Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner

Liang Xie, Michael B. Duncan, Jessica Pahler, Hikaru Sugimoto, Margot Martino, Julie Lively, Thomas Mundel, Mary Soubasakos, Kristofer Rubin, Takaaki Takeda, Masahiro Inoue, Jack Lawler, Richard O. Hynes, Douglas Hanahan, Raghu Kalluri

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)9939-9944
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Jun 14 2011
Externally publishedYes


  • Cell biology
  • Integrins

ASJC Scopus subject areas

  • General


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