Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis.
The interaction between the erbB tyrosine kinase receptors and their ligands plays an important role in tumor growth via the regulation of autocrine and paracrine loops. We report the effect of heregulin beta1, the ligand for erbB-3 and erbB-4 receptors, on the regulation of vascular endothelial growth factor (VEGF) expression, using a panel of breast and lung cancer cell lines with constitutive erbB-2 overexpression or engineered to stably overexpress the erbB-2 receptor. We demonstrate that heregulin beta1 induces VEGF secretion in most cancer cell lines, while no significant effect was observed in normal human mammary and bronchial primary cells. Overexpression of erbB-2 receptor results in induction of the basal level of VEGF and exposure to heregulin further enhances VEGF secretion. This is associated with increased VEGF mRNA expression. In contrast, VEGF induction is significantly decreased in a T47D cell line where erbB-2 is functionally inactivated. Conditioned media from heregulin-treated cancer cells, but not from normal cells, stimulates endothelial cell proliferation; this paracrine stimulation is inhibited by co-exposure to a specific VEGF neutralizing antibody. Furthermore, heregulin-mediated angiogenesis is observed in the in vivo CAM assay. This study reports the first evidence of VEGF regulation by heregulin in cancer cells. Oncogene (2000) 19, 3460 - 3469
Department of Medicine, Oncology, Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada.
L
L
Yen
X L
XL
You
A E
AE
Al Moustafa
G
G
Batist
N E
NE
Hynes
S
S
Mader
S
S
Meloche
M A
MA
Alaoui-Jamali
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000473:pathology; D001980:Bronchi / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D020890:Neuregulin-1 / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D066246:ErbB Receptors; D008222:Lymphokines; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C587689:ERBB4 protein, human