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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2009

Open Access 01-12-2009 | Research article

A compact VEGF signature associated with distant metastases and poor outcomes

Authors: Zhiyuan Hu, Cheng Fan, Chad Livasy, Xiaping He, Daniel S Oh, Matthew G Ewend, Lisa A Carey, Subbaya Subramanian, Robert West, Francis Ikpatt, Olufunmilayo I Olopade, Matt van de Rijn, Charles M Perou

Published in: BMC Medicine | Issue 1/2009

Login to get access

Abstract

Background

Tumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies.

Methods

Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases.

Results

When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables.

Conclusion

These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types.
This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.
Appendix
Available only for authorised users
Literature
1.
2.
Han B, Nakamura M, Mori I, Nakamura Y, Kakudo K: Urokinase-type plasminogen activator system and breast cancer (Review). Oncol Rep. 2005, 14 (1): 105-112.PubMed
3.
Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005, 8 (3): 197-209.CrossRefPubMed
4.
5.
Leek RD: The prognostic role of angiogenesis in breast cancer. Anticancer Res. 2001, 21 (6B): 4325-4331.PubMed
6.
7.
Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, Shenkier TN, Davidson NE: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). San Antonio Breast Cancer Symposium: 2005; San Antonio, TX. 2005
8.
Schneider BP, Sledge GW: Drug insight: VEGF as a therapeutic target for breast cancer. Nat Clin Pract Oncol. 2007, 4 (3): 181-189.CrossRefPubMed
9.
Ramaswamy S, Ross KN, Lander ES, Golub TR: A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003, 33 (1): 49-54.CrossRefPubMed
10.
Vijver van de MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, Velde van der T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002, 347 (25): 1999-2009.CrossRefPubMed
11.
van 't Veer LJ, Dai H, Vijver van de MJ, He YD, Hart AA, Mao M, Peterse HL, Kooy van der K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415 (6871): 530-536.CrossRefPubMed
12.
Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005, 365 (9460): 671-679.CrossRefPubMed
13.
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004, 351 (27): 2817-2826.CrossRefPubMed
14.
Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003, 3 (6): 537-549.CrossRefPubMed
15.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J: Genes that mediate breast cancer metastasis to lung. Nature. 2005, 436 (7050): 518-524.CrossRefPubMedPubMedCentral
16.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004, 117 (7): 927-939.CrossRefPubMed
17.
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K: Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004, 6 (1): 17-32.CrossRefPubMed
18.
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM: The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006, 7 (1): 96.CrossRefPubMedPubMedCentral
19.
Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, Wu J, Carey LA, Perou CM: Estrogen-Regulated Genes Predict Survival in Hormone Receptor-Positive Breast Cancers. J Clin Oncol. 2006, 24 (11): 1656-1664.CrossRefPubMed
20.
Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, Glas AM, Perou CM, Van't Veer LJ: Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res. 2005, 65 (20): 9155-9158.CrossRefPubMed
21.
Hu Z, Troester M, Perou CM: High reproducibility using sodium hydroxide-stripped long oligonucleotide DNA microarrays. Biotechniques. 2005, 38 (1): 121-124.CrossRefPubMed
22.
Novoradovskaya N, Whitfield ML, Basehore LS, Novoradovsky A, Pesich R, Usary J, Karaca M, Wong WK, Aprelikova O, Fero M, Perou CM, Botstein D, Braman J: Universal Reference RNA as a standard for microarray experiments. BMC Genomics. 2004, 5 (1): 20.CrossRefPubMedPubMedCentral
23.
Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998, 95 (25): 14863-14868.CrossRefPubMedPubMedCentral
24.
Saldanha AJ: Java Treeview – extensible visualization of microarray data. Bioinformatics. 2004, 20 (17): 3246-3248.CrossRefPubMed
25.
Tibshirani R, Hastie T, Narasimhan B, Chu G: Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA. 2002, 99 (10): 6567-6572.CrossRefPubMedPubMedCentral
26.
Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, Butterfoss D, Xiang D, Zanation A, Yin X, Shockley WW, Weissler MC, Dressler LG, Shores CG, Yarbrough WG, Perou CM: Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004, 5 (5): 489-500.CrossRefPubMed
27.
Camp RL, Dolled-Filhart M, Rimm DL: X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004, 10 (21): 7252-7259.CrossRefPubMed
28.
Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sørlie T, Dai H, He YD, van't Veer LJ, Bartelink H, Rijn van de M, Brown PO, Vijver van de MJ: Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA. 2005, 102 (10): 3738-3743.CrossRefPubMedPubMedCentral
29.
Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA. 2001, 98 (24): 13790-13795.CrossRefPubMedPubMedCentral
30.
Nutt CL, Mani DR, Betensky RA, Tamayo P, Cairncross JG, Ladd C, Pohl U, Hartmann C, McLaughlin ME, Batchelor TT, Black PM, von Deimling A, Pomeroy SL, Golub TR, Louis DN: Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res. 2003, 63 (7): 1602-1607.PubMed
31.
Benito M, Parker J, Du Q, Wu J, Xiang D, Perou CM, Marron JS: Adjustment of systematic microarray data biases. Bioinformatics. 2004, 20 (1): 105-114.CrossRefPubMed
32.
Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, Rijn van de M, Botstein D, Brown PO: Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004, 2 (2): E7.CrossRefPubMedPubMedCentral
33.
Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Børresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, Vijver van de MJ, Brown PO: Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers. PLoS Med. 2006, 3 (3): e47.CrossRefPubMedPubMedCentral
34.
Glinsky GV, Berezovska O, Glinskii AB: Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005, 115 (6): 1503-1521.CrossRefPubMedPubMedCentral
35.
Troester MA, Herschkowitz JI, Oh DS, He X, Hoadley KA, Barbier CS, Perou CM: Gene expression patterns associated with p53 status in breast cancer. BMC Cancer. 2006, 6: 276.CrossRefPubMedPubMedCentral
36.
West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, Rijn van de M: The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004, 165 (1): 107-113.CrossRefPubMedPubMedCentral
37.
Vleugel MM, Greijer AE, Shvarts A, Groep van der P, van Berkel M, Aarbodem Y, van Tinteren H, Harris AL, van Diest PJ, Wall van der E: Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol. 2005, 58 (2): 172-177.CrossRefPubMedPubMedCentral
38.
Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA. 2001, 98 (9): 5116-5121.CrossRefPubMedPubMedCentral
39.
Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS: Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 2001, 61 (16): 5979-5984.PubMed
40.
Hoch RV, Thompson DA, Baker RJ, Weigel RJ: GATA-3 is expressed in association with estrogen receptor in breast cancer. Int J Cancer. 1999, 84 (2): 122-128.CrossRefPubMed
41.
Perou CM, Sørlie T, Eisen MB, Rijn van de M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D: Molecular portraits of human breast tumours. Nature. 2000, 406 (6797): 747-752.CrossRefPubMed
42.
Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, Alexander KE, Matese JC, Perou CM, Hurt MM, Brown PO, Botstein D: Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell. 2002, 13 (6): 1977-2000.CrossRefPubMedPubMedCentral
43.
Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JC, Trent JM, Staudt LM, Hudson J, Boguski MS, Lashkari D, Shalon D, Botstein D, Brown PO: The transcriptional program in the response of human fibroblasts to serum [see comments]. Science. 1999, 283 (5398): 83-87.CrossRefPubMed
44.
45.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003, 100 (14): 8418-8423.CrossRefPubMedPubMedCentral
46.
Calza S, Hall P, Auer G, Bjöhle J, Klaar S, Kronenwett U, Liu ET, Miller L, Ploner A, Smeds J, Bergh J, Pawitan Y: Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients. Breast Cancer Res. 2006, 8 (4): R34.CrossRefPubMedPubMedCentral
47.
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama. 2006, 295 (21): 2492-2502.CrossRefPubMed
48.
Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DS, Nobel AB, van't Veer LJ, Perou CM: Concordance among gene-expression-based predictors for breast cancer. N Engl J Med. 2006, 355 (6): 560-569.CrossRefPubMed
49.
Warburg O: On respiratory impairment in cancer cells. Science. 1956, 124 (3215): 269-270.PubMed
50.
Semenza GL, Artemov D, Bedi A, Bhujwalla Z, Chiles K, Feldser D, Laughner E, Ravi R, Simons J, Taghavi P, Zhong H: 'The metabolism of tumours': 70 years later. Novartis Found Symp. 2001, 240: 251-260. discussion 260-254.CrossRefPubMed
51.
Loots GG, Ovcharenko I, Pachter L, Dubchak I, Rubin EM: rVista for comparative sequence-based discovery of functional transcription factor binding sites. Genome Res. 2002, 12 (5): 832-839.CrossRefPubMedPubMedCentral
52.
Fang J, Yan L, Shing Y, Moses MA: HIF-1alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis. Cancer Res. 2001, 61 (15): 5731-5735.PubMed
53.
Frede S, Freitag P, Otto T, Heilmaier C, Fandrey J: The proinflammatory cytokine interleukin 1beta and hypoxia cooperatively induce the expression of adrenomedullin in ovarian carcinoma cells through hypoxia inducible factor 1 activation. Cancer Res. 2005, 65 (11): 4690-4697.CrossRefPubMed
54.
Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J: REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase. Oncogene. 2005, 24 (7): 1138-1149.CrossRefPubMed
55.
Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Rijn Van de M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO: Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet. 2000, 24 (3): 227-235.CrossRefPubMed
56.
Winter SC, Buffa FM, Silva P, Miller C, Valentine HR, Turley H, Shah KA, Cox GJ, Corbridge RJ, Homer JJ, Musgrove B, Slevin N, Sloan P, Price P, West CM, Harris AL: Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res. 2007, 67 (7): 3441-3449.CrossRefPubMed
57.
Weigelt B, Glas AM, Wessels LF, Witteveen AT, Peterse JL, van't Veer LJ: Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci USA. 2003, 100 (26): 15901-15905.CrossRefPubMedPubMedCentral
58.
Whitfield ML, George LK, Grant GD, Perou CM: Common markers of proliferation. Nat Rev Cancer. 2006, 6 (2): 99-106.CrossRefPubMed
59.
Ross DT, Perou CM: A comparison of gene expression signatures from breast tumors and breast tissue derived cell lines. Dis Markers. 2001, 17 (2): 99-109.CrossRefPubMed
60.
Fritz-Six KL, Dunworth WP, Li M, Caron KM: Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest. 2008, 118 (1): 40-50.CrossRefPubMed
61.
Chen B, Nelson DM, Sadovsky Y: N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. J Biol Chem. 2006, 281 (5): 2764-2772.CrossRefPubMed
62.
Okuda T, Kokame K, Miyata T: [Functional analyses of NDRG1, a stress-responsive gene]. Seikagaku. 2005, 77 (7): 630-634.PubMed
63.
Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J: Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008, 68 (4): 989-997.CrossRefPubMed
64.
Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM: Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2005
Metadata
Title
A compact VEGF signature associated with distant metastases and poor outcomes
Authors
Zhiyuan Hu
Cheng Fan
Chad Livasy
Xiaping He
Daniel S Oh
Matthew G Ewend
Lisa A Carey
Subbaya Subramanian
Robert West
Francis Ikpatt
Olufunmilayo I Olopade
Matt van de Rijn
Charles M Perou
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2009
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-7-9

Other articles of this Issue 1/2009

BMC Medicine 1/2009 Go to the issue

Research article

Who uses firearms as a means of suicide? A population study exploring firearm accessibility and method choice

Research article

Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis

Research article

Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11)

Review

Varicella vaccination in Europe – taking the practical approach

Research article

Identification of pediatric septic shock subclasses based on genome-wide expression profiling

Research article

Calculating the return on investment of mobile healthcare