Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas
Background: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of suc...
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| Veröffentlicht in: | British journal of cancer 2014-03, Vol.110 (6), p.1525-1534 |
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| creator | Bain, G H Collie-Duguid, E Murray, G I Gilbert, F J Denison, A Mckiddie, F Ahearn, T Fleming, I Leeds, J Phull, P Park, K Nanthakumaran, S Grabsch, H I Tan, P Welch, A Schweiger, L Dahle-Smith, A Urquhart, G Finegan, M Petty, R D |
| description | Background:
Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.
Methods:
Tumour biopsies from patients (
n
=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (
n
=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (
n
=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for
in vitro
validation investigations.
Results:
We identified 520 genes with differential expression (Mann–Whitney
U
,
P |
| doi_str_mv | 10.1038/bjc.2014.45 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3960617</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3249773041</sourcerecordid><originalsourceid>FETCH-LOGICAL-c476t-410f1cef2beb33eb93a91eefde7d46e4f3fd582bad7abe3685d2a4dc9588f7033</originalsourceid><addsrcrecordid>eNptkU9v1DAQxS0EokvhxB1ZQj1BFjt2EueChCr-SZW4lLM1ccaJV4kd7GyhX6KfGa92KUXiYsszP795mkfIS862nAn1rtuZbcm43MrqEdnwSpQFV2XzmGwYY03B2pKdkWcp7fKzZap5Ss5KWdWtbKoNubvez2EfKf5aIqbkgqfB0gmX1XnqEoWUgnGwYk9_unWkZsQ5rCNGWG5p_uHSCt4gBd_TU7lwvscF8-FXusQw-JAxmvUGSGsMRcAUlhEGhIlCpoKBaJwPM6Tn5ImFKeGL031Ovn_6eH35pbj69vnr5YerwsimXgvJmeUGbdlhJwR2rYCWI9oem17WKK2wfaXKDvoGOhS1qvoSZG_aSinbMCHOyfuj7rLvZuxNthph0kt0M8RbHcDpfzvejXoIN1q0Nat5kwVenwRi-LHHtOpdXqPPnjWvmJJSlXWVqTdHysSQUkR7P4EzfQhP5_D0ITwtD_Srh6bu2T9pZeDiBEAyMNmYV-_SX06JtqwZz9zbI5dyyw8YH5j7z9zfu8W3hw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1508448265</pqid></control><display><type>article</type><title>Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Nature Journals Online</source><source>PubMed Central</source><creator>Bain, G H ; Collie-Duguid, E ; Murray, G I ; Gilbert, F J ; Denison, A ; Mckiddie, F ; Ahearn, T ; Fleming, I ; Leeds, J ; Phull, P ; Park, K ; Nanthakumaran, S ; Grabsch, H I ; Tan, P ; Welch, A ; Schweiger, L ; Dahle-Smith, A ; Urquhart, G ; Finegan, M ; Petty, R D</creator><creatorcontrib>Bain, G H ; Collie-Duguid, E ; Murray, G I ; Gilbert, F J ; Denison, A ; Mckiddie, F ; Ahearn, T ; Fleming, I ; Leeds, J ; Phull, P ; Park, K ; Nanthakumaran, S ; Grabsch, H I ; Tan, P ; Welch, A ; Schweiger, L ; Dahle-Smith, A ; Urquhart, G ; Finegan, M ; Petty, R D</creatorcontrib><description>Background:
Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.
Methods:
Tumour biopsies from patients (
n
=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (
n
=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (
n
=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for
in vitro
validation investigations.
Results:
We identified 520 genes with differential expression (Mann–Whitney
U
,
P
<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA
associated
with lack of radiological response (
P
=0.011). Similarly, in the independent cohort (
n
=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (
P
=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (
P
for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (
P
=0.008), but not to oxaliplatin (
P
=0.988) or 5fluorouracil (
P
=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.
Conclusions:
In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/bjc.2014.45</identifier><identifier>PMID: 24569475</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/2326 ; 631/67/1857 ; 692/699/67/1504/1477 ; 692/700/1750 ; Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Adult ; Aged ; Aged, 80 and over ; Biological and medical sciences ; Biomarkers ; Biomarkers, Tumor - biosynthesis ; Biomarkers, Tumor - genetics ; Biomedical and Life Sciences ; Biomedicine ; Biopsy ; Cancer Research ; Cancer therapies ; Cell Growth Processes - physiology ; Chemotherapy ; Cytotoxicity ; Drug Resistance ; Drug Resistance, Neoplasm ; Epidemiology ; Esophageal Neoplasms - drug therapy ; Esophageal Neoplasms - genetics ; Esophageal Neoplasms - metabolism ; Esophageal Neoplasms - pathology ; Esophagus ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene expression ; Gene Expression Profiling ; Humans ; Leptin - biosynthesis ; Leptin - genetics ; Male ; Medical prognosis ; Medical sciences ; Middle Aged ; Molecular Diagnostics ; Molecular Medicine ; Neoplasm Staging ; Oncology ; Pathology ; Prognosis ; Protein expression ; Proteins ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - genetics ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - pathology ; Surgery ; Toxicity ; Tumors</subject><ispartof>British journal of cancer, 2014-03, Vol.110 (6), p.1525-1534</ispartof><rights>The Author(s) 2014</rights><rights>2015 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Mar 18, 2014</rights><rights>Copyright © 2014 Cancer Research UK 2014 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-410f1cef2beb33eb93a91eefde7d46e4f3fd582bad7abe3685d2a4dc9588f7033</citedby><cites>FETCH-LOGICAL-c476t-410f1cef2beb33eb93a91eefde7d46e4f3fd582bad7abe3685d2a4dc9588f7033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960617/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960617/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28392601$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24569475$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bain, G H</creatorcontrib><creatorcontrib>Collie-Duguid, E</creatorcontrib><creatorcontrib>Murray, G I</creatorcontrib><creatorcontrib>Gilbert, F J</creatorcontrib><creatorcontrib>Denison, A</creatorcontrib><creatorcontrib>Mckiddie, F</creatorcontrib><creatorcontrib>Ahearn, T</creatorcontrib><creatorcontrib>Fleming, I</creatorcontrib><creatorcontrib>Leeds, J</creatorcontrib><creatorcontrib>Phull, P</creatorcontrib><creatorcontrib>Park, K</creatorcontrib><creatorcontrib>Nanthakumaran, S</creatorcontrib><creatorcontrib>Grabsch, H I</creatorcontrib><creatorcontrib>Tan, P</creatorcontrib><creatorcontrib>Welch, A</creatorcontrib><creatorcontrib>Schweiger, L</creatorcontrib><creatorcontrib>Dahle-Smith, A</creatorcontrib><creatorcontrib>Urquhart, G</creatorcontrib><creatorcontrib>Finegan, M</creatorcontrib><creatorcontrib>Petty, R D</creatorcontrib><title>Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background:
Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.
Methods:
Tumour biopsies from patients (
n
=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (
n
=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (
n
=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for
in vitro
validation investigations.
Results:
We identified 520 genes with differential expression (Mann–Whitney
U
,
P
<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA
associated
with lack of radiological response (
P
=0.011). Similarly, in the independent cohort (
n
=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (
P
=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (
P
for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (
P
=0.008), but not to oxaliplatin (
P
=0.988) or 5fluorouracil (
P
=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.
Conclusions:
In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.</description><subject>631/67/1059/2326</subject><subject>631/67/1857</subject><subject>692/699/67/1504/1477</subject><subject>692/700/1750</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - pathology</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biological and medical sciences</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - biosynthesis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biopsy</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Cell Growth Processes - physiology</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Epidemiology</subject><subject>Esophageal Neoplasms - drug therapy</subject><subject>Esophageal Neoplasms - genetics</subject><subject>Esophageal Neoplasms - metabolism</subject><subject>Esophageal Neoplasms - pathology</subject><subject>Esophagus</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Leptin - biosynthesis</subject><subject>Leptin - genetics</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Molecular Diagnostics</subject><subject>Molecular Medicine</subject><subject>Neoplasm Staging</subject><subject>Oncology</subject><subject>Pathology</subject><subject>Prognosis</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Stomach Neoplasms - drug therapy</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - pathology</subject><subject>Surgery</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkU9v1DAQxS0EokvhxB1ZQj1BFjt2EueChCr-SZW4lLM1ccaJV4kd7GyhX6KfGa92KUXiYsszP795mkfIS862nAn1rtuZbcm43MrqEdnwSpQFV2XzmGwYY03B2pKdkWcp7fKzZap5Ss5KWdWtbKoNubvez2EfKf5aIqbkgqfB0gmX1XnqEoWUgnGwYk9_unWkZsQ5rCNGWG5p_uHSCt4gBd_TU7lwvscF8-FXusQw-JAxmvUGSGsMRcAUlhEGhIlCpoKBaJwPM6Tn5ImFKeGL031Ovn_6eH35pbj69vnr5YerwsimXgvJmeUGbdlhJwR2rYCWI9oem17WKK2wfaXKDvoGOhS1qvoSZG_aSinbMCHOyfuj7rLvZuxNthph0kt0M8RbHcDpfzvejXoIN1q0Nat5kwVenwRi-LHHtOpdXqPPnjWvmJJSlXWVqTdHysSQUkR7P4EzfQhP5_D0ITwtD_Srh6bu2T9pZeDiBEAyMNmYV-_SX06JtqwZz9zbI5dyyw8YH5j7z9zfu8W3hw</recordid><startdate>20140318</startdate><enddate>20140318</enddate><creator>Bain, G H</creator><creator>Collie-Duguid, E</creator><creator>Murray, G I</creator><creator>Gilbert, F J</creator><creator>Denison, A</creator><creator>Mckiddie, F</creator><creator>Ahearn, T</creator><creator>Fleming, I</creator><creator>Leeds, J</creator><creator>Phull, P</creator><creator>Park, K</creator><creator>Nanthakumaran, S</creator><creator>Grabsch, H I</creator><creator>Tan, P</creator><creator>Welch, A</creator><creator>Schweiger, L</creator><creator>Dahle-Smith, A</creator><creator>Urquhart, G</creator><creator>Finegan, M</creator><creator>Petty, R D</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20140318</creationdate><title>Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas</title><author>Bain, G H ; Collie-Duguid, E ; Murray, G I ; Gilbert, F J ; Denison, A ; Mckiddie, F ; Ahearn, T ; Fleming, I ; Leeds, J ; Phull, P ; Park, K ; Nanthakumaran, S ; Grabsch, H I ; Tan, P ; Welch, A ; Schweiger, L ; Dahle-Smith, A ; Urquhart, G ; Finegan, M ; Petty, R D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-410f1cef2beb33eb93a91eefde7d46e4f3fd582bad7abe3685d2a4dc9588f7033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/67/1059/2326</topic><topic>631/67/1857</topic><topic>692/699/67/1504/1477</topic><topic>692/700/1750</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma - pathology</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biological and medical sciences</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor - biosynthesis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biopsy</topic><topic>Cancer Research</topic><topic>Cancer therapies</topic><topic>Cell Growth Processes - physiology</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>Drug Resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Epidemiology</topic><topic>Esophageal Neoplasms - drug therapy</topic><topic>Esophageal Neoplasms - genetics</topic><topic>Esophageal Neoplasms - metabolism</topic><topic>Esophageal Neoplasms - pathology</topic><topic>Esophagus</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Leptin - biosynthesis</topic><topic>Leptin - genetics</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Molecular Diagnostics</topic><topic>Molecular Medicine</topic><topic>Neoplasm Staging</topic><topic>Oncology</topic><topic>Pathology</topic><topic>Prognosis</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Stomach Neoplasms - drug therapy</topic><topic>Stomach Neoplasms - genetics</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - pathology</topic><topic>Surgery</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bain, G H</creatorcontrib><creatorcontrib>Collie-Duguid, E</creatorcontrib><creatorcontrib>Murray, G I</creatorcontrib><creatorcontrib>Gilbert, F J</creatorcontrib><creatorcontrib>Denison, A</creatorcontrib><creatorcontrib>Mckiddie, F</creatorcontrib><creatorcontrib>Ahearn, T</creatorcontrib><creatorcontrib>Fleming, I</creatorcontrib><creatorcontrib>Leeds, J</creatorcontrib><creatorcontrib>Phull, P</creatorcontrib><creatorcontrib>Park, K</creatorcontrib><creatorcontrib>Nanthakumaran, S</creatorcontrib><creatorcontrib>Grabsch, H I</creatorcontrib><creatorcontrib>Tan, P</creatorcontrib><creatorcontrib>Welch, A</creatorcontrib><creatorcontrib>Schweiger, L</creatorcontrib><creatorcontrib>Dahle-Smith, A</creatorcontrib><creatorcontrib>Urquhart, G</creatorcontrib><creatorcontrib>Finegan, M</creatorcontrib><creatorcontrib>Petty, R D</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health 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 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Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</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 China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bain, G H</au><au>Collie-Duguid, E</au><au>Murray, G I</au><au>Gilbert, F J</au><au>Denison, A</au><au>Mckiddie, F</au><au>Ahearn, T</au><au>Fleming, I</au><au>Leeds, J</au><au>Phull, P</au><au>Park, K</au><au>Nanthakumaran, S</au><au>Grabsch, H I</au><au>Tan, P</au><au>Welch, A</au><au>Schweiger, L</au><au>Dahle-Smith, A</au><au>Urquhart, G</au><au>Finegan, M</au><au>Petty, R D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2014-03-18</date><risdate>2014</risdate><volume>110</volume><issue>6</issue><spage>1525</spage><epage>1534</epage><pages>1525-1534</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>Background:
Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.
Methods:
Tumour biopsies from patients (
n
=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (
n
=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (
n
=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for
in vitro
validation investigations.
Results:
We identified 520 genes with differential expression (Mann–Whitney
U
,
P
<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA
associated
with lack of radiological response (
P
=0.011). Similarly, in the independent cohort (
n
=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (
P
=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (
P
for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (
P
=0.008), but not to oxaliplatin (
P
=0.988) or 5fluorouracil (
P
=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.
Conclusions:
In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24569475</pmid><doi>10.1038/bjc.2014.45</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-0920 |
| ispartof | British journal of cancer, 2014-03, Vol.110 (6), p.1525-1534 |
| issn | 0007-0920 1532-1827 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3960617 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Nature Journals Online; PubMed Central |
| subjects | 631/67/1059/2326 631/67/1857 692/699/67/1504/1477 692/700/1750 Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - metabolism Adenocarcinoma - pathology Adult Aged Aged, 80 and over Biological and medical sciences Biomarkers Biomarkers, Tumor - biosynthesis Biomarkers, Tumor - genetics Biomedical and Life Sciences Biomedicine Biopsy Cancer Research Cancer therapies Cell Growth Processes - physiology Chemotherapy Cytotoxicity Drug Resistance Drug Resistance, Neoplasm Epidemiology Esophageal Neoplasms - drug therapy Esophageal Neoplasms - genetics Esophageal Neoplasms - metabolism Esophageal Neoplasms - pathology Esophagus Female Gastroenterology. Liver. Pancreas. Abdomen Gene expression Gene Expression Profiling Humans Leptin - biosynthesis Leptin - genetics Male Medical prognosis Medical sciences Middle Aged Molecular Diagnostics Molecular Medicine Neoplasm Staging Oncology Pathology Prognosis Protein expression Proteins RNA, Messenger - biosynthesis RNA, Messenger - genetics Stomach Neoplasms - drug therapy Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Surgery Toxicity Tumors |
| title | Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T05%3A35%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tumour%20expression%20of%20leptin%20is%20associated%20with%20chemotherapy%20resistance%20and%20therapy-independent%20prognosis%20in%20gastro-oesophageal%20adenocarcinomas&rft.jtitle=British%20journal%20of%20cancer&rft.au=Bain,%20G%20H&rft.date=2014-03-18&rft.volume=110&rft.issue=6&rft.spage=1525&rft.epage=1534&rft.pages=1525-1534&rft.issn=0007-0920&rft.eissn=1532-1827&rft.coden=BJCAAI&rft_id=info:doi/10.1038/bjc.2014.45&rft_dat=%3Cproquest_pubme%3E3249773041%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1508448265&rft_id=info:pmid/24569475&rfr_iscdi=true |