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

G. H. Bain, E. Collie-Duguid, G. I. 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, R. D. Petty (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    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
    EventAmerican Society for Clinical Oncology 2012 Gastrointestinal Cancers Symposium - San Francisco, United States
    Duration: 19 Jan 201219 Jan 2012

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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

    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. / 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.
    @article{3bcb30854bf84b6f92be7b5413256d93,
    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, {G. I.} 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 Petty, {R. D.}",
    note = "This work was presented in part as an oral presentation (Abstract No. 1) at the American Society for Clinical Oncology 2012 Gastrointestinal Cancers Symposium, 19 January 2012, in San Francisco.",
    year = "2014",
    month = "3",
    day = "18",
    doi = "10.1038/bjc.2014.45",
    language = "English",
    volume = "110",
    pages = "1525--1534",
    journal = "British Journal of Cancer",
    issn = "0007-0920",
    publisher = "Cancer Research UK",
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    }

    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 & 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

    Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. / 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. (Lead / Corresponding author).

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

    Research output: Contribution to journalArticle

    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, G. I.

    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 - Petty, R. D.

    N1 - This work was presented in part as an oral presentation (Abstract No. 1) at the American Society for Clinical Oncology 2012 Gastrointestinal Cancers Symposium, 19 January 2012, in San Francisco.

    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 -