Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer

Authors: Madhuri Koti, Robert J Gooding, Paulo Nuin, Alexandria Haslehurst, Colleen Crane, Johanne Weberpals, Timothy Childs, Peter Bryson, Moyez Dharsee, Kenneth Evans, Harriet E Feilotter, Paul C Park, Jeremy A Squire

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer.

Methods

The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with standard platinum-based chemotherapy. Twelve patient tumours demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumours from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using an Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumours from the resistant group and the sensitive group.

Results

Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NF κB/ERK gene signalling networks.

Conclusions

This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. In addition, our results provide a pathway context for further experimental validations, and the findings are a significant step towards future therapeutic interventions.
Appendix
Available only for authorised users
Literature
1.
Mantia-Smaldone GM, Edwards RP, Vlad AM: Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies. Cancer Manag Res. 2011, 3: 25-38.PubMed
2.
3.
Berns EM, Bowtell DD: The changing view of high-grade serous ovarian cancer. Cancer Res. 2012, 72 (11): 2701-2704.CrossRefPubMed
4.
Shih I, Kurman RJ: Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004, 164 (5): 1511-1518.CrossRefPubMedPubMedCentral
5.
Karst AM, Drapkin R: Ovarian cancer pathogenesis: a model in evolution. J Oncol. 2010, 2010: 932371-CrossRefPubMed
6.
Vaughan S, Coward JI, Jr Bast RC, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011, 11 (10): 719-725.CrossRefPubMedPubMedCentral
7.
Gatti L, Zunino F: Overview of tumor cell chemoresistance mechanisms. Methods Mol Med. 2005, 111: 127-148.PubMed
8.
Cooke SL, Brenton JD: Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol. 2011, 12 (12): 1169-1174.CrossRefPubMed
9.
10.
Bachvarov D, L’esperance S, Popa I, Bachvarova M, Plante M, Tetu B: Gene expression patterns of chemoresistant and chemosensitive serous epithelial ovarian tumors with possible predictive value in response to initial chemotherapy. Int J Oncol. 2006, 29 (4): 919-933.PubMed
11.
Fekete T, Raso E, Pete I, Tegze B, Liko I, Munkacsy G, Sipos N, Rigojr J, Gyorffy B: Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples. Int J Cancer. 2012, 1: 95-105.CrossRef
12.
Sakamoto M, Kondo A, Kawasaki K, Goto T, Sakamoto H, Miyake K, Koyamatsu Y, Akiya T, Iwabuchi H, Muroya T, Ochiai K, Tanaka T, Kikuchi Y, Tenjin Y: Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray. Hum Cell. 2001, 14 (4): 305-315.PubMed
13.
Selvanayagam ZE, Cheung TH, Wei N, Vittal R, Lo KW, Yeo W, Kita T, Ravatn R, Chung TK, Wong YF, Chin KV: Prediction of chemotherapeutic response in ovarian cancer with DNA microarray expression profiling. Cancer Genet Cytogenet. 2004, 154 (1): 63-66.CrossRefPubMed
14.
Bernardini M, Lee CH, Beheshti B, Prasad M, Albert M, Marrano P, Begley H, Shaw P, Covens A, Murphy J, Rosen B, Minkin S, Squire JA, Macgregor PF: High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer. Neoplasia. 2005, 7 (6): 603-613.CrossRefPubMedPubMedCentral
15.
L’Esperance S, Popa I, Bachvarova M, Plante M, Patten N, Wu L, Tetu B, Bachvarov D: Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Int J Oncol. 2006, 29 (1): 5-24.PubMed
16.
Osterberg L, Levan K, Partheen K, Delle U, Olsson B, Sundfeldt K, Horvath G: Potential predictive markers of chemotherapy resistance in stage III ovarian serous carcinomas. BMC Cancer. 2009, 9: 368-CrossRefPubMedPubMedCentral
17.
Helleman J, Smid M, Jansen MP, van der Burg ME, Berns EM: Pathway analysis of gene lists associated with platinum-based chemotherapy resistance in ovarian cancer: the big picture. Gynecol Oncol. 2010, 117 (2): 170-176.CrossRefPubMed
18.
Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldeira S, Skomedal H, Tu IP, Hernandez-Boussard T, Johnson SW, O’Dwyer PJ, Fero MJ, Kristensen GB, Borresen-Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI: Gene expression patterns in ovarian carcinomas. Mol Biol Cell. 2003, 14 (11): 4376-4386.CrossRefPubMedPubMedCentral
19.
Jazaeri AA, Awtrey CS, Chandramouli GV, Chuang YE, Khan J, Sotiriou C, Aprelikova O, Yee CJ, Zorn KK, Birrer MJ, Barrett JC, Boyd J: Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res. 2005, 11 (17): 6300-6310.CrossRefPubMed
20.
Roberts D, Schick J, Conway S, Biade S, Laub PB, Stevenson JP, Hamilton TC, O’Dwyer PJ, Johnson SW: Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells. Br J Cancer. 2005, 92 (6): 1149-1158.CrossRefPubMedPubMedCentral
21.
Kauffmann A, Gentleman R, Huber W: arrayQualityMetrics – a bioconductor package for quality assessment of microarray data. Bioinformatics. 2009, 25 (3): 415-416.CrossRefPubMed
22.
Gautier L, Cope L, Bolstad BM, Irizarry RA: affy – Analysis of affymetrix GeneChip data at the probe level. Bioinformatics. 2004, 20 (3): 307-315.CrossRefPubMed
23.
Millenaar FF, Okyere J, May ST, van Zanten M, Voesenek LACJ, Peeters AJM: How does one decide? Different methods of calculating gene expression from short oligonucleotide arrays will give different results. BMC Informatics. 2006, 7: 137-CrossRef
24.
Li C, Wong WH: Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA. 2001, 98: 31-36.CrossRefPubMed
25.
Wu Z, Irizarry RA, Gentleman R, Martinez-Murillo F, Spencer F: A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc. 2004, 99: 909-CrossRef
26.
Schmittgen TD, Livak KJ: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC(T)) Method. Nat Protoc. 2008, 3 (6): 1101-1108.CrossRefPubMed
27.
Stephanie Schneider W, Smith T, Hansen U: SCOREM: statistical consolidation of redundant expression measures. Nucleic Acids Res. 2012, 40 (6): e46-CrossRefPubMed
28.
Verhaak RGW, Sanders MA, Bijl MA, Delwel R, Horsman S, Moorhouse MJ, van der Spek PJ, Löwenberg B, Valk PJM: HeatMapper: powerful combined visualization of gene expression profile correlations, genotypes, phenotypes and sample characteristics. BMC Bioninformatics. 2006, 7: 33-CrossRef
29.
Myers JL, Well AD: Research design and statistical analysis (2nd ed). 2003, Mahwah, NJ: LEA
30.
Pollack M: The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012, 12 (3): 159-69.
31.
Alokail MS, Al-Daghri NM, Al-Attas OS, Alkharfy KM, Sabico SB, Ullrich A: Visceral obesity and inflammation markers in relation to serum prostate volume biomarkers among apparently healthy men. Eur J Clin Invest. 2011, 41 (9): 987-994.CrossRefPubMed
32.
Price AJ, Allen NE, Appleby PN, Crowe FL, Travis RC, Tipper SJ, Overvad K, Gronbaek H, Tjonneland A, Johnsen NF, Rinaldi S, Kaaks R, Lukanova A, Boeing H, Aleksandrova K, Trichopoulou A, Trichopoulos D, Andarakis G, Palli D, Krogh V, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Arguelles MV, Sanchez MJ, Chirlaque MD, Barricarte A, Larranaga N, Gonzalez CA, Stattin P, et al: Insulin-like growth factor-I concentration and risk of prostate cancer: results from the, European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2012, 21 (9): 1531-1541.CrossRefPubMed
33.
Park SL, Setiawan VW, Kanetsky PA, Zhang ZF, Wilkens LR, Kolonel LN, Le Marchand L: Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma. Cancer Causes Control. 2011, 22 (9): 1267-1275.CrossRefPubMedPubMedCentral
34.
Gao Y, Katki H, Graubard B, Pollak M, Martin M, Tao Y, Schoen RE, Church T, Hayes RB, Greene MH, Berndt SI: Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma. Int J Cancer. 2012, 131 (2): E105-13.CrossRefPubMed
35.
Al-Delaimy WK, Flatt SW, Natarajan L, Laughlin GA, Rock CL, Gold EB, Caan BJ, Parker BA, Pierce JP: IGF1 and risk of additional breast cancer in the WHEL study. Endocr Relat Cancer. 2011, 18 (2): 235-244.PubMed
36.
Rowlands MA, Holly JM, Hamdy F, Phillips J, Goodwin L, Marsden G, Gunnell D, Donovan J, Neal DE, Martin RM: Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer. Cancer Causes Control. 2012, 23 (2): 347-354.CrossRefPubMed
37.
Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, Scadden DT: Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008, 2 (3): 274-283.CrossRefPubMedPubMedCentral
38.
Ashihara E, Kawata E, Nakagawa Y, Shimazaski C, Kuroda J, Taniguchi K, Uchiyama H, Tanaka R, Yokota A, Takeuchi M, Kamitsuji Y, Inaba T, Taniwaki M, Kimura S, Maekawa T: β-catenin small interfering RNA successfully suppressed progression of multiple myeloma in a mouse model. Clin Cancer Res. 2009, 15 (8): 2731-2738.CrossRefPubMed
39.
Artim SC, Mendrola JM, Lemmon MA: Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochem J. 2012, 448 (2): 213-220.CrossRefPubMedPubMedCentral
40.
Pierre-Eugene C, Pagesy P, Nguyen TT, Neuille M, Tschank G, Tennagels N, Hampe C, Issad T: Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLoS One. 2012, 7 (7): e41992-CrossRefPubMedPubMedCentral
41.
Gualberto A, Pollak M: Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 2009, 28 (34): 3009-3021.CrossRefPubMed
42.
Alvino CL, Ong SC, McNeil KA, Delaine C, Booker GW, Wallace JC, Forbes BE: Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II. PLoS One. 2011, 6 (11): e27488-CrossRefPubMedPubMedCentral
43.
Tzivion G, Dobson M, Ramakrishnan G: FoxO transcription factors; regulation by AKT and 14–3-3 proteins. Biochim Biophys Acta. 2011, 1813 (11): 1938-1945.CrossRefPubMed
44.
Kalra N, Zhang J, Yu Y, Ho M, Merino M, Cao L, Hassan R: Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell. Int J Cancer. 2012, 131 (9): 2143-2152.CrossRefPubMedPubMedCentral
45.
Serin IS, Tanriverdi F, Yilmaz MO, Ozcelik B, Unluhizarci K: Serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women. Gynecol Endocrinol. 2008, 24: 117-121.CrossRefPubMed
46.
King ER, Zu Z, Tsang YT, Deavers MT, Malpica A, Mok SC, Gershenson DM, Wong KK: The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma. Gynecol Oncol. 2011, 123 (1): 13-18.CrossRefPubMedPubMedCentral
47.
Lau MT, Leung PC: The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett. 2012, 326 (2): 191-198.CrossRefPubMed
48.
Conover CA, Hartmann LC, Bradley S, Stalboerger P, Klee GG, Kalli KR, Jenkins RB: Biological characterization of human epithelial ovarian carcinoma cells in primary culture: the insulin-like growth factor system. Exp Cell Res. 1998, 238: 439-449.CrossRefPubMed
49.
Eckstein N, Servan K, Hildebrandt B, Pölitz A, von Jonquirés, Wolf-Kümmeth S, Napierski I, Hamacher A, Kassack MU, Budczies J, Beier M, Dietel M, Royer-Pokora B, Denkert C, Royer HD: Hyperactivation of the insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. Cancer Res. 2009, 69: 2996-3003.CrossRefPubMed
50.
Buck E, Gokhale PC, Koujak S, Brown E, Eyzaguirre A, Tao N, Rosenfeld-Franklin M, Lerner L, Chiu MI, Wild R, Epstein D, Pachter JA, Miglarese MR: Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol Cancer Ther. 2010, 9 (10): 2652-64.CrossRefPubMed
51.
Zhao H, Desai V, Wang J, Epstein D, Miglarese M, Buck E: Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines. Mol Cancer Ther. 2012, 11: 503-13.CrossRefPubMed
52.
Chao SY, Chiang JH, Huang AM, Chang WS: An integrative approach to identifying cancer chemoresistance-associated pathways. BMC Med Genomics. 2011, 4: 23-CrossRefPubMedPubMedCentral
53.
Lee S, Choi EJ, Jin C, Kim DH: Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol. 2005, 97 (1): 26-34.CrossRefPubMed
54.
Bashashati A, Ha G, Tone A, Ding J, Prentice LM, Roth A, Rosner J, Shumansky K, Kalloger S, Senz J, Yang W, McConechy M, Melnyk N, Anglesio M, Luk MT, Tse K, Zeng T, Moore R, Zhao Y, Marra MA, Gilks B, Yip S, Huntsman DG, McAlpine JN: Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J Pathol. 2013,, doi: 10.1002/path.4230
55.
De Cecco L, Marchionni L, Gariboldi M, Reid JF, Lagonigro MS, Caramuta S, Ferrario C, Bussani E, Mezzanzanica D, Turatti F, Delia D, Daidone MG, Oggionni M, Bertuletti N, Ditto A, Raspagliesi F, Pilotti S, Pierotti MA, Canevari S, Schneider C: Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2. Oncogene. 2004, 23 (49): 8171-8183.CrossRefPubMed
56.
Etemadmoghadam D, deFazio A, Beroukhim R, Mermel C, George J, Getz G, Tothill R, Okamoto A, Raeder MB, Harnett P, Lade S, Akslen LA, Tinker AV, Locandro B, Alsop K, Chiew YE, Traficante N, Fereday S, Johnson D, Fox S, Sellers W, Urashima M, Salvesen HB, Meyerson M, Bowtell D: AOCS Study Group: Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clin Cancer Res. 2009, 15 (4): 1417-1427.CrossRefPubMedPubMedCentral
57.
Ju W, Yoo BC, Kim IJ, Kim JW, Kim SC, Lee HP: Identification of genes with differential expression in chemoresistant epithelial ovarian cancer using high-density oligonucleotide microarrays. Oncol Res. 2009, 18 (2-3): 47-56.CrossRefPubMed
58.
Barlin JN, Jelinic P, Olvera N, Bogomolniy F, Bisogna M, Dao F, Barakat RR, Chi DS, Levine DA: Validated gene targets associated with curatively treated advanced serous ovarian carcinoma. Gynecol Oncol. 2013, 128 (3): 512-7. doi:10.1016/j.ygyno.2012.11.018. Epub 2012 Nov 17.CrossRefPubMed
59.
Rosen DG, Yang G, Deavers MT, Malpica A, Kavanagh JJ, Mills GB, Liu J: Cyclin E expression is correlated with tumor progression and predicts a poor prognosis in patients with ovarian carcinoma. Cancer. 2006, 106 (9): 1925-1932.CrossRefPubMed
60.
Kaur M, Agarwal R: Transcription factors: molecular targets for prostate cancer intervention by phytochemicals. Curr Cancer Drug Targets. 2007, 7 (4): 355-67.CrossRefPubMed
Metadata
Title
Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer
Authors
Madhuri Koti
Robert J Gooding
Paulo Nuin
Alexandria Haslehurst
Colleen Crane
Johanne Weberpals
Timothy Childs
Peter Bryson
Moyez Dharsee
Kenneth Evans
Harriet E Feilotter
Paul C Park
Jeremy A Squire
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-549

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Potentiation of in vitro and in vivoantitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells

Research article

Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression

Case report

Severe pan-uveitis in a patient treated with vemurafenib for metastatic melanoma

Research article

The role of hepatocyte nuclear factor 4alpha in metastatic tumor formation of hepatocellular carcinoma and its close relationship with the mesenchymal–epithelial transition markers

Research article

A phase II trial of personalized peptide vaccination in castration-resistant prostate cancer patients: prolongation of prostate-specific antigen doubling time

Research article

Low Annexin A1 expression predicts benefit from induction chemotherapy in oral cancer patients with moderate or poor pathologic differentiation grade
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits