Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases.
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.
Morrissey
Colm
C
Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Seattle, WA 98195, USA. cmorriss@u.washington.edu
True
Lawrence D
LD
Roudier
Martine P
MP
Coleman
Ilsa M
IM
Hawley
Sarah
S
Nelson
Peter S
PS
Coleman
Roger
R
Wang
Ya-Chun
YC
Corey
Eva
E
Lange
Paul H
PH
Higano
Celestia S
CS
Vessella
Robert L
RL
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
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