Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells.
We hypothesize that expression of proangiogenic genes correlates with the metastatic potential of prostate cancer cells. LNCaP, DU-145, and PC-3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as we demonstrated by their capacity to invade an extracellular matrix, an established tumor invasion assay. The constitutive gene expression of the proangiogenic factors, vascular endothelial growth factor, intercellular adhesion molecule-1, interleukin-8, and transforming growth factor-beta2, was significantly greater in the more metastatic DU-145 and PC-3 cells as compared with LNCaP cells. Matrix metalloproteinase (MMP)-9 is thought to contribute to the invasive phenotype of tumor cells. PC-3 cells showed increased expression of MMP-9 and membrane type 4-MMP as compared with LNCaP and DU-145. Tissue inhibitors of metalloproteinase 1 and 4 gene expression were elevated in DU-145 and PC-3 cells, but paradoxically, LNCaP cells had undetectable levels of these genes. We transfected and overexpressed MMP-9 in poorly metastatic LNCaP cells and measured their invasive activity. Transient expression of human MMP-9 in LNCaP cells produced a 3-5-fold increase in MMP-9 activity with a comparable increase in invasiveness. Antisense ablation of the expression of MMP-9 in DU-145 and PC-3 cells produced concomitant inhibition of the gene expression of the proangiogenic factors, vascular endothelial growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of DU-145 and PC-3 cells with a selective chemical inhibitor of MMP-9 proteinase activity also inhibited their invasive activity. These results support our hypothesis that metastatic potential of prostate cancer cells correlates with expression of proangiogenic factors.
Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, 100 High Street, Buffalo, NY 14203, USA.
Ravikumar
R
Aalinkeel
Madhavan P N
MP
Nair
Gerald
G
Sufrin
Supriya D
SD
Mahajan
Kailash C
KC
Chadha
Ram P
RP
Chawda
Stanley A
SA
Schwartz
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D042501:Angiogenic Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2; D014407:Tumor Cells, Cultured
D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9