This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krneta, J. Articles by Augustin, H. G. Search for Related Content PubMed PubMed Citation Articles by Krneta, J. Articles by Augustin, H. G.

Dissociation of Angiogenesis and Tumorigenesis in Follistatin- and Activin-Expressing Tumors

¹ Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center Freiburg, Freiburg, Germany; Departments of ² Hematology and Oncology, ³ Radiology, and ⁴ Laboratory Animals, University of Göttingen, Göttingen, Germany; and ⁵ Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

Requests for reprints: Hellmut G. Augustin, Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center Freiburg, Breisacher Strasse 117, 79106 Freiburg, Germany. Phone: 49-761-206-1500; Fax: 49-761-206-1505; E-mail: augustin{at}angiogenese.de.

The transforming growth factor-ß superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2–induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained. (Cancer Res 2006; 66(11): 5686-95)

This article has been cited by other articles:

				P. Florio, F.M. Reis, P.B. Torres, F. Calonaci, M.S. Abrao, L.L. Nascimento, M. Franchini, L. Cianferoni, and F. Petraglia High serum follistatin levels in women with ovarian endometriosis Hum. Reprod., June 23, 2009; (2009) dep195v1. [Abstract] [Full Text] [PDF]

				S.-Y. Lin, R. G. Craythorn, A. E. O'Connor, M. M. Matzuk, J. E. Girling, J. R. Morrison, and D. M. de Kretser Female Infertility and Disrupted Angiogenesis Are Actions of Specific Follistatin Isoforms Mol. Endocrinol., February 1, 2008; 22(2): 415 - 429. [Abstract] [Full Text] [PDF]

				J. E. Talmadge Follistatin as an Inhibitor of Experimental Metastasis Clin. Cancer Res., February 1, 2008; 14(3): 624 - 626. [Full Text] [PDF]

				H. Ogino, S. Yano, S. Kakiuchi, H. Muguruma, K. Ikuta, M. Hanibuchi, H. Uehara, K. Tsuchida, H. Sugino, and S. Sone Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell-Depleted SCID Mice Clin. Cancer Res., February 1, 2008; 14(3): 660 - 667. [Abstract] [Full Text] [PDF]

				D. Razanajaona, S. Joguet, A.-S. Ay, I. Treilleux, S. Goddard-Leon, L. Bartholin, and R. Rimokh Silencing of FLRG, an Antagonist of Activin, Inhibits Human Breast Tumor Cell Growth Cancer Res., August 1, 2007; 67(15): 7223 - 7229. [Abstract] [Full Text] [PDF]

				T. M. Robinson-Smith, I. Isaacsohn, C. A. Mercer, M. Zhou, N. Van Rooijen, N. Husseinzadeh, M. M. McFarland-Mancini, and A. F. Drew Macrophages Mediate Inflammation-Enhanced Metastasis of Ovarian Tumors in Mice Cancer Res., June 15, 2007; 67(12): 5708 - 5716. [Abstract] [Full Text] [PDF]