Moving Tumor Cells: Going Beyond Isolation and Identification
DOI:
https://doi.org/10.17140/plmoj.2024.v5.i01.pp20-28.2214Keywords:
Circulating tumor cell (CTC), Circulating, Tumor cell, Cancer, Isolation, Detection, Metastasis, PrognosisAbstract
Circulating tumor cells (CTCs) are the precursors to metastases and increased numbers of CTCs in the peripheral circulation have been shown to correlate with decreased progression-free and overall survival. Although the current clinical utility has been focused on the prognostic significance, other clinical applications are being explored, such as determining if a patient is a candidate for treatment, determining the efficacy of treatment, evaluation for resistance to therapy, prediction of metastatic site, or as an early predictor of metastases. Current methodologies are based on quantifying CTCs and include technologies based on physical, immunological, and molecular techniques. However, these have limitations, of which most of them do not have the ability to perform morphological evaluation. Using morphological evaluation, CTCs in body fluids could be used for primary diagnosis in the setting of cancer of unknown primary (CUP) or in initial or early diagnostic scenarios. Additionally, cytological specimens have been shown to be useful for ancillary testing in patients when surgical resection specimens or biopsies are not available. Evaluation of CTCs should incorporate histological, immunehistochemical, and molecular characterization to enable clinicians to obtain the comprehensive diagnostic, prognostic and therapeutic information necessary to provide appropriate personalized care to cancer patients.
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69(1): 7-34. doi: 10.3322/caac.21551
American Cancer Society. Cancer Facts & Figures 2019. Web site. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html. Accessed Oc-tober 14, 2019.
Taketo MM. Reflections on the spread of metastasis to can-cer prevention. Cancer Prev Res (Phila). 2011; 4(3): 324-328. doi: 10.1158/1940-6207.CAPR-11-0046
Kowalik A, Kowalewska M, Góźdź S. Current approaches for avoiding the limitations of circulating tumor cells detection meth-ods—implications for diagnosis and treatment of patients with solid tumors. Transl Res. 2017; 185: 58-84.e15. doi: 10.1016/j. trsl.2017.04.002
National Cancer Institute. SEER Cancer Statistics Review, 1975- 2015. Web site. https://seer.cancer.gov/archive/csr/1975_2015/ index.html#contents. Accessed October 14, 2019.
Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging--predicting overall survival in metastatic breast can-cer. Clin Cancer Res. 2006; 12(21): 6403-6409. doi: 10.1158/1078- 0432.CCR-05-1769
Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Eng J Med. 2004; 351(8): 781-791. doi: 10.1056/NEJMoa040766
Cristofanilli M, Hayes DF, Budd GT, et al. Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol. 2005; 23(7): 1420-1430. doi: 10.1200/ JCO.2005.08.140
Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006; 12(14): 4218-4224. doi: 10.1158/1078-0432. CCR-05-2821
Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer pa-tients. J Natl Cancer Inst. 2014; 106(5): pii: dju066. doi: 10.1093/ jnci/dju066
Serrano MJ, Rovira PS, Martínez-Zubiaurre I, Rodriguez MD, Fernández M, Lorente JA. Dynamics of circulating tumor cells in early breast cancer under neoadjuvant therapy. Exp Ther Med. 2012; 4(1): 43-48. doi: 10.3892/etm.2012.540
American College of Surgeons (ACS). AJCC Cancer Staging Manual. 8th ed: NY, USA: Springer International Publishing; 2017.
Giuliano AE, Connolly JL, Edge SB, et al.Ca Breast Cancer— Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; 67(4): 290- 303. doi: 10.3322/caac.21393
Thiele JA, Bethel K, Králíčková M, Kuhn P. Circulating tu-mor cells: Fluid surrogates of solid tumors. Annu Rev Pathol. 2017; 12(1): 419-447. doi: 10.1146/annurev-pathol-052016-100256
Wan L, Pantel K, Kang Y. Tumor metastasis: Moving new bio-logical insights into the clinic. Nat Med. 2013;19:1450-1460. doi: 10.1038/nm.3391
Jacob K, Sollier C, Jabado N. Circulating tumor cells: Detec-tion, molecular profiling and future prospects. Expert Rev Proteomics. 2007; 4(6): 741-756. doi: 10.1586/14789450.4.6.741
Valastyan S, Weinberg RA. Tumor metastasis: Molecular in-sights and evolving paradigms. Cell. 2011; 147(2): 275-292. doi: 10.1016/j.cell.2011.09.024
Cohen SJ, Punt CJA, Iannotti N, et al. Relationship of circulat-ing tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(19): 3213-3221. doi: 10.1200/JCO.2007.15.8923
Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007; 13(23): 7053-7058. doi: 10.1158/1078- 0432.CCR-07-1506
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of muta-tions in EGFR in circulating lung-cancer cells. N Engl J Med. 2008; 359(4): 366-377. doi: 10.1056/NEJMoa0800668
Moreno JG, O’Hara SM, Gross S, et al. Changes in circulating carcinoma cells in patients with metastatic prostate cancer corre-late with disease status. Urology. 2001; 58(3): 386-392. doi: 10.1016/ s0090-4295(01)01191-8
Uen Y-H, Lu C-Y, Tsai H-L, et al. Persistent presence of post-operative circulating tumor cells is a poor prognostic factor for patients with stage I-III colorectal cancer after curative resection. Ann Surg Oncol. 2008; 15(8): 2120-2128. doi: 10.1245/s10434-008- 9961-7 25 McNamara MJ
King JD, Casavant BP, Lang JM. Rapid translation of circulat-ing tumor cell biomarkers into clinical practice: Technology de-velopment, clinical needs and regulatory requirements. Lab Chip. 2014; 14(1): 24-31. doi: 10.1039/c3lc50741f
de Bruin EC, McGranahan N, Mitter R, et al. Spatial and tem-poral diversity in genomic instability processes defines lung can-cer evolution. Science. 2014; 346(6206): 251-256. doi: 10.1126/sci-ence.1253462
Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor hetero-geneity and branched evolution revealed by multiregion sequenc-ing. N Engl J Med. 2012; 366(10): 883-892. doi: 10.1056/NEJ-Moa1113205
Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011; 472(7341): 90-94. doi: 10.1038/nature09807
Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene. 2016; 35(10): 1216-1224. doi: 10.1038/onc.2015.192
Tsao SC-H, Wang J, Wang Y, Behren A, Cebon J, Trau M. Char-acterising the phenotypic evolution of circulating tumour cells dur-ing treatment. Nat Commun. 2018; 9(1): 1482. doi: 10.1038/s41467- 018-03725-8
Paterlini-Bréchot P. Organ-specific markers in circulating tu-mor cell screening: An early indicator of metastasis-capable ma-lignancy. Future Oncol. 2011; 7(7): 849-871. doi: 10.2217/fon.11.32
Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004; 10(20): 6897-6904. doi: 10.1158/1078-0432.CCR-04-0378
Politaki E, Agelaki S, Apostolaki S, et al. A comparison of Three methods for the detection of circulating tumor cells in pa-tients with early and metastatic breast cancer. Cell Physiol Biochem. 2017; 44(2): 594-606. doi: 10.1159/000485115
Klein CA. Parallel progression of primary tumours and metas-tases. Nat Rev Cancer. 2009; 9(4): 302-312. doi: 10.1038/nrc2627
Li J, Sharkey CC, Wun B, Liesveld JL, King MR. Genetic engi-neering of platelets to neutralize circulating tumor cells. J Control Release. 2016; 228: 38-47. doi: 10.1016/j.jconrel.2016.02.036
Cross SE, Jin Y-S, Rao J, Gimzewski JK. Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol. 2007; 2(12): 780-783. doi: 10.1038/nnano.2007.388
Shaw Bagnall J, Byun S, Begum S, et al. Deformability of tu-mor cells versus blood cells. Sci. Rep. 2015; 5: 18542. doi: 10.1038/ srep18542
Guck J, Schinkinger S, Lincoln B, et al. Optical deformabil-ity as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys J. 2005; 88(5): 3689-3698. doi: 10.1529/biophysj.104.045476
Farace F, Massard C, Vimond N, et al. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in pa-tients with metastatic carcinomas. Br J Cancer. 2011; 105: 847-853. doi: 10.1038/bjc.2011.294
GE Healthcare. Isolation of mononuclear cells: Methodology and applications. Web site. https://www.sigmaaldrich.com/con-tent/dam/sigma-aldrich/docs/Sigma-Aldrich/General_Informa-tion/1/ge-isolation-of-mononuclear-cells.pdf. Accessed October 14, 2019.
Gertler RR, Fuehrer K, Dahm M, Nekarda H, Siewert JR. Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. In: Allgayer HMM, Schildberg FW, eds. Staging of Cancer. Recent Results in Cancer Research. Berlin, Heidel-berg: Springer; 2003.
Di Trapani M, Manaresi N, Medoro G. DEPArray™ system: An automatic image-based sorter for isolation of pure circulating tumor cells. Cytometry A. 2018; 93(12): 1260-1266. doi: 10.1002/ cyto.a.23687
Nagrath S, Sequist LV, Maheswaran S, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technolo-gy. Nature. 2007; 450(7173): 1235-1239. doi: 10.1038/nature06385
Placke T, Örgel M, Schaller M, et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012; 72(2): 440-448. doi: 10.1158/0008-5472.CAN-11-1872
Andree KC, van Dalum G, Terstappen LW. Challenges in cir-culating tumor cell detection by the CellSearch system. Mol Oncol. 2016; 10(3): 395-407. doi: 10.1016/j.molonc.2015.12.002
Riethdorf S, Fritsche H, Müller V, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: A validation study of the CellSearch system. Clin Cancer Res. 2007; 13(3): 920-928. doi: 10.1158/1078-0432.CCR-06-1695
Zhang L, Riethdorf S, Wu G, et al. Meta-analysis of the prog-nostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012; 18: 5701-5710. doi: 10.1158/1078-0432.CCR-12-1587
Bidard F-C, Peeters DJ, Fehm T, et al. Clinical validity of cir-culating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol. 2014; 15(4): 406-414. doi: 10.1016/S1470-2045(14)70069-5
Miller MC, Doyle GV, Terstappen LW. Significance of circu-lating tumor cells detected by the CellSearch system in patients McNamara MJ with metastatic breast colorectal and prostate cancer. J Oncol. 2010; 2010: 617421-617421. doi: 10.1155/2010/617421
Balic M, Dandachi N, Hofmann G, et al. Comparison of two methods for enumerating circulating tumor cells in carcinoma pa-tients. Cytometry B Clin Cytom. 2005; 68B(1): 25-30. doi: 10.1002/ cyto.b.20065
Allen JE, El-Deiry WS. Circulating tumor cells and colorectal cancer. Curr Colorectal Cancer Rep. 2010; 6(4): 212-220. doi: 10.1007/ s11888-010-0069-7
Fehm T, Müller V, Aktas B, et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010; 124(2): 403-412. doi: 10.1007/s10549-010-1163-x
Maly V, Maly O, Kolostova K, Bobek V. Circulating tumor cells in diagnosis and treatment of lung cancer. In Vivo. 2019; 33(4): 1027-1037. doi: 10.21873/invivo.11571
Matthew EM, Zhou L, Yang Z, et al. A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells. Oncotarget. 2016; 7(4): 3662-3676. doi: 10.18632/oncotarget.6657
Wong SC, Chan CM, Ma BB, et al. Clinical significance of cy-tokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients. Clin Cancer Res. 2009; 15(3): 1005-1012. doi: 10.1158/1078-0432. CCR-08-1515
Wong SCC, Ng SSM, Cheung MT, et al. Clinical significance of CDX2-positive circulating tumour cells in colorectal can-cer patients. Br J Cancer. 2011; 104(6): 1000-1006. doi: 10.1038/ bjc.2011.32
Alix-Panabières C, Pantel K. Clinical applications of circulat-ing tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov. 2016; 6(5): 479-491. doi: 10.1158/2159-8290.CD-15-1483
Marrinucci D, Bethel K, Bruce RH, et al. Case study of the morphologic variation of circulating tumor cells. Hum Pathol. 2007; 38(3): 514-519. doi: 10.1016/j.humpath.2006.08.027
Marrinucci D, Bethel K, Luttgen M, Bruce RH, Nieva J, Kuhn P. Circulating tumor cells from well-differentiated lung adenocar-cinoma retain cytomorphologic features of primary tumor type. Arch Pathol Lab Med. 2009; 133(9): 1468-1471. doi: 10.1043/1543- 2165-133.9.1468
Demay RM. The Art & Science of Cytopathology. 2nd ed. Chicago, USA: ASCP Press; 2011.
Hardingham JE, Hewett PJ, Sage RE, et al. Molecular detection of blood-borne epithelial cells in colorectal cancer patients and in patients with benign bowel disease. Int J Cancer. 2000; 89(1): 8-13.
Pantel K, Denève E, Nocca D, et al. Circulating epithelial cells in patients with benign colon diseases. Clin Chem. 2012; 58(5): 936- 940. doi: 10.1373/clinchem.2011.175570
Motherby H, Nadjari B, Friegel P, Kohaus J, Ramp U, Böcking A. Diagnostic accuracy of effusion cytology. Di-agn Cytopathol. 1999; 20(6): 350-357. doi: 10.1002/(sici)1097- 0339(199906)20:6<350::aid-dc5>3.0.co;2-7
Cakir E, Demirag F, Aydin M, Unsal E. Cytopathologic dif-ferential diagnosis of malignant mesothelioma, adenocarcinoma and reactive mesothelial cells: A logistic regression analysis. Diagnos Cytopathol. 2009; 37(1): 4-10. doi: 10.1002/dc.20938
Light RW. Pleural effusion. N Eng J Med. 2002; 346(25): 1971- 1977. doi: 10.1056/NEJMcp010731
Light RW, Erozan YS, Ball WC. Cells in pleural fluid: Their val-ue in differential diagnosis. JAMA Intern Med. 1973; 132: 854-860.
Prakash UBS, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: Analysis of 414 cases. Mayo Clin Proc. 1985; 60(3): 158-164. doi: 10.1016/ s0025-6196(12)60212-2
Pai R, Shenoy K, Minal J, Suresh P, Chakraborti S, Lobo F. Use of the term atypical cells in the reporting of ascitic fluid cytology: A caveat. Cytojournal. 2019; 16(1): 13. doi: 10.4103/cytojournal.cy-tojournal_37_18
Roh MH. Triage of cytologic direct smears for ancillary stud-ies: A case-based illustration and review. Arch Pathol Lab Med. 2013; 137(9): 1185-1190. doi: 10.5858/arpa.2013-0235-CR
Kim L, Tsao MS. Tumour tissue sampling for lung cancer man-agement in the era of personalised therapy: What is good enough for molecular testing? Eur Respir J. 2014; 44(4): 1011-1022. doi: 10.1183/09031936.00197013
Malapelle U, Bellevicine C, Zeppa P, Palombini L, Troncone G. Cytology-based gene mutation tests to predict response to anti-epidermal growth factor receptor therapy: A review. Diagn Cytopa-thol. 2011; 39(9): 703-710. doi: 10.1002/dc.21512
Nicholson AG, Gonzalez D, Shah P, et al. Refining the diagno-sis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis. J Thorac Oncol. 2010; 5(4): 436-441. doi: 10.1097/JTO.0b013e3181c6ed9b
Bochtler T, Krämer A. Does cancer of unknown primary (CUP) truly exist as a distinct cancer entity? Front Oncol. 2019; 9: 402. doi: 10.3389/fonc.2019.00402 27 McNamara MJ
Travis WD, Rekhtman N, Riley GJ, et al. Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: A paradigm shift. J Thorac Oncol. 2010; 5(4): 411-414. doi: 10.1097/ JTO.0b013e3181d57f6e
da Cunha Santos G, Saieg MA, Geddie W, Leighl N. EGFR gene status in cytological samples of nonsmall cell lung carcinoma. Cancer Cytopathol. 2011; 119(2): 80-91. doi: 10.1002/cncy.20150
Sun P-L, Jin Y, Kim H, Lee C-T, Jheon S, Chung J-H. High concordance of EGFR mutation status between histologic and corresponding cytologic specimens of lung adenocarcinomas. Cancer Cytopathol. 2013; 121(6): 311-319. doi: 10.1002/cncy.21260
Knoepp SM, Roh MH. Ancillary techniques on direct-smear as-pirate slides. Cancer Cytopathol. 2013; 121(3): 120-128. doi: 10.1002/ cncy.21214
Roy-Chowdhuri S. From cytopathology in focus: Updated NSCLC guideline moves molecular cytopathology forward. CAP Today. Web site. https://www.captodayonline.com/cytopatholo-gy-infocus-updated-nsclc-guideline-moves-molecular-cytopathol-ogy-forward/. Accessed October 14, 2019.
Chinen LTD, de Carvalho FM, Rocha BMM, et al. Cytokeratin-based CTC counting unrelated to clinical follow up. J Thorac Dis. 2013; 5(5): 593-599. doi: 10.3978/j.issn.2072-1439.2013.09.18
Ferreira MM, Ramani VC, Jeffrey SS. Circulating tumor cell technologies. Mol Oncol. 2016; 10(3): 374-394. doi: 10.1016/j. molonc.2016.01.007
Zheng S, Lin HK, Lu B, et al. 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Micro-devices. 2011; 13(1): 203-213. doi: 10.1007/s10544-010-9485-3
Lin E, Cao T, Nagrath S, King MR. Circulating tumor cells: Diagnostic and therapeutic applications. Ann Rev Biomed Eng. 2018; 20(1): 329-352. doi: 10.1146/annurev-bioeng-062117-120947
Peeters DJE, De Laere B, Van den Eynden GG, et al. Semiauto-mated isolation and molecular characterisation of single or highly purified tumour cells from CellSearch enriched blood samples us-ing dielectrophoretic cell sorting. Br J Cancer. 2013; 108(6): 1358- 1367. doi: 10.1038/bjc.2013.92
Baker MK, Mikhitarian K, Osta W, et al. Molecular detection of breast cancer cells in the peripheral blood of advanced-stage breast cancer patients using multimarker real-time reverse transcription-polymerase chain reaction and a novel porous barrier density gra-dient centrifugation technology. Clin Cancer Res. 2003; 9(13): 4865- 4871.
Gabriel MT, Calleja LR, Chalopin A, Ory B, Heymann D. Cir-culating tumor cells: A review of non–EpCAM-Based approaches for cell enrichment and isolation. Clin Chem. 2016; 62(4) :571-581. doi: 10.1373/clinchem.2015.249706
Bankó P, Lee SY, Nagygyörgy V, et al. Technologies for cir-culating tumor cell separation from whole blood. J Hematol Oncol. 2019; 12(1): 48. doi: 10.1186/s13045-019-0735-4
Harouaka RA, Nisic M, Zheng SY. Circulating tumor cell en-richment based on physical properties. J Lab Autom. 2013; 18(6): 455-468. doi: 10.1177/2211068213494391 Submit your article to this journal | https://openventio.org/submit-manuscript/ McNamara MJ
Lustberg M, Jatana KR, Zborowski M, Chalmers JJ. Emerg-ing technologies for CTC detection based on depletion of normal cells. Recent Results Cancer Res. 2012; 195: 97-110. doi: 10.1007/978- 3-642-28160-0_9
Yin J, Wang Y, Yin H, et al. Circulating tumor cells enriched by the depletion of leukocytes with bi-antibodies in non-small cell lung cancer: Potential clinical application. PLoS One. 2015; 10(8): e0137076-e0137076. doi: 10.1371/journal.pone.0137076
Downloads
Published
How to Cite
Issue
Section
License

This work is licensed under a Creative Commons Attribution 4.0 International License.
All content published in Pathology and Laboratory Medicine (PLM) is licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license allows anyone to copy, distribute, transmit, and adapt the work — including for commercial purposes — provided appropriate credit is given to the original author(s) and source.