Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin

Alfonso Calvo, Yumi Yokoyama, Lois E. Smith, Iqbal Ali, Shu Ching Shih, Andrew L. Feldman, Steven K. Libutti, Ramakrishnan Sundaram, Jeffrey E. Green

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 VEGF188 mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Fit-1) become highlyxpressed 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 I 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 Fit-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.

Original languageEnglish (US)
Pages (from-to)224-234
Number of pages11
JournalInternational Journal of Cancer
Volume101
Issue number3
DOIs
StatePublished - Sep 20 2002
Externally publishedYes

Fingerprint

Endostatins
Transgenic Mice
Breast Neoplasms
Neoplasms
Endothelial Cells
Angiopoietin-2
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor
Cell Adhesion Molecules
Blood Vessels
Blood Platelets
RNA Isoforms
Carcinoma
Messenger RNA
Human Mammary Glands
Growth
Tumor Burden
Adenocarcinoma

Keywords

  • Angiogenesis
  • Endostatin
  • Mammary cancer
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. / Calvo, Alfonso; Yokoyama, Yumi; Smith, Lois E.; Ali, Iqbal; Shih, Shu Ching; Feldman, Andrew L.; Libutti, Steven K.; Sundaram, Ramakrishnan; Green, Jeffrey E.

In: International Journal of Cancer, Vol. 101, No. 3, 20.09.2002, p. 224-234.

Research output: Contribution to journalArticle

Calvo, A, Yokoyama, Y, Smith, LE, Ali, I, Shih, SC, Feldman, AL, Libutti, SK, Sundaram, R & Green, JE 2002, 'Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin', International Journal of Cancer, vol. 101, no. 3, pp. 224-234. https://doi.org/10.1002/ijc.10589
Calvo, Alfonso ; Yokoyama, Yumi ; Smith, Lois E. ; Ali, Iqbal ; Shih, Shu Ching ; Feldman, Andrew L. ; Libutti, Steven K. ; Sundaram, Ramakrishnan ; Green, Jeffrey E. / Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. In: International Journal of Cancer. 2002 ; Vol. 101, No. 3. pp. 224-234.
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