OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma
IntroductionStromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease a...
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| Veröffentlicht in: | Gut 2012-07, Vol.61 (Suppl 2), p.A52-A53 |
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| description | IntroductionStromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease and therefore only 20% of patients are suitable for treatment with curative intent. Cancer associated fibroblasts (CAFs) have an activated, myofibroblastic phenotype and have been recognised as mediators of tumour progression in a range of solid tumours. This study investigates the role of CAFs in EAC invasion and resistance to chemotherapy.MethodsFunctional biological analyses comparing primary fibroblasts from tumour stroma (CAF) and normal oesophagus (NOF) were carried out using organotypic culture, transwell invasion assays, collagen-1 gel contraction assays, siRNA gene silencing and colony forming assays. T-Tests (>95% CI) were carried out for all statistical analyses.ResultsPrimary oesophageal CAFs displayed an activated phenotype as demonstrated by α-SMA expression and increased collagen-1 gel contraction in comparison to NOFs (p |
| doi_str_mv | 10.1136/gutjnl-2012-302514a.121 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2038752226</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2038752226</sourcerecordid><originalsourceid>FETCH-LOGICAL-b2601-ebd37c4f21441a7beb250c0615980ac92da266c18610d7ddb490b981529cc9f93</originalsourceid><addsrcrecordid>eNqNkc1uFDEQhC0EEkvgGbDE2cHt-bHnCBtCQBG5QK5W2-PNepmxF9u7IjcuvAPPx5Pg1QTOnPryVZWqi5CXwM8Bmv713aHswsQEB8EaLjpo8RwEPCIraHvFGqHUY7LiHCTrZDs8Jc9y3nHOlRpgRX7drFmlf__4eelNimbCXCja4o9YfAzUB1q2jpbDHA-Jzt6m6MLRpxhmFwrdpzjH4vJfwLppqpoj5pMYw0iTyz4XDLaaRGq3rvJbl3B_f_KOLsf9Fu8cThRHF6LFZH2IMz4nTzY4Zffi4Z6RL5fvPq-v2PXN-w_rN9fMiJ4Dc2ZspG03AtoWUBpnRMct76EbFEc7iBFF31tQPfBRjqNpB24GBZ0YrB02Q3NGXi2-tcq3g8tF72qRUCO14I2SnRCir5RcqNo_5-Q2ep_8jOleA9enGfQygz7NoB9m0PWxVckWZf2C-_5Phumr7mUjO_3pdq3bj3DV3F681ReVFwtv5t1_h_wBscKgcQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2038752226</pqid></control><display><type>article</type><title>OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma</title><source>BMJ Journals - NESLi2</source><source>PubMed Central</source><creator>Hayden, A L ; Derouet, M F ; Noble, F ; Primrose, J N ; Blaydes, J P ; Thomas, G ; Underwood, T J</creator><creatorcontrib>Hayden, A L ; Derouet, M F ; Noble, F ; Primrose, J N ; Blaydes, J P ; Thomas, G ; Underwood, T J</creatorcontrib><description>IntroductionStromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease and therefore only 20% of patients are suitable for treatment with curative intent. Cancer associated fibroblasts (CAFs) have an activated, myofibroblastic phenotype and have been recognised as mediators of tumour progression in a range of solid tumours. This study investigates the role of CAFs in EAC invasion and resistance to chemotherapy.MethodsFunctional biological analyses comparing primary fibroblasts from tumour stroma (CAF) and normal oesophagus (NOF) were carried out using organotypic culture, transwell invasion assays, collagen-1 gel contraction assays, siRNA gene silencing and colony forming assays. T-Tests (>95% CI) were carried out for all statistical analyses.ResultsPrimary oesophageal CAFs displayed an activated phenotype as demonstrated by α-SMA expression and increased collagen-1 gel contraction in comparison to NOFs (p<0.01). CAF conditioned medium supported tumour colony formation in the presence of cisplatin and 5-Fluorouracil compared to NOF conditioned medium (p<0.05). Ex vivo analysis revealed a twofold (p<0.05) increase in EAC cell invasion in response to primary (CAF) conditioned medium in transwell invasion assays that was replicated in 3D organotypic models containing co-cultures of fibroblasts and EAC tumour cells. Down-regulation of the CAF secreted molecule Periostin (PN) resulted in a 70% reduction in tumour cell invasion in transwell assays (p<0.05), and a total loss of invasion in organotypic culture. Furthermore, collagen-1 gel contraction was abrogated by PN down-regulation. NOFs exposed to TGF-β from 72 h demonstrate features of myofibroblastic activation including, PN expression and the ability to support increased EAC tumour cell invasion (p<0.05).ConclusionThis study has demonstrated that oesophageal derived primary CAF protect EAC cells from chemotherapy and promote tumour cell invasion. Increased α-SMA expression and collagen-1 gel contraction indicates CAF have a myofibroblast like phenotype. PN siRNA reduced gel contraction supports a hypothesis of autocrine regulation of the myofibroblast phenotype. Therefore targeting pathways that determine fibroblast activation may offer a novel therapy for preventing oesophageal cancer invasion and metastasis.Competing interestsNone declared.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2012-302514a.121</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>5-Fluorouracil ; Adenocarcinoma ; Autocrine signalling ; Cell culture ; Chemotherapy ; Cisplatin ; Collagen ; Collagen (type I) ; Colonies ; Contraction ; Esophageal cancer ; Esophagus ; Fibroblasts ; Gene silencing ; Genotype & phenotype ; Metastases ; Metastasis ; Phenotypes ; siRNA ; Solid tumors ; Statistical analysis ; Stroma ; Tumor microenvironment</subject><ispartof>Gut, 2012-07, Vol.61 (Suppl 2), p.A52-A53</ispartof><rights>2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><rights>Copyright: 2012 © 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b2601-ebd37c4f21441a7beb250c0615980ac92da266c18610d7ddb490b981529cc9f93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttp://gut.bmj.com/content/61/Suppl_2/A52.2.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttp://gut.bmj.com/content/61/Suppl_2/A52.2.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,314,776,780,3182,23551,27903,27904,77347,77378</link.rule.ids></links><search><creatorcontrib>Hayden, A L</creatorcontrib><creatorcontrib>Derouet, M F</creatorcontrib><creatorcontrib>Noble, F</creatorcontrib><creatorcontrib>Primrose, J N</creatorcontrib><creatorcontrib>Blaydes, J P</creatorcontrib><creatorcontrib>Thomas, G</creatorcontrib><creatorcontrib>Underwood, T J</creatorcontrib><title>OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma</title><title>Gut</title><addtitle>Gut</addtitle><description>IntroductionStromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease and therefore only 20% of patients are suitable for treatment with curative intent. Cancer associated fibroblasts (CAFs) have an activated, myofibroblastic phenotype and have been recognised as mediators of tumour progression in a range of solid tumours. This study investigates the role of CAFs in EAC invasion and resistance to chemotherapy.MethodsFunctional biological analyses comparing primary fibroblasts from tumour stroma (CAF) and normal oesophagus (NOF) were carried out using organotypic culture, transwell invasion assays, collagen-1 gel contraction assays, siRNA gene silencing and colony forming assays. T-Tests (>95% CI) were carried out for all statistical analyses.ResultsPrimary oesophageal CAFs displayed an activated phenotype as demonstrated by α-SMA expression and increased collagen-1 gel contraction in comparison to NOFs (p<0.01). CAF conditioned medium supported tumour colony formation in the presence of cisplatin and 5-Fluorouracil compared to NOF conditioned medium (p<0.05). Ex vivo analysis revealed a twofold (p<0.05) increase in EAC cell invasion in response to primary (CAF) conditioned medium in transwell invasion assays that was replicated in 3D organotypic models containing co-cultures of fibroblasts and EAC tumour cells. Down-regulation of the CAF secreted molecule Periostin (PN) resulted in a 70% reduction in tumour cell invasion in transwell assays (p<0.05), and a total loss of invasion in organotypic culture. Furthermore, collagen-1 gel contraction was abrogated by PN down-regulation. NOFs exposed to TGF-β from 72 h demonstrate features of myofibroblastic activation including, PN expression and the ability to support increased EAC tumour cell invasion (p<0.05).ConclusionThis study has demonstrated that oesophageal derived primary CAF protect EAC cells from chemotherapy and promote tumour cell invasion. Increased α-SMA expression and collagen-1 gel contraction indicates CAF have a myofibroblast like phenotype. PN siRNA reduced gel contraction supports a hypothesis of autocrine regulation of the myofibroblast phenotype. Therefore targeting pathways that determine fibroblast activation may offer a novel therapy for preventing oesophageal cancer invasion and metastasis.Competing interestsNone declared.</description><subject>5-Fluorouracil</subject><subject>Adenocarcinoma</subject><subject>Autocrine signalling</subject><subject>Cell culture</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Collagen</subject><subject>Collagen (type I)</subject><subject>Colonies</subject><subject>Contraction</subject><subject>Esophageal cancer</subject><subject>Esophagus</subject><subject>Fibroblasts</subject><subject>Gene silencing</subject><subject>Genotype & phenotype</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Phenotypes</subject><subject>siRNA</subject><subject>Solid tumors</subject><subject>Statistical analysis</subject><subject>Stroma</subject><subject>Tumor microenvironment</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkc1uFDEQhC0EEkvgGbDE2cHt-bHnCBtCQBG5QK5W2-PNepmxF9u7IjcuvAPPx5Pg1QTOnPryVZWqi5CXwM8Bmv713aHswsQEB8EaLjpo8RwEPCIraHvFGqHUY7LiHCTrZDs8Jc9y3nHOlRpgRX7drFmlf__4eelNimbCXCja4o9YfAzUB1q2jpbDHA-Jzt6m6MLRpxhmFwrdpzjH4vJfwLppqpoj5pMYw0iTyz4XDLaaRGq3rvJbl3B_f_KOLsf9Fu8cThRHF6LFZH2IMz4nTzY4Zffi4Z6RL5fvPq-v2PXN-w_rN9fMiJ4Dc2ZspG03AtoWUBpnRMct76EbFEc7iBFF31tQPfBRjqNpB24GBZ0YrB02Q3NGXi2-tcq3g8tF72qRUCO14I2SnRCir5RcqNo_5-Q2ep_8jOleA9enGfQygz7NoB9m0PWxVckWZf2C-_5Phumr7mUjO_3pdq3bj3DV3F681ReVFwtv5t1_h_wBscKgcQ</recordid><startdate>201207</startdate><enddate>201207</enddate><creator>Hayden, A L</creator><creator>Derouet, M F</creator><creator>Noble, F</creator><creator>Primrose, J N</creator><creator>Blaydes, J P</creator><creator>Thomas, G</creator><creator>Underwood, T J</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</general><scope>BSCLL</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>201207</creationdate><title>OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma</title><author>Hayden, A L ; Derouet, M F ; Noble, F ; Primrose, J N ; Blaydes, J P ; Thomas, G ; Underwood, T J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b2601-ebd37c4f21441a7beb250c0615980ac92da266c18610d7ddb490b981529cc9f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>5-Fluorouracil</topic><topic>Adenocarcinoma</topic><topic>Autocrine signalling</topic><topic>Cell culture</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Collagen</topic><topic>Collagen (type I)</topic><topic>Colonies</topic><topic>Contraction</topic><topic>Esophageal cancer</topic><topic>Esophagus</topic><topic>Fibroblasts</topic><topic>Gene silencing</topic><topic>Genotype & phenotype</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Phenotypes</topic><topic>siRNA</topic><topic>Solid tumors</topic><topic>Statistical analysis</topic><topic>Stroma</topic><topic>Tumor microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hayden, A L</creatorcontrib><creatorcontrib>Derouet, M F</creatorcontrib><creatorcontrib>Noble, F</creatorcontrib><creatorcontrib>Primrose, J N</creatorcontrib><creatorcontrib>Blaydes, J P</creatorcontrib><creatorcontrib>Thomas, G</creatorcontrib><creatorcontrib>Underwood, T J</creatorcontrib><collection>Istex</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayden, A L</au><au>Derouet, M F</au><au>Noble, F</au><au>Primrose, J N</au><au>Blaydes, J P</au><au>Thomas, G</au><au>Underwood, T J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma</atitle><jtitle>Gut</jtitle><addtitle>Gut</addtitle><date>2012-07</date><risdate>2012</risdate><volume>61</volume><issue>Suppl 2</issue><spage>A52</spage><epage>A53</epage><pages>A52-A53</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>IntroductionStromal and other non-malignant cells have the potential to undergo modifications that can synergistically create a supportive microenvironment for tumour growth, invasion and metastasis. Oesophageal adenocarcinoma (EAC) is characterised by early invasion, leading to metastatic disease and therefore only 20% of patients are suitable for treatment with curative intent. Cancer associated fibroblasts (CAFs) have an activated, myofibroblastic phenotype and have been recognised as mediators of tumour progression in a range of solid tumours. This study investigates the role of CAFs in EAC invasion and resistance to chemotherapy.MethodsFunctional biological analyses comparing primary fibroblasts from tumour stroma (CAF) and normal oesophagus (NOF) were carried out using organotypic culture, transwell invasion assays, collagen-1 gel contraction assays, siRNA gene silencing and colony forming assays. T-Tests (>95% CI) were carried out for all statistical analyses.ResultsPrimary oesophageal CAFs displayed an activated phenotype as demonstrated by α-SMA expression and increased collagen-1 gel contraction in comparison to NOFs (p<0.01). CAF conditioned medium supported tumour colony formation in the presence of cisplatin and 5-Fluorouracil compared to NOF conditioned medium (p<0.05). Ex vivo analysis revealed a twofold (p<0.05) increase in EAC cell invasion in response to primary (CAF) conditioned medium in transwell invasion assays that was replicated in 3D organotypic models containing co-cultures of fibroblasts and EAC tumour cells. Down-regulation of the CAF secreted molecule Periostin (PN) resulted in a 70% reduction in tumour cell invasion in transwell assays (p<0.05), and a total loss of invasion in organotypic culture. Furthermore, collagen-1 gel contraction was abrogated by PN down-regulation. NOFs exposed to TGF-β from 72 h demonstrate features of myofibroblastic activation including, PN expression and the ability to support increased EAC tumour cell invasion (p<0.05).ConclusionThis study has demonstrated that oesophageal derived primary CAF protect EAC cells from chemotherapy and promote tumour cell invasion. Increased α-SMA expression and collagen-1 gel contraction indicates CAF have a myofibroblast like phenotype. PN siRNA reduced gel contraction supports a hypothesis of autocrine regulation of the myofibroblast phenotype. Therefore targeting pathways that determine fibroblast activation may offer a novel therapy for preventing oesophageal cancer invasion and metastasis.Competing interestsNone declared.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><doi>10.1136/gutjnl-2012-302514a.121</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 5-Fluorouracil Adenocarcinoma Autocrine signalling Cell culture Chemotherapy Cisplatin Collagen Collagen (type I) Colonies Contraction Esophageal cancer Esophagus Fibroblasts Gene silencing Genotype & phenotype Metastases Metastasis Phenotypes siRNA Solid tumors Statistical analysis Stroma Tumor microenvironment |
| title | OC-121 Fibroblast activation in the tumour microenvironment promotes tumour cell invasion and resistance to chemotherapy in oesophageal adenocarcinoma |
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