Alama, A

Coco, S

Grossi, F

Vanni, I

International Journal of Molecular Sciences

English

Angela Alama

Simona Coco

Irene Vanni

Francesco Grossi

Directory of Open Access Journals

Reply to the Letter to the Editor by C. Nicolazzo et al.: “Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy”

Reply: Thank you for the valuable comments. We agree with the concern that distinguishing genuine circulating tumor cells (CTCs) from other circulating cells by morphology may be questionable.[...

Multidisciplinary Digital Publishing Institute

Alama A.

Coco S.

Vanni I.

Grossi F.

Archivio istituzionale della ricerca - Università di Genova

 International Journal of Molecular SciencesReplyReply to the Letter to the Editor by C. Nicolazzo et al.:“Circulating Cell-Free DNA and Circulating TumorCells as Prognostic and Predictive Biomarkers inAdvanced Non-Small Cell Lung Cancer PatientsTreated with First-Line Chemotherapy”Angela Alama *, Simona Coco, Irene Vanni and Francesco GrossiLung Cancer Unit, IRCCS AOU San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi 10,16132 Genova, Italy; simona.coco@hsanmartino.it (S.C.); irene.vanni@hsanmartino.it (I.V.);francesco.grossi@hsanmartino.it (F.G.)* Correspondence: angela.alama@hsanmartino.it; Tel.: +39-010-5550-8318Academic Editors: William Chi-shing Cho and Stephen A. BustinReceived: 16 June 2017; Accepted: 16 June 2017; Published: 19 June 2017Reply:Thank you for the valuable comments. We agree with the concern that distinguishing genuinecirculating tumor cells (CTCs) from other circulating cells by morphology may be questionable.Currently, the CellSearch isolation system (Janssen Diagnostics, Raritan, NJ, USA) is the only Foodand Drug Administration (FDA) approved methodology to identify CTCs in breast, prostate andcolon cancers. [1,2]. However, immunophenotyping with pan-cytokeratins and CD45 (for leukocytes)cannot ensure the certain nature of neoplastic elements shed from primary or metastatic tumorsinto the bloodstream. Indeed, circulating cells with epithelial-to-mesenchymal transition phenotypes(reduced or absent epithelial cell adhesion molecule (EpCAM) expression) are often missed by thistechnique and can be underestimated [3]. For the same reason, the characterization of CTCs solelyusing a panel of cytokeratins in non-small-cell lung cancer (NSCLC) remains a matter of debate [4]and, to the best of our knowledge, data on CTC expressing thyroid transcription factor 1 (TTF-1) inNSCLC are rare and not conclusive [5]. In the attempt to overcome this controversial issue, we referredto the isolated non-hematologic circulating cells with malignant features in our study. These cellswere morphologically identified and enumerated according to the criteria described by Wechsler [6]excluding clearly distinguishable contaminant leukocytes and ambiguous elements such as circulatinggiant macrophages, monocytes and megakaryocytes, if present.In a preliminary explorative study, we investigated the presence of suspicious malignant elementsin the peripheral blood of cancer patients and healthy individuals by morphology associated toimmunofluorescence for 4',6-diamidino-2-phenylindole (DAPI) and cytokeratin 7 (CK7). Moreover, ina collaboration study with Bozzetti et al. [7], a non-EpCAM-based capture method was performed toisolate and characterize suspicious malignant elements in the peripheral blood of cancer patients andhealthy subjects. Unexpectedly, after depletion of leukocytes and erythroid cells, suspicious circulatingelements were also found in healthy individuals [7].As correctly suggested, additional molecular characterizations of isolated non-hematologiccirculating cells with malignant features would help support our results. However, immunocytochemicaland/or molecular investigations are not always feasible for the low presence of suspicious cells requiringreliable challenging procedures to confirm their malignant origin.Int. J. Mol. Sci. 2017, 18, 1309; doi:10.3390/ijms18061309 www.mdpi.com/journal/ijmsInt. J. Mol. Sci. 2017, 18, 1309 2 of 2Acknowledgments: Simona Coco is a PhD supported by Italian Ministry of Health (GR 2011-12; 02350922).Conflicts of Interest: The authors declare no conflict of interest.References1. Allard, W.J.; Matera, J.; Miller, M.C.; Repollet, M.; Connelly, M.C.; Rao, C.; Tibbe, A.G.; Uhr, J.W.;Terstappen, L.W. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthysubjects or patients with nonmalignant diseases. Clin. Cancer Res. 2004, 10, 6897–6904. [CrossRef] [PubMed]2. Cell Search. Available online: http://www.cellsearchctc.com/ (accessed on 14 June 2017).3. Hanseen, A.; Loges, S.; Pantel, K.; Wikman, H. Detection of Circulating Tumor Cells in Non-Small Cell LungCancer. Front. Oncol. 2015, 5, 207. [CrossRef] [PubMed]4. Alama, A.; Truini, A.; Coco, S.; Genova, C.; Grossi, F. Prognostic and predictive relevance of circulatingtumor cells in patients with non-small-cell lung cancer. Drug Discov. Today 2014, 19, 1671–1676. [CrossRef][PubMed]5. Lu, S.H.; Tsai, W.S.; Chang, Y.H.; Chou, T.Y.; Pang, S.T.; Lin, P.H.; Tsai, C.M.; Cha, Y.C. Identifying cancerorigin using circulating tumor cells. Cancer Biol. Ther. 2016, 17, 430–438. [CrossRef] [PubMed]6. Wechsler, J. Cellules Tumorales Circulantes des Cancers Solides/Circulating Tumor Cells from Solid Cancers;Sauramps Medical: Montpellier, France, 2015; pp. 1–72.7. Bozzetti, C.; Quaini, F.; Squadrilli, A.; Tiseo, M.; Frati, C.; Lagrasta, C.; Azzoni, C.; Bottarelli, L.; Galetti, M.;Alama, A.; et al. Isolation and Characterization of Circulating Tumor Cells in Squamous Cell Carcinoma ofthe Lung Using a Non-EpCAM-Based Capture Method. PLoS ONE 2015, 10, 0142891. [CrossRef] [PubMed]© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Reply to the Letter to the Editor by C. Nicolazzo et al.: “Circulating cell-free DNA and circulating tumor cells as prognostic and predictive biomarkers in advanced non-small cell lung cancer patients treated with first-line chemotherapy”

Alama A

Coco S

Vanni I

Grossi F

Archivio istituzionale della ricerca - Università dell'Insubria

reply to the letter to the editor by C.Nicolazzo et al.: "circulating cell-free DNA and circulating tumor cells as prognostic and predictive biomarkers in advanced non-small cell lung cancer patients treated with first-line chemotherapy"

https://iris.unige.it/bitstream/11567/1035708/1/ijms-18-01309.pdf

reply to the letter to the editor by C.Nicolazzo et al.: "circulating cell-free DNA and circulating tumor cells as prognostic and predictive biomarkers in advanced non-small cell lung cancer patients treated with first-line chemotherapy"

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Archivio istituzionale della ricerca - Università di Genova

Archivio istituzionale della ricerca - Università dell'Insubria