Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas

G H Bain, E Collie-Duguid, Graeme Ian Murray, F J Gilbert, A Denison, F McKiddie, T Ahearn, I Fleming, J Leeds, P Phull, K Park, S Nanthakumaran, H I Grabsch, P Tan, A Welch, L Schweiger, A Dahle-Smith, G Urquhart, M Finegan, Katarzyna Monika Matula & 1 others R D Petty

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1525-1534
Number of pages10
JournalBritish Journal of Cancer
Volume110
Issue number6
DOIs
Publication statusPublished - 18 Mar 2014

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Leptin
Adenocarcinoma
Drug Therapy
Neoplasms
Cell Line
Immunohistochemistry
Cisplatin
oxaliplatin
Therapeutics
Gene Expression Profiling
Combination Drug Therapy
Platinum
Stomach
Proteins
Biomarkers
Genes
Biopsy
Leptin Receptors
Adipokines
Survival

Keywords

  • Adenocarcinoma
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Growth Processes
  • Drug Resistance, Neoplasm
  • Esophageal Neoplasms
  • Female
  • Gene Expression Profiling
  • Humans
  • Leptin
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • RNA, Messenger
  • Stomach Neoplasms
  • Tumor Markers, Biological

Cite this

Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. / Bain, G H; Collie-Duguid, E; Murray, Graeme Ian; 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; Matula, Katarzyna Monika; Petty, R D.

In: British Journal of Cancer, Vol. 110, No. 6, 18.03.2014, p. 1525-1534.

Research output: Contribution to journalArticle

Bain, GH, Collie-Duguid, E, Murray, GI, Gilbert, FJ, Denison, A, McKiddie, F, Ahearn, T, Fleming, I, Leeds, J, Phull, P, Park, K, Nanthakumaran, S, Grabsch, HI, Tan, P, Welch, A, Schweiger, L, Dahle-Smith, A, Urquhart, G, Finegan, M, Matula, KM & Petty, RD 2014, 'Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas', British Journal of Cancer, vol. 110, no. 6, pp. 1525-1534. https://doi.org/10.1038/bjc.2014.45
Bain, G H ; Collie-Duguid, E ; Murray, Graeme Ian ; 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 ; Matula, Katarzyna Monika ; Petty, R D. / Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. In: British Journal of Cancer. 2014 ; Vol. 110, No. 6. pp. 1525-1534.
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title = "Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas",
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.",
keywords = "Adenocarcinoma, Adult, Aged, Aged, 80 and over, Cell Growth Processes, Drug Resistance, Neoplasm, Esophageal Neoplasms, Female, Gene Expression Profiling, Humans, Leptin, Male, Middle Aged, Neoplasm Staging, Prognosis, RNA, Messenger, Stomach Neoplasms, Tumor Markers, Biological",
author = "Bain, {G H} and E Collie-Duguid and Murray, {Graeme Ian} and Gilbert, {F J} and A Denison and F McKiddie and T Ahearn and I Fleming and J Leeds and P Phull and K Park and S Nanthakumaran and Grabsch, {H I} and P Tan and A Welch and L Schweiger and A Dahle-Smith and G Urquhart and M Finegan and Matula, {Katarzyna Monika} and Petty, {R D}",
note = "This research was supported by The Friends of Aberdeen and the North Centre for Oncology, Haematology and Radiotherapy, The Scottish Government Chief Scientist Office (Grant number CZB/4/747), the Grampian Gastro-oesophageal Cancer Research Fund (GASTROCAN), and National Health Service Grampian Research & Development. We are grateful to Nicky Fyfe for assistance with construction of the tissue microarray and to Dr Khyati Parikh for assistance with the leptin antagonist experiments. We are also grateful to the NHS Grampian bio-repository for their assistance.",
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month = "3",
day = "18",
doi = "10.1038/bjc.2014.45",
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pages = "1525--1534",
journal = "British Journal of Cancer",
issn = "0007-0920",
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TY - JOUR

T1 - Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas

AU - Bain, G H

AU - Collie-Duguid, E

AU - Murray, Graeme Ian

AU - Gilbert, F J

AU - Denison, A

AU - McKiddie, F

AU - Ahearn, T

AU - Fleming, I

AU - Leeds, J

AU - Phull, P

AU - Park, K

AU - Nanthakumaran, S

AU - Grabsch, H I

AU - Tan, P

AU - Welch, A

AU - Schweiger, L

AU - Dahle-Smith, A

AU - Urquhart, G

AU - Finegan, M

AU - Matula, Katarzyna Monika

AU - Petty, R D

N1 - This research was supported by The Friends of Aberdeen and the North Centre for Oncology, Haematology and Radiotherapy, The Scottish Government Chief Scientist Office (Grant number CZB/4/747), the Grampian Gastro-oesophageal Cancer Research Fund (GASTROCAN), and National Health Service Grampian Research & Development. We are grateful to Nicky Fyfe for assistance with construction of the tissue microarray and to Dr Khyati Parikh for assistance with the leptin antagonist experiments. We are also grateful to the NHS Grampian bio-repository for their assistance.

PY - 2014/3/18

Y1 - 2014/3/18

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Cell Growth Processes

KW - Drug Resistance, Neoplasm

KW - Esophageal Neoplasms

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Leptin

KW - Male

KW - Middle Aged

KW - Neoplasm Staging

KW - Prognosis

KW - RNA, Messenger

KW - Stomach Neoplasms

KW - Tumor Markers, Biological

U2 - 10.1038/bjc.2014.45

DO - 10.1038/bjc.2014.45

M3 - Article

VL - 110

SP - 1525

EP - 1534

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 6

ER -