,et al.  A simulation study of cross-validation for selecting an optimal cutpoint in univariate survival analysis. , 1996, Statistics in medicine.

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

[139]  W. Sauerbrei,et al.  Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. , 1994, Journal of the National Cancer Institute.

[140]  E. Cooper,et al.  Tumor markers in prostate cancer , 1992, Cancer.

[141]  L. Gold,et al.  Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. , 1990, Science.

[142]  O Ouchterlony,et al.  A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. , 1983, Journal of immunological methods.

[143]  I. Carr.  Experimental lymphatic metastasis , 1983, Journal of microscopy.

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

[145]  P. Gullino,et al.  Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. , 1975, Cancer research.

[146]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[147]  D. Nie,et al.  Growth factors in tumor microenvironment. , 2010, Frontiers in bioscience.

[148]  J. Schellens,et al.  Application of PET/CT in the development of novel anticancer drugs. , 2008, The oncologist.

[149]  M. Fleischhacker,et al.  Circulating nucleic acids (CNAs) and cancer--a survey. , 2007, Biochimica et biophysica acta.

[150]  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.

[151]  J. Soria,et al.  The molecular detection of circulating tumor cells in bladder cancer using telomerase activity. , 2002, The Journal of urology.

[152]  F. Greene,et al.  AJCC cancer staging handbook : from the AJCC cancer staging manual , 2002 .

[153]  J F Leary,et al.  Strategies for rare cell detection and isolation. , 1994, Methods in cell biology.

[154]  James F. Leary,et al.  Chapter 20 Strategies for Rare Cell Detection and Isolation , 1994 .