Liquid biopsy and NSCLC

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Ma M, Zhu H, Zhang C, Sun X, Gao X, Chen G. “Liquid biopsy”-ctDNA detection with great potential and challenges. Ann. Transl. Med. 3(16), 235 (2015).
  MedlineGoogle Scholar
• 2 Kawaguchi T, Holland WS, Gumerlock PH. Methods for isolation and genetic analysis of circulating tumor DNA in patient plasma. Methods Mol. Med. 85, 257–262 (2003).
  Medline CASGoogle Scholar
• 3 Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat. Rev. Cancer 14(9), 623–631 (2014). • This report proposes a conceptual framework of circulating tumor cells assays and point out current challenges of circulating tumor cell research, which might structure this dynamic field of translational cancer research.
  Medline CASGoogle Scholar
• 4 Kosaka N. Decoding the secret of cancer by means of extracellular vesicles. J. Clin. Med. 5(2), 22 (2016).
  MedlineGoogle Scholar
• 5 Aceto N, Bardia A, Miyamoto DT et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5), 1110–1122 (2014).
  Medline CASGoogle Scholar
• 6 Grover PK, Cummins AG, Price TJ, Roberts-Thomson IC, Hardingham JE. Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann. Oncol. 25(8), 1506–1516 (2014).
  Medline CASGoogle Scholar
• 7 Maheswaran S, Sequist LV, Nagrath S et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359(4), 366–377 (2008).
  Medline CASGoogle Scholar
• 8 Cohen SJ, Punt CJ, Iannotti N et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann. Oncol. 20(7), 1223–1229 (2009).
  Medline CASGoogle Scholar
• 9 Stott SL, Lee RJ, Nagrath S et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci. Transl. Med. 2(25), 25ra23 (2010).
  MedlineGoogle Scholar
• 10 Krebs MG, Hou JM, Sloane R et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J. Thorac. Oncol. 7(2), 306–315 (2012).
  MedlineGoogle Scholar
• 11 Yu M, Bardia A, Wittner BS et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119), 580–584 (2013).
  Medline CASGoogle Scholar
• 12 Tjensvoll K, Nordgard O, Smaaland R. Circulating tumor cells in pancreatic cancer patients: methods of detection and clinical implications. Int. J. Cancer 134(1), 1–8 (2014).
  MedlineGoogle Scholar
• 13 Sullivan JP, Nahed BV, Madden MW et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov. 4(11), 1299–1309 (2014).
  Medline CASGoogle Scholar
• 14 Luo X, Mitra D, Sullivan RJ et al. Isolation and molecular characterization of circulating melanoma cells. Cell Rep. 7(3), 645–653 (2014).
  Medline CASGoogle Scholar
• 15 Comen E, Norton L. Self-seeding in cancer. Recent Results Cancer Res. 195, 13–23 (2012).
  MedlineGoogle Scholar
• 16 Comen E, Norton L, Massague J. Clinical implications of cancer self-seeding. Nat. Rev. Clin. Oncol. 8(6), 369–377 (2011). •• The self-seeding model was proposed in this article to answer to many of the mysteries inherent to cancer metastasis. Reframing our understanding of metastasis within the self-seeding model offers new opportunities for prevention and cure of metastatic cancer.
  MedlineGoogle Scholar
• 17 Krebs MG, Sloane R, Priest L et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J. Clin. Oncol. 29(12), 1556–1563 (2011).
  MedlineGoogle Scholar
• 18 Normanno N, Rossi A, Morabito A et al. Prognostic value of circulating tumor cells’ reduction in patients with extensive small-cell lung cancer. Lung Cancer 85(2), 314–319 (2014).
  MedlineGoogle Scholar
• 19 Igawa S, Gohda K, Fukui T et al. Circulating tumor cells as a prognostic factor in patients with small cell lung cancer. Oncol. Lett. 7(5), 1469–1473 (2014).
  Medline CASGoogle Scholar
• 20 Hamilton G, Rath B, Holzer S, Hochmair M. Second-line therapy for small cell lung cancer: exploring the potential role of circulating tumor cells. Transl. Lung Cancer Res. 5(1), 71–77 (2016).
  Medline CASGoogle Scholar
• 21 Dorsey JF, Kao GD, MacArthur KM et al. Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot study results. Cancer 121(1), 139–149 (2015).
  MedlineGoogle Scholar
• 22 Hofman V, Bonnetaud C, Ilie MI et al. Preoperative circulating tumor cell detection using the isolation by size of epithelial tumor cell method for patients with lung cancer is a new prognostic biomarker. Clin. Cancer Res. 17(4), 827–835 (2011).
  Medline CASGoogle Scholar
• 23 Bayarri-Lara C, Ortega FG, Cueto Ladron De Guevara A et al. Circulating tumor cells identify early recurrence in patients with non-small cell lung cancer undergoing radical resection. PLoS ONE 11(2), e0148659 (2016).
  MedlineGoogle Scholar
• 24 Hofman V, Ilie M, Long E et al. Detection of circulating tumor cells from lung cancer patients in the era of targeted therapy: promises, drawbacks and pitfalls. Curr. Mol. Med. 14(4), 440–456 (2014).
  Medline CASGoogle Scholar
• 25 Zhang C, Guan Y, Sun Y, Ai D, Guo Q. Tumor heterogeneity and circulating tumor cells. Cancer Lett. 374(2), 216–223 (2016).
  Medline CASGoogle Scholar
• 26 Marchetti A, Del Grammastro M, Felicioni L et al. Assessment of EGFR mutations in circulating tumor cell preparations from NSCLC patients by next generation sequencing: toward a real-time liquid biopsy for treatment. PLoS ONE 9(8), e103883 (2014).
  MedlineGoogle Scholar
• 27 Punnoose EA, Atwal S, Liu W et al. Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a Phase II clinical trial of pertuzumab and erlotinib. Clin. Cancer Res. 18(8), 2391–2401 (2012).
  Medline CASGoogle Scholar
• 28 Sawada T, Watanabe M, Fujimura Y et al. Sensitive cytometry based system for enumeration, capture and analysis of gene mutations of circulating tumor cells. Cancer Sci. 107(3), 307–314 (2016).
  Medline CASGoogle Scholar
• 29 Hata AN, Niederst MJ, Archibald HL et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22(3), 262–269 (2016). •• Acquired resistance caused by the EGFR T790M gatekeeper mutation in lung cancer can occur either by selection of pre-existing EGFR T790M-positive clones or via genetic evolution of initially EGFR T790M-negative drug-tolerant cells. This provides evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
  Medline CASGoogle Scholar
• 30 Douillard JY, Ostoros G, Cobo M et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J. Thorac. Oncol. 9(9), 1345–1353 (2014).
  Medline CASGoogle Scholar
• 31 Pailler E, Adam J, Barthelemy A et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J. Clin. Oncol. 31(18), 2273–2281 (2013).
  MedlineGoogle Scholar
• 32 Ilina O, Friedl P. Mechanisms of collective cell migration at a glance. J. Cell Sci. 122(Pt 18), 3203–3208 (2009).
  Medline CASGoogle Scholar
• 33 Erpenbeck L, Schon MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 115(17), 3427–3436 (2010).
  Medline CASGoogle Scholar
• 34 Berezovskaya O, Schimmer AD, Glinskii AB et al. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res. 65(6), 2378–2386 (2005).
  Medline CASGoogle Scholar
• 35 Luzzi KJ, MacDonald IC, Schmidt EE et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153(3), 865–873 (1998).
  Medline CASGoogle Scholar
• 36 Glinsky VV, Glinsky GV, Glinskii OV et al. Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Res. 63(13), 3805–3811 (2003).
  Medline CASGoogle Scholar
• 37 Im JH, Fu W, Wang H et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 64(23), 8613–8619 (2004).
  Medline CASGoogle Scholar
• 38 Gabriel MT, Calleja LR, Chalopin A, Ory B, Heymann D. Circulating tumor cells: a review of non-EpCAM-based approaches for cell enrichment and isolation. Clin. Chem. 62(4), 571–581 (2016).
  Medline CASGoogle Scholar
• 39 Naito T, Tanaka F, Ono A et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J. Thorac. Oncol. 7(3), 512–519 (2012).
  MedlineGoogle Scholar
• 40 Scheel C, Weinberg RA. Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22(5–6), 396–403 (2012).
  Medline CASGoogle Scholar
• 41 Karabacak NM, Spuhler PS, Fachin F et al. Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat. Protoc. 9(3), 694–710 (2014).
  Medline CASGoogle Scholar
• 42 Lin HK, Zheng S, Williams AJ et al. Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin. Cancer Res. 16(20), 5011–5018 (2010).
  Medline CASGoogle Scholar
• 43 Hofman V, Long E, Ilie M et al. Morphological analysis of circulating tumour cells in patients undergoing surgery for non-small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method. Cytopathology 23(1), 30–38 (2012).
  Medline CASGoogle Scholar
• 44 Ozkumur E, Shah AM, Ciciliano JC et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci. Transl. Med. 5(179), 179ra147 (2013).
  Google Scholar
• 45 Mandel P, Metais P. [Les acides nucléiques du plasma sanguin chez l'homme]. C. R. Seances Soc. Biol. Fil. 142(3–4), 241–243 (1948).
  Medline CASGoogle Scholar
• 46 Diehl F, Li M, Dressman D et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl Acad. Sci. USA 102(45), 16368–16373 (2005).
  Medline CASGoogle Scholar
• 47 Allegra CJ, Jessup JM, Somerfield MR et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 27(12), 2091–2096 (2009).
  MedlineGoogle Scholar
• 48 Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med. 63, 199–215 (2012).
  Medline CASGoogle Scholar
• 49 Perkins G, Yap TA, Pope L et al. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PLoS ONE 7(11), e47020 (2012).
  Medline CASGoogle Scholar
• 50 Figg WD 2nd, Reid J. Monitor tumor burden with circulating tumor DNA. Cancer Biol. Ther. 14(8), 697–698 (2013).
  Medline CASGoogle Scholar
• 51 Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32(6), 579–586 (2014). •• Recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cell-free DNA for somatic genomic alterations found in tumors. The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real-time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.
  MedlineGoogle Scholar
• 52 Mouliere F, Robert B, Arnau Peyrotte E et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS ONE 6(9), e23418 (2011).
  Medline CASGoogle Scholar
• 53 Mauger F, Dulary C, Daviaud C, Deleuze JF, Tost J. Comprehensive evaluation of methods to isolate, quantify, and characterize circulating cell-free DNA from small volumes of plasma. Anal. Bioanal. Chem. 407(22), 6873–6878 (2015).
  Medline CASGoogle Scholar
• 54 Benesova L, Belsanova B, Suchanek S et al. Mutation-based detection and monitoring of cell-free tumor DNA in peripheral blood of cancer patients. Anal. Biochem. 433(2), 227–234 (2013).
  Medline CASGoogle Scholar
• 55 Diehl F, Li M, Dressman D et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl Acad. Sci. USA 102(45), 16368–16373 (2005).
  Medline CASGoogle Scholar
• 56 Xue X, Teare MD, Holen I, Zhu YM, Woll PJ. Optimizing the yield and utility of circulating cell-free DNA from plasma and serum. Clin. Chim. Acta 404(2), 100–104 (2009).
  Medline CASGoogle Scholar
• 57 Fong SL, Zhang JT, Lim CK, Eu KW, Liu Y. Comparison of 7 methods for extracting cell-free DNA from serum samples of colorectal cancer patients. Clin. Chem. 55(3), 587–589 (2009).
  Medline CASGoogle Scholar
• 58 Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 11(6), 426–437 (2011).
  Medline CASGoogle Scholar
• 59 Norton SE, Luna KK, Lechner JM, Qin J, Fernando MR. A new blood collection device minimizes cellular DNA release during sample storage and shipping when compared to a standard device. J. Clin. Lab. Anal. 27(4), 305–311 (2013).
  Medline CASGoogle Scholar
• 60 Sherwood JL, Corcoran C, Brown H, Sharpe AD, Musilova M, Kohlmann A. Optimised pre-analytical methods improve KRAS mutation detection in circulating tumour DNA (ctDNA) from patients with non-small cell lung cancer (NSCLC). PLoS ONE 11(2), e0150197 (2016).
  MedlineGoogle Scholar
• 61 El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: preanalytical considerations. Clin. Chim. Acta 424, 222–230 (2013).
  Medline CASGoogle Scholar
• 62 Norton SE, Lechner JM, Williams T, Fernando MR. A stabilizing reagent prevents cell-free DNA contamination by cellular DNA in plasma during blood sample storage and shipping as determined by digital PCR. Clin. Biochem. 46(15), 1561–1565 (2013).
  Medline CASGoogle Scholar
• 63 Bettegowda C, Sausen M, Leary RJ et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6(224), 224ra224 (2014).
  Google Scholar
• 64 Brevet M, Johnson ML, Azzoli CG, Ladanyi M. Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors. Lung Cancer 73(1), 96–102 (2011).
  MedlineGoogle Scholar
• 65 Goto K, Ichinose Y, Ohe Y et al. Epidermal growth factor receptor mutation status in circulating free DNA in serum: from IPASS, a Phase III study of gefitinib or carboplatin/paclitaxel in non-small cell lung cancer. J. Thorac. Oncol. 7(1), 115–121 (2012).
  Medline CASGoogle Scholar
• 66 Nakamura T, Sueoka-Aragane N, Iwanaga K et al. Application of a highly sensitive detection system for epidermal growth factor receptor mutations in plasma DNA. J. Thorac. Oncol. 7(9), 1369–1381 (2012).
  Medline CASGoogle Scholar
• 67 Chen YM, Fan WC, Tseng PC et al. Plasma epidermal growth factor receptor mutation analysis and possible clinical applications in pulmonary adenocarcinoma patients treated with erlotinib. Oncol. Lett. 3(3), 713–717 (2012).
  Medline CASGoogle Scholar
• 68 Thress KS, Brant R, Carr TH et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 90(3), 509–515 (2015).
  MedlineGoogle Scholar
• 69 Marchetti A, Palma JF, Felicioni L et al. Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of NSCLC patients. J. Thorac. Oncol. 10(10), 1437–1443 (2015). •• This is the first study showing a strong correlation between the EGFR copy number mutations in the first days of treatment and clinical response with relevant implications for patient management.
  Medline CASGoogle Scholar
• 70 Fenizia F, De Luca A, Pasquale R et al. EGFR mutations in lung cancer: from tissue testing to liquid biopsy. Future Oncol. 11(11), 1611–1623 (2015).
  CASGoogle Scholar
• 71 Luo J, Shen L, Zheng D. Diagnostic value of circulating free DNA for the detection of EGFR mutation status in NSCLC: a systematic review and meta-analysis. Sci. Rep. 4, 6269 (2014).
  Medline CASGoogle Scholar
• 72 Bordi P, Del Re M, Tiseo M. Crizotinib resensitization by compound mutation. N. Engl. J. Med. 374(18), 1790 (2016).
  MedlineGoogle Scholar
• 73 Liang W, He Q, Chen Y et al. Metastatic EML4–ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report. BMC Cancer 16, 62 (2016).
  MedlineGoogle Scholar
• 74 Jamal-Hanjani M, Wilson GA, Horswell S et al. Detection of ubiquitous and heterogeneous mutations in cell-free DNA from patients with early-stage non-small-cell lung cancer. Ann. Oncol. 27(5), 862–867 (2016).
  Medline CASGoogle Scholar
• 75 Begum S, Brait M, Dasgupta S et al. An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. Clin. Cancer Res. 17(13), 4494–4503 (2011).
  Medline CASGoogle Scholar
• 76 Wielscher M, Vierlinger K, Kegler U, Ziesche R, Gsur A, Weinhausel A. Diagnostic performance of plasma DNA methylation profiles in lung cancer, pulmonary fibrosis and COPD. EBioMedicine 2(8), 927–934 (2015).
  Google Scholar
• 77 Zhang Y, Wang R, Song H et al. Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. Cancer Lett. 303(1), 21–28 (2011).
  Medline CASGoogle Scholar
• 78 Nie K, Jia Y, Zhang X. Cell-free circulating tumor DNA in plasma/serum of non-small cell lung cancer. Tumour Biol. 36(1), 7–19 (2015).
  Medline CASGoogle Scholar
• 79 Zhang Y, Wang R, Song H et al. Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. Cancer Lett. 303(1), 21–28 (2011).
  Medline CASGoogle Scholar
• 80 Lee SM, Park JY, Kim DS. Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer. Mol. Cells 34(2), 171–176 (2012).
  Medline CASGoogle Scholar
• 81 Zhang YW, Miao YF, Yi J, Geng J, Wang R, Chen LB. Transcriptional inactivation of secreted frizzled-related protein 1 by promoter hypermethylation as a potential biomarker for non-small cell lung cancer. Neoplasma 57(3), 228–233 (2010).
  Medline CASGoogle Scholar
• 82 Hoffmann AC, Vallbohmer D, Prenzel K et al. Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome. J. Cancer Res. Clin. Oncol. 135(9), 1231–1237 (2009).
  Medline CASGoogle Scholar
• 83 Li M, Chen WD, Papadopoulos N et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat. Biotechnol. 27(9), 858–863 (2009). • The methyl-BEAMing technology was developed to enable absolute quantification of the number of methylated molecules in a sample and was applied to detect methylation in DNA from plasma.
  MedlineGoogle Scholar
• 84 Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin. Chem. 61(1), 112–123 (2015).
  Medline CASGoogle Scholar
• 85 Murtaza M, Dawson SJ, Tsui DW et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447), 108–112 (2013).
  Medline CASGoogle Scholar
• 86 Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations – a review. Transl. Lung Cancer Res. 4(1), 67–81 (2015).
  Medline CASGoogle Scholar
• 87 Denis MG, Vallee A, Theoleyre S. EGFR T790M resistance mutation in non small-cell lung carcinoma. Clin. Chim. Acta 444, 81–85 (2015).
  Medline CASGoogle Scholar
• 88 Zheng D, Ye X, Zhang MZ et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci. Rep. 6, 20913 (2016).
  Medline CASGoogle Scholar
• 89 Thress KS, Paweletz CP, Felip E et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21(6), 560–562 (2015). •• The cell-free plasma DNA collected from subjects with advanced lung cancer whose tumors had developed resistance to the EGFR-tyrosine kinase inhibitor AZD9291 was studied. A new acquired EGFR C797S mutation was identified as new mechanism of acquired resistance to AZD9291.
  Medline CASGoogle Scholar
• 90 Imamura F, Uchida J, Kukita Y et al. Monitoring of treatment responses and clonal evolution of tumor cells by circulating tumor DNA of heterogeneous mutant EGFR genes in lung cancer. Lung Cancer 94, 68–73 (2016).
  MedlineGoogle Scholar
• 91 Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9(6), 654–659 (2007).
  Medline CASGoogle Scholar
• 92 Yanez-Mo M, Siljander PR, Andreu Z et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).
  MedlineGoogle Scholar
• 93 Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. (Berl.) 91(4), 431–437 (2013). • This review highlights the functional relevance of exosomes in cancer, as related to tumor microenvironment, tumor immunology, angiogenesis and metastasis.
  Medline CASGoogle Scholar
• 94 Kowal J, Arras G, Colombo M et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113(8), E968–E977 (2016).
  Medline CASGoogle Scholar
• 95 Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9(6), 654–659 (2007).
  Medline CASGoogle Scholar
• 96 Balaj L, Lessard R, Dai L et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011).
  MedlineGoogle Scholar
• 97 Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39(16), 7223–7233 (2011).
  Medline CASGoogle Scholar
• 98 Nolte-'t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, T Hoen PA. Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 40(18), 9272–9285 (2012).
  MedlineGoogle Scholar
• 99 Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).
  Medline CASGoogle Scholar
• 100 Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20(9), 1487–1495 (2006).
  Medline CASGoogle Scholar
• 101 De Toro J, Herschlik L, Waldner C, Mongini C. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol. 6, 203 (2015).
  MedlineGoogle Scholar
• 102 Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40(Database issue), D1241–D1244 (2012).
  Medline CASGoogle Scholar
• 103 Weidle UH, Birzele F, Kollmorgen G, Ruger R. Molecular basis of lung tropism of metastasis. Cancer Genomics Proteomics 13(2), 129–139 (2016).
  Medline CASGoogle Scholar
• 104 Qin X, Xu H, Gong W, Deng W. The tumor cytosol miRNAs, fluid miRNAs, and exosome miRNAs in lung cancer. Front. Oncol. 4, 357 (2015).
  MedlineGoogle Scholar
• 105 Zhang HG, Zhuang X, Sun D, Liu Y, Xiang X, Grizzle WE. Exosomes and immune surveillance of neoplastic lesions: a review. Biotech. Histochem. 87(3), 161–168 (2012).
  Medline CASGoogle Scholar
• 106 Zhang HG, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am. J. Pathol. 184(1), 28–41 (2014).
  Medline CASGoogle Scholar
• 107 He M, Crow J, Roth M, Zeng Y, Godwin AK. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab. Chip 14(19), 3773–3780 (2014).
  Medline CASGoogle Scholar
• 108 Jakobsen KR, Paulsen BS, Baek R, Varming K, Sorensen BS, Jorgensen MM. Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J. Extracell. Vesicles 4, 26659 (2015).
  MedlineGoogle Scholar
• 109 Jorgensen M, Baek R, Pedersen S, Sondergaard EK, Kristensen SR, Varming K. Extracellular vesicle (EV) array: microarray capturing of exosomes and other extracellular vesicles for multiplexed phenotyping. J. Extracell. Vesicles 18, 2 (2013).
  Google Scholar
• 110 Chen C, Skog J, Hsu CH et al. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab. Chip 10(4), 505–511 (2010).
  Medline CASGoogle Scholar
• 111 Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin. Chem. 61(1), 56–63 (2015).
  Medline CASGoogle Scholar
• 112 Eitan E, Zhang S, Witwer Kw, Mattson MP. Extracellular vesicle-depleted fetal bovine and human sera have reduced capacity to support cell growth. J. Extracell. Vesicles 4, 26373 (2015).
  MedlineGoogle Scholar
• 113 Thakur BK, Zhang H, Becker A et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24(6), 766–769 (2014).
  Medline CASGoogle Scholar
• 114 Balaj L, Lessard R, Dai L et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011).
  MedlineGoogle Scholar
• 115 Thakur BK, Zhang H, Becker A et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24(6), 766–769 (2014).
  Medline CASGoogle Scholar
• 116 Nilsson RJ, Karachaliou N, Berenguer J et al. Rearranged EML4–ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 7(1), 1066–1075 (2016).
  MedlineGoogle Scholar
• 117 Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin. Lung Cancer 10(1), 42–46 (2009).
  Medline CASGoogle Scholar
• 118 Sharma A, Khatun Z, Shiras A. Tumor exosomes: cellular postmen of cancer diagnosis and personalized therapy. Nanomedicine (Lond.) 11(4), 421–437 (2016). • This review provides an updated information in exosomes isolation strategies, presence of exosomes biomarkers and importance of tumor-derived exosomes in gauging tumor heterogeneity for their potential use in cancer diagnosis, therapy.
  CASGoogle Scholar
• 119 Fontana S, Saieva L, Taverna S, Alessandro R. Contribution of proteomics to understanding the role of tumor-derived exosomes in cancer progression: state of the art and new perspectives. Proteomics 13(10–11), 1581–1594 (2013).
  Medline CASGoogle Scholar