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Circulating Tumour Cells from Patients with Colorectal Cancer Have Gut Online First, published on July 25, 2016 as 10.1136/gutjnl-2016-311447 GI cancer ORIGINAL ARTICLE Circulating tumour cells from patients with Gut: first published as 10.1136/gutjnl-2016-311447 on 25 July 2016. Downloaded from colorectal cancer have cancer stem cell hallmarks in ex vivo culture Fanny Grillet,1,2,3 Elsa Bayet,1,2,3 Olivia Villeronce,1,2,3 Luke Zappia,4 Ebba Louise Lagerqvist,1,2,3 Sebastian Lunke,4 Emmanuelle Charafe-Jauffret,5 Kym Pham,4,6 Christina Molck,4 Nathalie Rolland,7 Jean François Bourgaux,8 Michel Prudhomme,9 Claire Philippe,9 Sophie Bravo,10 Jean Christophe Boyer,10 Lucile Canterel-Thouennon,11 Graham Roy Taylor,4 Arthur Hsu,4 Jean Marc Pascussi,1,2,3 Frédéric Hollande,1,2,3,4 Julie Pannequin1,2,3 ▸ Additional material is ABSTRACT published online only. To view Objective Although counting of circulating tumour Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ cells (CTC) has attracted a broad interest as potential gutjnl-2016-311447). markers of tumour progression and treatment response, the lack of functional characterisation of these cells had What is already known on this subject? become a bottleneck in taking these observations to the ▸ fi Circulating tumour cells (CTCs) contain key For numbered af liations see clinic. Our objective was to culture these cells in order to end of article. prognostic markers for patients with metastatic understand them and exploit their therapeutic potential colorectal cancer (CRC). Correspondence to to the full. ▸ CTCs are scarce among blood cells and they are Dr Julie Pannequin, Design Here, hypothesising that some CTC potentially also heterogeneous. Institut de Génomique have cancer stem cell (CSC) phenotype, we generated ▸ Functional characterisation of CTCs is thus Fonctionnelle, 141 rue de la Cardonille, Montpellier Cedex several CTC lines from the blood of patients with needed. 34094, France; advanced metastatic colorectal cancer (CRC) based on ▸ In vitro CTC models are lacking in the CRC [email protected] their self-renewal abilities. Multiple standard tests were field. then employed to characterise these cells. Frédéric Hollande, Department Results Our CTC lines self-renew, express CSC markers What are the new findings? http://gut.bmj.com/ of Pathology, University of and have multilineage differentiation ability, both in vitro ▸ CTC lines contain functional cancer stem cells. Melbourne, Parkville, Victoria, ▸ Australia; frederic.hollande@ and in vivo. Patient-derived CTC lines are tumorigenic in CTC lines are genetically and phenotypically unimelb.edu.au subcutaneous xenografts and are also able to colonise heterogeneous. the liver after intrasplenic injection. RNA sequencing ▸ Identification of gene subset commonly EB, OV and LZ contributed enriched in cultured CTC of the present study equally. analyses strikingly demonstrate that drug metabolising FH and JP jointly supervised pathways represent the most upregulated feature among and previously published CTCs from colon and this work. CTC lines in comparison with primary CRC cells grown other cancers. on September 25, 2021 by guest. Protected copyright. under similar conditions. This result is corroborated by ▸ CTC lines express high levels of drug Received 12 January 2016 the high resistance of the CTC lines to conventional metabolism genes and are resistant to Revised 20 June 2016 conventional therapies. Accepted 22 June 2016 cytotoxic compounds. Conclusions Taken together, our results directly How might it impact on clinical practice in demonstrate the existence of patient-derived colorectal the foreseeable future? CTCs that bear all the functional attributes of CSCs. The ▸ This study is the first experimental CTC culture model described here is simple and takes demonstration that CTCs isolated from patients <1 month from blood collection to drug testing, with CRC express cancer stem cell phenotype therefore, routine clinical application could facilitate and can be used to determine drug sensitivity access to personalised medicine. thus, culturing CTCs could drive a personalised Clinical Trial Registration ClinicalTrial.gov approach to patients with metastatic CRC. NCT01577511. vast majority of deaths from colorectal cancer INTRODUCTION (CRC),3 making it the third leading cause of cancer To cite: Grillet F, Bayet E, Circulating tumour cells (CTCs) are commonly death in the developed world. In recent years, Villeronce O, et al. Gut 1 Published Online First: present in the blood of solid cancer patients, CTCs have attracted interest as a precious tool to [please include Day Month transit through the bloodstream and constitute better understand mechanisms underlying meta- Year] doi:10.1136/gutjnl- seeds for subsequent metastasis development in static progression and also as clinically relevant 2016-311447 distant organs.2 This process is responsible for the prognostic markers, since the number of CTCs has Grillet F, et al. Gut 2016;0:1–9. doi:10.1136/gutjnl-2016-311447 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BSG) under licence. GI cancer been correlated with poor prognosis notably in patients with metastasis biopsies from patients 44 and 45 are shown in online CRC.4 supplementary figure S1. Two important obstacles currently hamper our ability to gain Gut: first published as 10.1136/gutjnl-2016-311447 on 25 July 2016. Downloaded from deeper understanding of CTCs: their heterogeneity and scarcity. CTC cell lines contain multipotent cells responsible for These problems have recently been partially overcome by single phenotypic heterogeneity cell analyses such as RNA or exon sequencing.56While these We then observed that the three CTC lines were able to differ- studies did not address the functional aspects of CTC biology, entiate towards all three main intestinal lineages in they did identify different CTC subpopulations within a single vivo (figure 2A) and in vitro within spheres (figure 2B). blood sample.7 Heterogeneity of CTCs has been demonstrated Indeed, terminally differentiated cells expressing markers of at the phenotypic level in breast cancer.8 In CRC, potential enteroendocrine-like cells (chromogranin-A), goblet cells CTC markers such as plastin 3 have been proposed but are yet (mucin-2) and enterocyte cells (villin) were represented within to be validated,9 and aneuploidy has been used to detect CTCs CTC spheres and CTC-derived xenografts. To determine whether that undergo epithelial to mesenchymal transition.10 Although the presence of cells with multiple different phenotypes emerged the scarcity of CTCs has restricted the number of functional from the presence of cells with multipotent ability within these studies, subpopulations of metastasis-initiating breast cancer cell lines, we amplified several clones established from single CTCs11 and tumorigenic lung cancer CTCs12 have been cells. Multiple lineages were also represented in several of these described in vivo, and molecular characterisation studies have single cell-derived clones (figure 2C), demonstrating that pheno- suggested that CTC-driven metastatic progression might rely typic heterogeneity in these patient-derived CTC populations upon their cancer stem cell (CSC) properties.13 Culturing emerges from the presence of multipotent cells, which strongly human CTCs would overcome the difficulty of characterising suggests that CSCs are present in these cell populations. these rare cells and allow both researchers and clinicians to study them. Accordingly, recent publications in several CTC lines display hallmarks of CSCs – cancers14 17 have described in vitro CTC culture models. We then determined that the CTC lines had the ability to self- However, for CRC research, thorough general functional char- renew over long periods (20 passages) when grown as spheroids acterisation of CTCs still represents a major challenge as sys- in serum-free medium at very low density. Using extreme limit- temic CTC number is particularly low compared with other ing dilution analysis19 on spheres that were passaged at least 3 solid cancers.18 times, we quantified CSC frequency and found that CTC41, In order to functionally characterise colorectal CTCs, we CTC44 and CTC45, respectively contained 4.2, 1.3 and 1.2% developed CTC lines from several patients with metastatic CRC, self-renewing cells (figure 3A). In following experiments, we by growing them under conditions that promote the survival of compared CTC lines with cell lines freshly established from self-renewing cells. Our CTC lines were compared with some of primary tumours (CPP24, CPP25 and CPP44) or liver metasta- the established patient-derived cells isolated from primary sis biopsies (CPP19, CPP30 and CPP45) and grown in suspen- tumours and liver metastases in our team; and grown under the sion under similar conditions (table 1). Importantly, the CTC44 same conditions. We demonstrate that CTC lines contain cells and CTC45 lines were isolated from the same patients, respect- http://gut.bmj.com/ that have the functional characteristics of CSCs as they have ively, as CPP44 and CPP45. Clinical data for each of these maintained their self-renewal and multilineage differentiation patients are detailed in the online supplementary table 2. We properties. These cells robustly express CSC markers and were also used HT29, a cell line known to have a strong CSC able to initiate metastasis development in vivo. Strikingly, we phenotype.20 found clear overexpression of genes involved in xenobiotic To validate the strong
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