title: Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin.
abstract: Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Lois E
authors.initials: LE
authors.lastname: Smith
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ali
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Shih
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Sundaram
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D000818:Animals; D001835:Body Weight; D003001:Cloning, Molecular; D003094:Collagen / Q000235:genetics / Q000627:therapeutic use*; D017931:DNA Primers / Q000737:chemistry; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D017931:DNA Primers; D043169:Endostatins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor