Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture
Identifieur interne : 000A71 ( Pmc/Checkpoint ); précédent : 000A70; suivant : 000A72Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture
Auteurs : Fanny Grillet [France] ; Elsa Bayet [France] ; Olivia Villeronce [France] ; Luke Zappia [Australie] ; Ebba Louise Lagerqvist [France] ; Sebastian Lunke [Australie] ; Emmanuelle Charafe-Jauffret [France] ; Kym Pham [Australie] ; Christina Molck [Australie] ; Nathalie Rolland [France] ; Jean François Bourgaux [France] ; Michel Prudhomme [France] ; Claire Philippe [France] ; Sophie Bravo [France] ; Jean Christophe Boyer [France] ; Lucile Canterel-Thouennon [France] ; Graham Roy Taylor [Australie] ; Arthur Hsu [Australie] ; Jean Marc Pascussi [France] ; Frédéric Hollande [France, Australie] ; Julie Pannequin [France]Source :
- Gut [ 0017-5749 ] ; 2016.
Abstract
Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.
Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.
Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both
Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.
ClinicalTrial.gov NCT01577511.
Url:
DOI: 10.1136/gutjnl-2016-311447
PubMed: 27456153
PubMed Central: 5595103
Affiliations:
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PMC:5595103Le document en format XML
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<author><name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
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<affiliation wicri:level="1"><nlm:aff id="af3"><institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zappia, Luke" sort="Zappia, Luke" uniqKey="Zappia L" first="Luke" last="Zappia">Luke Zappia</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lagerqvist, Ebba Louise" sort="Lagerqvist, Ebba Louise" uniqKey="Lagerqvist E" first="Ebba Louise" last="Lagerqvist">Ebba Louise Lagerqvist</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><institution>Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af2"><institution>Institut National de la Santé et de la Recherche Médicale, U661</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lunke, Sebastian" sort="Lunke, Sebastian" uniqKey="Lunke S" first="Sebastian" last="Lunke">Sebastian Lunke</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Charafe Jauffret, Emmanuelle" sort="Charafe Jauffret, Emmanuelle" uniqKey="Charafe Jauffret E" first="Emmanuelle" last="Charafe-Jauffret">Emmanuelle Charafe-Jauffret</name>
<affiliation wicri:level="1"><nlm:aff id="af5"><institution>Centre de Recherche en Cancérologie de Marseille, U1068 Inserm</institution>
,<addr-line>Marseille</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pham, Kym" sort="Pham, Kym" uniqKey="Pham K" first="Kym" last="Pham">Kym Pham</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af6"><institution>Center for Translational Pathology, The University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Molck, Christina" sort="Molck, Christina" uniqKey="Molck C" first="Christina" last="Molck">Christina Molck</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rolland, Nathalie" sort="Rolland, Nathalie" uniqKey="Rolland N" first="Nathalie" last="Rolland">Nathalie Rolland</name>
<affiliation wicri:level="1"><nlm:aff id="af7"><institution>Service d'anatomopathologie, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bourgaux, Jean Francois" sort="Bourgaux, Jean Francois" uniqKey="Bourgaux J" first="Jean François" last="Bourgaux">Jean François Bourgaux</name>
<affiliation wicri:level="1"><nlm:aff id="af8"><institution>Service d'Hépato-Gastroentérologie, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Prudhomme, Michel" sort="Prudhomme, Michel" uniqKey="Prudhomme M" first="Michel" last="Prudhomme">Michel Prudhomme</name>
<affiliation wicri:level="1"><nlm:aff id="af9"><institution>Service de Chirurgie Digestive, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Philippe, Claire" sort="Philippe, Claire" uniqKey="Philippe C" first="Claire" last="Philippe">Claire Philippe</name>
<affiliation wicri:level="1"><nlm:aff id="af9"><institution>Service de Chirurgie Digestive, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bravo, Sophie" sort="Bravo, Sophie" uniqKey="Bravo S" first="Sophie" last="Bravo">Sophie Bravo</name>
<affiliation wicri:level="1"><nlm:aff id="af10"><addr-line>Laboratoire de Biochimie</addr-line>
,<institution>CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Boyer, Jean Christophe" sort="Boyer, Jean Christophe" uniqKey="Boyer J" first="Jean Christophe" last="Boyer">Jean Christophe Boyer</name>
<affiliation wicri:level="1"><nlm:aff id="af10"><addr-line>Laboratoire de Biochimie</addr-line>
,<institution>CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Canterel Thouennon, Lucile" sort="Canterel Thouennon, Lucile" uniqKey="Canterel Thouennon L" first="Lucile" last="Canterel-Thouennon">Lucile Canterel-Thouennon</name>
<affiliation wicri:level="1"><nlm:aff id="af11"><institution>Plateforme MPCC—SIRIC Montpellier Cancer, IRCM</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Taylor, Graham Roy" sort="Taylor, Graham Roy" uniqKey="Taylor G" first="Graham Roy" last="Taylor">Graham Roy Taylor</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hsu, Arthur" sort="Hsu, Arthur" uniqKey="Hsu A" first="Arthur" last="Hsu">Arthur Hsu</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><institution>Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af2"><institution>Institut National de la Santé et de la Recherche Médicale, U661</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><institution>Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af2"><institution>Institut National de la Santé et de la Recherche Médicale, U661</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><institution>Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af2"><institution>Institut National de la Santé et de la Recherche Médicale, U661</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Gut</title>
<idno type="ISSN">0017-5749</idno>
<idno type="eISSN">1468-3288</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Objective</title>
<p>Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.</p>
</sec>
<sec><title>Design</title>
<p>Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.</p>
</sec>
<sec><title>Results</title>
<p>Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both <italic>in vitro</italic>
and <italic>in vivo</italic>
. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.</p>
</sec>
<sec><title>Conclusions</title>
<p>Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.</p>
</sec>
<sec><title>Clinical Trial Registration</title>
<p>ClinicalTrial.gov NCT01577511.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Gut</journal-id>
<journal-id journal-id-type="iso-abbrev">Gut</journal-id>
<journal-id journal-id-type="hwp">gutjnl</journal-id>
<journal-id journal-id-type="publisher-id">gut</journal-id>
<journal-title-group><journal-title>Gut</journal-title>
</journal-title-group>
<issn pub-type="ppub">0017-5749</issn>
<issn pub-type="epub">1468-3288</issn>
<publisher><publisher-name>BMJ Publishing Group</publisher-name>
<publisher-loc>BMA House, Tavistock Square, London, WC1H 9JR</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27456153</article-id>
<article-id pub-id-type="pmc">5595103</article-id>
<article-id pub-id-type="publisher-id">gutjnl-2016-311447</article-id>
<article-id pub-id-type="doi">10.1136/gutjnl-2016-311447</article-id>
<article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>1506</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>GI cancer</subject>
</subj-group>
<series-title>Original article</series-title>
</article-categories>
<title-group><article-title>Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in <italic>ex vivo</italic>
culture</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Grillet</surname>
<given-names>Fanny</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
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<given-names>Elsa</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
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<given-names>Olivia</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zappia</surname>
<given-names>Luke</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
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<given-names>Ebba Louise</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
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<given-names>Sebastian</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
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<contrib contrib-type="author"><name><surname>Charafe-Jauffret</surname>
<given-names>Emmanuelle</given-names>
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<xref ref-type="aff" rid="af5">5</xref>
</contrib>
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<given-names>Kym</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
<xref ref-type="aff" rid="af6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Molck</surname>
<given-names>Christina</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rolland</surname>
<given-names>Nathalie</given-names>
</name>
<xref ref-type="aff" rid="af7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bourgaux</surname>
<given-names>Jean François</given-names>
</name>
<xref ref-type="aff" rid="af8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Prudhomme</surname>
<given-names>Michel</given-names>
</name>
<xref ref-type="aff" rid="af9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Philippe</surname>
<given-names>Claire</given-names>
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<xref ref-type="aff" rid="af9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bravo</surname>
<given-names>Sophie</given-names>
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<xref ref-type="aff" rid="af10">10</xref>
</contrib>
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<given-names>Jean Christophe</given-names>
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<xref ref-type="aff" rid="af10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Canterel-Thouennon</surname>
<given-names>Lucile</given-names>
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<xref ref-type="aff" rid="af11">11</xref>
</contrib>
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<given-names>Graham Roy</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
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<given-names>Arthur</given-names>
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<xref ref-type="aff" rid="af4">4</xref>
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<given-names>Jean Marc</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
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<given-names>Frédéric</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
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<xref ref-type="aff" rid="af4">4</xref>
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<given-names>Julie</given-names>
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<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
</contrib-group>
<aff id="af1"><label>1</label>
<institution>Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</aff>
<aff id="af2"><label>2</label>
<institution>Institut National de la Santé et de la Recherche Médicale, U661</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</aff>
<aff id="af3"><label>3</label>
<institution>Université de Montpellier, UMR5203</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</aff>
<aff id="af4"><label>4</label>
<addr-line>Department of Pathology</addr-line>
,<institution>University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</aff>
<aff id="af5"><label>5</label>
<institution>Centre de Recherche en Cancérologie de Marseille, U1068 Inserm</institution>
,<addr-line>Marseille</addr-line>
,<country>France</country>
</aff>
<aff id="af6"><label>6</label>
<institution>Center for Translational Pathology, The University of Melbourne</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</aff>
<aff id="af7"><label>7</label>
<institution>Service d'anatomopathologie, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</aff>
<aff id="af8"><label>8</label>
<institution>Service d'Hépato-Gastroentérologie, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</aff>
<aff id="af9"><label>9</label>
<institution>Service de Chirurgie Digestive, CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</aff>
<aff id="af10"><label>10</label>
<addr-line>Laboratoire de Biochimie</addr-line>
,<institution>CHU Carémeau</institution>
,<addr-line>Nîmes</addr-line>
,<country>France</country>
</aff>
<aff id="af11"><label>11</label>
<institution>Plateforme MPCC—SIRIC Montpellier Cancer, IRCM</institution>
,<addr-line>Montpellier</addr-line>
,<country>France</country>
</aff>
<author-notes><corresp><label>Correspondence to</label>
Dr Julie Pannequin, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, Montpellier Cedex 34094, France; <email>julie.pannequin@igf.cnrs.fr</email>
Frédéric Hollande, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; <email>frederic.hollande@unimelb.edu.au</email>
</corresp>
<fn><p>EB, OV and LZ contributed equally. FH and JP jointly supervised this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>10</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="epub"><day>25</day>
<month>7</month>
<year>2016</year>
</pub-date>
<volume>66</volume>
<issue>10</issue>
<fpage>1802</fpage>
<lpage>1810</lpage>
<history><date date-type="received"><day>12</day>
<month>1</month>
<year>2016</year>
</date>
<date date-type="rev-recd"><day>20</day>
<month>6</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>22</day>
<month>6</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/</copyright-statement>
<copyright-year>2016</copyright-year>
<license license-type="open-access"><license-p>This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>
</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:href="gutjnl-2016-311447.pdf"></self-uri>
<abstract><sec><title>Objective</title>
<p>Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.</p>
</sec>
<sec><title>Design</title>
<p>Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.</p>
</sec>
<sec><title>Results</title>
<p>Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both <italic>in vitro</italic>
and <italic>in vivo</italic>
. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.</p>
</sec>
<sec><title>Conclusions</title>
<p>Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.</p>
</sec>
<sec><title>Clinical Trial Registration</title>
<p>ClinicalTrial.gov NCT01577511.</p>
</sec>
</abstract>
<kwd-group><kwd>COLORECTAL CANCER</kwd>
<kwd>LIVER METASTASES</kwd>
<kwd>DRUG TOXICITY</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>special-feature</meta-name>
<meta-value>unlocked</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>France</li>
</country>
</list>
<tree><country name="France"><noRegion><name sortKey="Grillet, Fanny" sort="Grillet, Fanny" uniqKey="Grillet F" first="Fanny" last="Grillet">Fanny Grillet</name>
</noRegion>
<name sortKey="Bayet, Elsa" sort="Bayet, Elsa" uniqKey="Bayet E" first="Elsa" last="Bayet">Elsa Bayet</name>
<name sortKey="Bayet, Elsa" sort="Bayet, Elsa" uniqKey="Bayet E" first="Elsa" last="Bayet">Elsa Bayet</name>
<name sortKey="Bayet, Elsa" sort="Bayet, Elsa" uniqKey="Bayet E" first="Elsa" last="Bayet">Elsa Bayet</name>
<name sortKey="Bourgaux, Jean Francois" sort="Bourgaux, Jean Francois" uniqKey="Bourgaux J" first="Jean François" last="Bourgaux">Jean François Bourgaux</name>
<name sortKey="Boyer, Jean Christophe" sort="Boyer, Jean Christophe" uniqKey="Boyer J" first="Jean Christophe" last="Boyer">Jean Christophe Boyer</name>
<name sortKey="Bravo, Sophie" sort="Bravo, Sophie" uniqKey="Bravo S" first="Sophie" last="Bravo">Sophie Bravo</name>
<name sortKey="Canterel Thouennon, Lucile" sort="Canterel Thouennon, Lucile" uniqKey="Canterel Thouennon L" first="Lucile" last="Canterel-Thouennon">Lucile Canterel-Thouennon</name>
<name sortKey="Charafe Jauffret, Emmanuelle" sort="Charafe Jauffret, Emmanuelle" uniqKey="Charafe Jauffret E" first="Emmanuelle" last="Charafe-Jauffret">Emmanuelle Charafe-Jauffret</name>
<name sortKey="Grillet, Fanny" sort="Grillet, Fanny" uniqKey="Grillet F" first="Fanny" last="Grillet">Fanny Grillet</name>
<name sortKey="Grillet, Fanny" sort="Grillet, Fanny" uniqKey="Grillet F" first="Fanny" last="Grillet">Fanny Grillet</name>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<name sortKey="Lagerqvist, Ebba Louise" sort="Lagerqvist, Ebba Louise" uniqKey="Lagerqvist E" first="Ebba Louise" last="Lagerqvist">Ebba Louise Lagerqvist</name>
<name sortKey="Lagerqvist, Ebba Louise" sort="Lagerqvist, Ebba Louise" uniqKey="Lagerqvist E" first="Ebba Louise" last="Lagerqvist">Ebba Louise Lagerqvist</name>
<name sortKey="Lagerqvist, Ebba Louise" sort="Lagerqvist, Ebba Louise" uniqKey="Lagerqvist E" first="Ebba Louise" last="Lagerqvist">Ebba Louise Lagerqvist</name>
<name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
<name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
<name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
<name sortKey="Philippe, Claire" sort="Philippe, Claire" uniqKey="Philippe C" first="Claire" last="Philippe">Claire Philippe</name>
<name sortKey="Prudhomme, Michel" sort="Prudhomme, Michel" uniqKey="Prudhomme M" first="Michel" last="Prudhomme">Michel Prudhomme</name>
<name sortKey="Rolland, Nathalie" sort="Rolland, Nathalie" uniqKey="Rolland N" first="Nathalie" last="Rolland">Nathalie Rolland</name>
<name sortKey="Villeronce, Olivia" sort="Villeronce, Olivia" uniqKey="Villeronce O" first="Olivia" last="Villeronce">Olivia Villeronce</name>
<name sortKey="Villeronce, Olivia" sort="Villeronce, Olivia" uniqKey="Villeronce O" first="Olivia" last="Villeronce">Olivia Villeronce</name>
<name sortKey="Villeronce, Olivia" sort="Villeronce, Olivia" uniqKey="Villeronce O" first="Olivia" last="Villeronce">Olivia Villeronce</name>
</country>
<country name="Australie"><noRegion><name sortKey="Zappia, Luke" sort="Zappia, Luke" uniqKey="Zappia L" first="Luke" last="Zappia">Luke Zappia</name>
</noRegion>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<name sortKey="Hsu, Arthur" sort="Hsu, Arthur" uniqKey="Hsu A" first="Arthur" last="Hsu">Arthur Hsu</name>
<name sortKey="Lunke, Sebastian" sort="Lunke, Sebastian" uniqKey="Lunke S" first="Sebastian" last="Lunke">Sebastian Lunke</name>
<name sortKey="Molck, Christina" sort="Molck, Christina" uniqKey="Molck C" first="Christina" last="Molck">Christina Molck</name>
<name sortKey="Pham, Kym" sort="Pham, Kym" uniqKey="Pham K" first="Kym" last="Pham">Kym Pham</name>
<name sortKey="Pham, Kym" sort="Pham, Kym" uniqKey="Pham K" first="Kym" last="Pham">Kym Pham</name>
<name sortKey="Taylor, Graham Roy" sort="Taylor, Graham Roy" uniqKey="Taylor G" first="Graham Roy" last="Taylor">Graham Roy Taylor</name>
</country>
</tree>
</affiliations>
</record>
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