INTRODUCTION: Breast cancer can metastasize via lymphatic and hematogenous pathways. Hypoxia and (lymph)angiogenesis are closely related processes that play a pivotal role in the tumor progression and metastasis. The aim of this study was to compare expression of hypoxia and (lymph)angiogenesis-related genes between primary breast tumors and metastases in different tissues. MATERIALS AND METHODS: A gene list of 269 hypoxia and (lymph)angiogenesis-related genes was composed and validated using Onto-Express, Pathway-express and Ingenuity software. The expression of these genes was compared in microarray data of 62 samples of primary tumors and metastases of 31 patients with breast cancer retrieved from Gene Expression Omnibus. Similarity between samples was investigated using unsupervised hierarchical clustering analysis, principal component analysis and permutation testing. Differential gene expression between primary tumors and metastases and between metastases from different organs was analyzed using Kruskall-Wallis and Mann-Whitney statistics. RESULTS: Unsupervised hierarchical cluster analysis demonstrated that hypoxia and (lymph)angiogenesis-related gene expression was more similar between samples from the same patient, than between samples from the same organ. Principal component analysis indicated that 22.7% and 7.0% of the total variation in the gene list was respectively patient and organ related. When differences in gene expression were studied between different organs, liver metastases seemed to differ most from the other secondary sites. Some of the best characterized molecules differentially expressed were VEGFA, PDGFRB, FGF4, TIMP1, TGFB-R1 and collagen 18A1 (precursor of endostatin). To confirm the results of these experiments at the protein level, immunohistochemical experiments were performed with antibodies for VEGFA and MMP-2. CONCLUSIONS: Our results suggest that hypoxia and (lymph)angiogenesis-related gene expression is more dependent on the characteristics of the primary tumor than on the characteristics of the organs that bear the metastasis. However, when different organs are compared, the expression in liver metastases differs most from other metastatic sites and primary tumors, possibly due to organ-specific angiogenic and lymphangiogenic responses to metastasis-related hypoxia.
INTRODUCTION: Breast cancer can metastasize via lymphatic and hematogenous pathways. Hypoxia and (lymph)angiogenesis are closely related processes that play a pivotal role in the tumor progression and metastasis. The aim of this study was to compare expression of hypoxia and (lymph)angiogenesis-related genes between primary breast tumors and metastases in different tissues. MATERIALS AND METHODS: A gene list of 269 hypoxia and (lymph)angiogenesis-related genes was composed and validated using Onto-Express, Pathway-express and Ingenuity software. The expression of these genes was compared in microarray data of 62 samples of primary tumors and metastases of 31 patients with breast cancer retrieved from Gene Expression Omnibus. Similarity between samples was investigated using unsupervised hierarchical clustering analysis, principal component analysis and permutation testing. Differential gene expression between primary tumors and metastases and between metastases from different organs was analyzed using Kruskall-Wallis and Mann-Whitney statistics. RESULTS: Unsupervised hierarchical cluster analysis demonstrated that hypoxia and (lymph)angiogenesis-related gene expression was more similar between samples from the same patient, than between samples from the same organ. Principal component analysis indicated that 22.7% and 7.0% of the total variation in the gene list was respectively patient and organ related. When differences in gene expression were studied between different organs, liver metastases seemed to differ most from the other secondary sites. Some of the best characterized molecules differentially expressed were VEGFA, PDGFRB, FGF4, TIMP1, TGFB-R1 and collagen 18A1 (precursor of endostatin). To confirm the results of these experiments at the protein level, immunohistochemical experiments were performed with antibodies for VEGFA and MMP-2. CONCLUSIONS: Our results suggest that hypoxia and (lymph)angiogenesis-related gene expression is more dependent on the characteristics of the primary tumor than on the characteristics of the organs that bear the metastasis. However, when different organs are compared, the expression in liver metastases differs most from other metastatic sites and primary tumors, possibly due to organ-specific angiogenic and lymphangiogenic responses to metastasis-related hypoxia.
Authors: Reinhard Bos; Petra van der Groep; Astrid E Greijer; Avi Shvarts; Sybren Meijer; Herbert M Pinedo; Gregg L Semenza; Paul J van Diest; Elsken van der Wall Journal: Cancer Date: 2003-03-15 Impact factor: 6.860
Authors: Petri Bono; Veli-Matti Wasenius; Päivi Heikkilä; Johan Lundin; David G Jackson; Heikki Joensuu Journal: Clin Cancer Res Date: 2004-11-01 Impact factor: 12.531
Authors: C M Perou; T Sørlie; M B Eisen; M van de Rijn; S S Jeffrey; C A Rees; J R Pollack; D T Ross; H Johnsen; L A Akslen; O Fluge; A Pergamenschikov; C Williams; S X Zhu; P E Lønning; A L Børresen-Dale; P O Brown; D Botstein Journal: Nature Date: 2000-08-17 Impact factor: 49.962
Authors: M Skobe; T Hawighorst; D G Jackson; R Prevo; L Janes; P Velasco; L Riccardi; K Alitalo; K Claffey; M Detmar Journal: Nat Med Date: 2001-02 Impact factor: 53.440
Authors: E R Horak; R Leek; N Klenk; S LeJeune; K Smith; N Stuart; M Greenall; K Stepniewska; A L Harris Journal: Lancet Date: 1992-11-07 Impact factor: 79.321
Authors: Holly K Dressman; Christopher Hans; Andrea Bild; John A Olson; Eric Rosen; P Kelly Marcom; Vlayka B Liotcheva; Ellen L Jones; Zeljko Vujaskovic; Jeffrey Marks; Mark W Dewhirst; Mike West; Joseph R Nevins; Kimberly Blackwell Journal: Clin Cancer Res Date: 2006-02-01 Impact factor: 12.531
Authors: Monika Schindl; Sebastian F Schoppmann; Hellmut Samonigg; Hubert Hausmaninger; Werner Kwasny; Michael Gnant; Raimund Jakesz; Ernst Kubista; Peter Birner; Georg Oberhuber Journal: Clin Cancer Res Date: 2002-06 Impact factor: 12.531
Authors: F Stessels; G Van den Eynden; I Van der Auwera; R Salgado; E Van den Heuvel; A L Harris; D G Jackson; C G Colpaert; E A van Marck; L Y Dirix; P B Vermeulen Journal: Br J Cancer Date: 2004-04-05 Impact factor: 7.640
Authors: Tina Cascone; Li Xu; Heather Y Lin; Wenbin Liu; Hai T Tran; Yuan Liu; Kathryn Howells; Vincent Haddad; Emer Hanrahan; Monique B Nilsson; Maria A Cortez; Uma Giri; Humam Kadara; Babita Saigal; Yun-Yong Park; Weiyi Peng; Ju-Seog Lee; Anderson J Ryan; Juliane M Jüergensmeier; Roy S Herbst; Jing Wang; Robert R Langley; Ignacio I Wistuba; Jack J Lee; John V Heymach Journal: Clin Cancer Res Date: 2017-05-30 Impact factor: 12.531
Authors: Tina Cascone; Matthew H Herynk; Li Xu; Zhiqiang Du; Humam Kadara; Monique B Nilsson; Carol J Oborn; Yun-Yong Park; Baruch Erez; Jörg J Jacoby; Ju-Seog Lee; Heather Y Lin; Fortunato Ciardiello; Roy S Herbst; Robert R Langley; John V Heymach Journal: J Clin Invest Date: 2011-03-23 Impact factor: 14.808
Authors: Mariya B Aksenenko; Nadezhda V Palkina; Olga N Sergeeva; Ekaterina Yu Sergeeva; Andrey K Kirichenko; Tatiana G Ruksha Journal: Int J Exp Pathol Date: 2020-02-11 Impact factor: 1.925
Authors: Ning Wang; Kristin A Eckert; Ali R Zomorrodi; Ping Xin; Weihua Pan; Debra A Shearer; Judith Weisz; Costas D Maranus; Gary A Clawson Journal: PLoS One Date: 2012-06-26 Impact factor: 3.240