title: Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases.
abstract: Our objective was to elucidate phenotypic differences between prostate cancer (PCa) liver, lymph node, and bone metastases. PCa metastases were obtained through a rapid tissue acquisition necropsy protocol. We grossly dissected metastatic foci from frozen samples and performed expression analyses using cDNA microarrays. Immunohistochemical analyses using a tissue microarray from thirty individuals with PCa metastases to lymph nodes, liver, and bone was used to confirm the gene expression changes associated with each metastatic site. Transcript alterations statistically-associated with bone metastases included increased expression of IBSP (Bone sialoprotein), F13A1 (factor XIII), and decreased expression of EFNA1 (ephrin-A1) and ANGPT2 (angiopoietin-2) when compared to liver and lymph node metastases. The metastasis-associated changes in proteins involved in coagulation and angiogenesis prompted further analysis of additional factors known to participate in the clotting cascade and blood vessel formation (angiopoitein-1, PAI-1, uPA, PAI-RBP-1 and hepsin). We also assessed tumor-associated microvessel density and distribution in liver, lymph node, and bone metastasis. Intense fibrin(ogen) and fibulin-1 staining was localized to epithelial cells at the periphery of metastatic tumors possibly to facilitate angiogenesis. The expression of hepsin, uPA, PAI-RBP1, PAI-1, and factor XIII may influence fibrinolysis and are regulated by the tumor microenvironment. The expression of angiopoietin-2 and apparent silencing of angiopoietin-1 in PCa bone, liver, and lymph node metastases may be critical for angiogenesis in this tumor type. In addition, the resulting tumor-associated microvessel density and distribution was significantly different between liver and bone metastasis possibly in response to the protein expression changes detailed above.
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Seattle, WA 98195, USA. cmorriss@u.washington.edu
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.forename: Martine P
authors.initials: MP
authors.lastname: Roudier
authors.forename: Ilsa M
authors.initials: IM
authors.lastname: Coleman
authors.forename: Sarah
authors.initials: S
authors.lastname: Hawley
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics; D015944:Factor VIIIa / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D002135:Calcium-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D016601:RNA-Binding Proteins; C428129:SERBP1 protein, human; C060820:fibulin; D015944:Factor VIIIa; D014568:Urokinase-Type Plasminogen Activator