Dissociation of angiogenesis and tumorigenesis in follistatin- and activin-expressing tumors.
The transforming growth factor-beta 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.
Krneta
Jelena
J
Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center Freiburg, Freiburg, Germany.
Kroll
Jens
J
Alves
Frauke
F
Prahst
Claudia
C
Sananbenesi
Farahnaz
F
Dullin
Christian
C
Kimmina
Sarah
S
Phillips
David J
DJ
Augustin
Hellmut G
HG
D028341:Activins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D038681:Follistatin / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
D038681:Follistatin; D028341:Activins