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Title of Journal: Cancer Microenvironment

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Abbravation: Cancer Microenvironment

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Springer Netherlands

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10.1002/ajpa.1330360326

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1875-2284

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Circulating Tumor Cells: Who is the Killer?

Authors: Patrizia Paterlini-Bréchot,

Publish Date: 2014/12/20
Volume: 7, Issue:3, Pages: 161-176
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Abstract

This article is a critical note on the subject of Circulating Tumor Cells (CTC). It takes into account the tumor identity of Circulating Tumor Cells as cancer seeds in transit from primary to secondary soils, rather than as a “biomarker”, and considers the help this field could bring to cancer patients. It is not meant to duplicate information already available in a large number of reviews, but to stimulate considerations, further studies and development helping the clinical use of tumor cells isolated from blood as a modern personalized, non-invasive, predictive test to improve cancer patients’ life. The analysis of CTC challenges, methodological bias and critical issues points out to the need of referring to tumor cells extracted from blood without any bias and identified by cytopathological diagnosis as Circulating Cancer Cells (CCC). Finally, this article highlights recent developments and identifies burning questions which should be addressed to improve our understanding of the domain of CCC and their potential to change the clinical practice.Some words bear a deadly meaning. The word “killer” means «who can kill ». Likewise, the word “tumor cell” means “potentially tumorigenic”. Killers identification is clearly easier when they are found on the crime scene, alias the primary or metastatic tumor, than if they are in the street. These “killers in the street” are circulating tumor cells (CTC).Our work and interest in the domain of CTC and the study of the “CTC literature” has generated the view that the possibility to improve cancer patients’ life using CTC- based tests is linked to their unbiased isolation and identification without mistake.This article is a critical note on CTC which takes into account the tumor identity of Circulating Tumor Cells as cancer seeds in transit from the primary to the secondary soils, and the change that this field could bring to the clinical practice. It is not meant to duplicate information already available in a large number of reviews [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11], but to stimulate consideration, studies and further development helping the successful clinical use of CTC, as a modern personalized, non-invasive, predictive test to improve cancer patients’ life. Since we focus on a non-invasive test, Disseminated Tumor Cells (DTC), which are tumor cells located in the bone marrow, lymph nodes or distant organs, and angiotropic tumor cells [12], which are tumor cells migrating along the vessels, despite their relevance for the appraisal of tumor invasion, are not in the scope of this article.Tumor invasion and formation of distant metastasis is known to occur via three major routes: i) blood, ii) lymphatic vessels, and iii) transcoelomic spread into the pleural, pericardial, and abdominal cavities [14], to which Lugassy and Barnhill [12] have added the angiotropic tumor cells invasion. Of these fourth routes, only blood can be exploited to develop an early and non-invasive detection of tumor invasion, which could be of clinical help by taking advantage from the slow and inefficient process leading to metastasis formation [13, 15].For patients with solid cancer, the sensitive and reliable detection and enumeration of cancer cells in blood is expected to provide a powerful diagnostic tool for early detection of tumor invasion and early assessment of treatment efficacy. Furthermore, genetic tests targeted to circulating cancer cells collected without bias and diagnosed without mistake could allow the kinetic assessment of theranostic/escape DNA mutations in the circulating cancer cell compartment (non-invasive theranostic use of CTC). For subjects at increased risk of developing solid cancers, the ultrasensitive and diagnostic detection of cancer cells in blood could provide a tool for early diagnosis of invasive cancers before they become detectable by imaging. This would be a remarkable step forward to decrease mortality related to invasive cancers, and would require not only diagnostic identification of cancer cells in blood but also characterization analyses to identify the organ from which the cancer cells have spread.However, the CTC field is far from these goals. Its critical analysis shows that, despite more than 15,190 publications and 270 clinical trials [16], CTC are not really implemented in clinical practice, are generally not recognized to be of “clinical utility” [11], and many trials evaluate their impact in metastatic patients, when “it is too late”. Therefore, it is also our responsibility, as physicians and scientists working in the field of CTC, to try to understand the causes impairing the energies, time and money devoted to this topic.


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