Detection of tumor angiogenesis in vivo by _v3-targeted magnetic resonance imaging

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis¹⁻³. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma⁴⁻⁷. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin _v3, has been shown to correlate with tumor grade⁸⁻¹⁰. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial _v3 via the LM609 monoclonal antibody¹¹. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angio-genic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of _v3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.

1. Folkman, J. The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3, 65−71 (1992). | PubMed  | ChemPort |
2. Weinstat-Saslow, D. & Steeg, P.S. Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J. 8, 401−407 (1994). | PubMed  | ChemPort |
3. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1, 27−31 (1995). | PubMed  | ISI | ChemPort |
4. Horak, E.R. et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicators of node metastases and survival in breast cancer. Lancet 340, 1120−1124 (1992). | Article | PubMed  | ISI | ChemPort |
5. Carrau, R.L. et al. Tumor angiogenesis as a predictor of tumor aggressiveness and metastatic potential in squamous cell carcinoma of the head and neck. Invasion Metastasis 15, 197−202 (1995). | PubMed  | ISI | ChemPort |
6. Meitar, D., Crawford, S.E., Rademaker, A.W. & Cohn, S.L. Tumor angiogenesis correlates with metastatic disease, N-myc amplification, and poor outcome in human neuroblastoma. J. Clin. Oncol. 14, 405−414 (1996). | PubMed  | ISI | ChemPort |
7. Takebayashi, Y., Aklyama, S., Yamada, K., Akiba, S. & Aikou, T. Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer 78, 226−231 (1996). | Article | PubMed  | ISI | ChemPort |
8. Brooks, P.C., Clark, R.A.F. & Cheresh, D.A. Requirement of vascular integrin v3 for angiogenesis. Science 264, 569−571 (1994). | PubMed  | ISI | ChemPort |
9. Brooks, P.C. et al. Antiintegrin alpha v beta3 blocks human breast cancer growth and angiogenesis in human skin. J. Clin. Invest. 96, 1815−1822 (1995). | PubMed  | ISI | ChemPort |
10. Gladson, C.L. Expression of integrin v3 in small blood vessels of glioblastoma tumors. J Neuropath Exp Neurol 55, 1143−1149 (1996). | PubMed  | ISI | ChemPort |
11. Gupta, H. & Weissleder, R. Targeted contrast agents in MR imaging. MRI Clinics of North America 4, 171−184 (1996). | PubMed  | ChemPort |
12. Storrs, R.W. et al. Paramagnetic polymerized liposomes: Synthesis, characterization and applications for magnetic resonance imaging. J. Am. Chem. Soc. 117, 7301−7306 (1995). | ISI | ChemPort |
13. Storrs, R.W. et al. Paramagnetic polymerized liposomes as new recirculating MR contrast agents. JMRI 5, 719−724 (1995). | PubMed  | ISI | ChemPort |
14. Allen, T.M., Hansen, C. & Rutledge, J. Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim. Biophys. Acta 981, 27−35 (1989). | Article | PubMed  | ISI | ChemPort |
15. Strauli, P. & Haemmerli, G. The V2 carcinoma of the rabbit as an integrated model of tumor invasion. Bull. Cancer (Paris) 71, 447−452 (1984). | PubMed  | ChemPort |
16. Weidner, N., Semple, J.P., Welch, W.R. & Folkman, J. Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1−8 (1991). | PubMed  | ISI | ChemPort |
17. Brooks, P.C. et al. Integrin v3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157−1164 (1994). | Article | PubMed  | ISI | ChemPort |
18. Brasch, R.C. in MRI Contrast Enhancement in the Central Nervous System: A Case Study Approach (ed. Brasch, R.C.e.a.) 1−10 (Raven Press, New York, 1993).
19. Jolesz, F.A. & Blumenfeld, S.M. Interventional use of magnetic resonance imaging. Mag. Res. Quar. 10, 85−96 (1994). | ISI | ChemPort |
20. Weinreb, J.C. & Newstead, G. Controversies in breast MRI. Mag. Res. Quar. 10, 67−83 (1994). | ISI | ChemPort |

	Top

	Top