TY - JOUR
T1 - Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner
AU - Xie, Liang
AU - Duncan, Michael B.
AU - Pahler, Jessica
AU - Sugimoto, Hikaru
AU - Martino, Margot
AU - Lively, Julie
AU - Mundel, Thomas
AU - Soubasakos, Mary
AU - Rubin, Kristofer
AU - Takeda, Takaaki
AU - Inoue, Masahiro
AU - Lawler, Jack
AU - Hynes, Richard O.
AU - Hanahan, Douglas
AU - Kalluri, Raghu
PY - 2011/6/14
Y1 - 2011/6/14
N2 - Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.
AB - Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.
KW - Cell biology
KW - Integrins
UR - http://www.scopus.com/inward/record.url?scp=79960014831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960014831&partnerID=8YFLogxK
U2 - 10.1073/pnas.1105041108
DO - 10.1073/pnas.1105041108
M3 - Article
C2 - 21622854
AN - SCOPUS:79960014831
SN - 0027-8424
VL - 108
SP - 9939
EP - 9944
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -