Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis.
Hormone refractory metastatic prostate cancer remains an incurable disease. We found that high expression levels of the chemokine receptor CXCR4 correlated with the presence of metastatic disease in prostate cancer patients. Positive staining for CXCL12, the ligand for CXCR4, was mainly present in the tumor-associated blood vessels and basal cell hyperplasia. Subcutaneous xenografts of PC3 and 22Rv1 prostate tumors that overexpressed CXCR4 in NOD/SCID mice were two- to threefold larger in volume and weight vs. controls. Moreover, blood vessel density, functionality, invasiveness of tumors into the surrounding tissues, and metastasis to the lymph node and lung were significantly increased in these tumors. Neutralizing the interactions of CXCL12/CXCR4 in vivo with CXCR4 specific antibodies inhibited the CXCR4-dependent tumor growth and vascularization. In vitro, CXCL12 induced the proliferation and VEGF secretion but not migration of PC3 and 22Rv1 cells overexpressing CXCR4. Similar effects of CXCR4 overexpression on tumor growth in vivo were also noted in two breast cancer lines, suggesting that the observed effect of CXCR4 is not unique to prostate tumor cells. Thus high levels of the chemokine receptor CXCR4 induce a more aggressive phenotype in prostate cancer cells and identify CXCR4 as a potential therapeutic target in advanced cases of metastatic prostate cancer.
Darash-Yahana
Merav
M
Goldyne Savad Institute of Gene Therapy, HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Pikarsky
Eli
E
Abramovitch
Rinat
R
Zeira
Evelyne
E
Pal
Boaz
B
Karplus
Rebekah
R
Beider
Katia
K
Avniel
Shani
S
Kasem
Shafika
S
Galun
Eithan
E
Peled
Amnon
A
D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis / Q000494:pharmacology; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000473:pathology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A