Stage-specific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advanced-stage disease.
OBJECTIVE
The vascular endothelial growth factor (VEGF) family plays a critical role in tumor angiogenesis and lymphangiogenesis. We characterized, at the mRNA and protein levels, the expression of VEGF-A and VEGF-D and their cognate receptors, VEGFR-1, VEGFR-2, and VEGFR-3 in early- and advanced-stage prostate cancer specimens.


METHODS
The levels of VEGF-A and VEGF-D mRNA in early- and advanced-stage specimens were compared using an angiogenic gene array and were confirmed by quantitative real-time PCR. Receptor protein levels and activation status were determined by immunoblotting. Spatial expression of the proteins was evaluated using immunohistochemistry with fresh and archival tissues from benign prostatic hypertrophy specimens, early-stage prostate specimens, and advanced-stage metastatic specimens. Circulating plasma levels of these growth factors were measured using ELISAs.


RESULTS
We observed that expression patterns of VEGF isotypes corresponded to the prostate cancer stage: high expression of angiogenic growth factor VEGF-A was observed in early-stage prostate specimens, whereas high expression of lymphangiogenic growth factor VEGF-D was associated with advanced-stage metastatic disease. All VEGF receptors were present at variable levels in all specimens, but their activation states varied in a stage-specific manner. VEGFR-1 and, to a limited extent, VEGFR-2 were activated in early-stage specimens, whereas VEGFR-2 and VEGFR-3 were activated in advanced-stage specimens.


CONCLUSIONS
Our results suggest that lymphangiogenic markers, such as VEGF-D and VEGFR-2 and VEGFR-3, may be better than angiogenic markers as targets of therapeutic intervention in advanced-stage prostate disease.
Kaushal
Varsha
V
Department of Internal Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA. Kaushalvarsha@uams.edu
Mukunyadzi
Perkins
P
Dennis
Richard A
RA
Siegel
Eric R
ER
Johnson
Donald E
DE
Kohli
Manish
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism* / Q000556:secondary; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D018076:DNA, Complementary; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3