Reference SummaryXie L, Proc Natl Acad Sci U S A 2011 Jun 14;108(24):9939-44

Title

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

Authors

Xie L; Duncan MB; Pahler J; Sugimoto H; Martino M; Lively J; Mundel T; Soubasakos M; Rubin K; Takeda T; Inoue M; Lawler J; Hynes RO; Hanahan D; Kalluri R

Journal

Proc Natl Acad Sci U S A

Volume

108

Issue

24

Year

2011

Pages

9939-44

Abstract

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.

Links

J:173322 – Mouse Genome Informatics
21622854 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Trp53tm1Brd Leukocyte lymphoma Leukocyte

observed - 16.7

C57BL/6-Col4a3tm1Dec Trp53tm1Brd Leukocyte lymphoma Leukocyte

observed - 35.2

C57BL/6-Col4a3tm1Dec Thbs1tm1Hyn Trp53tm1Brd Leukocyte lymphoma Leukocyte

observed - 41.7

C57BL/6-Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

5.55

C57BL/6-Col4a3tm1Dec Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

3.91

C57BL/6-Col4a3tm1Dec Thbs1tm1Hyn Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

4.165

C57BL/6-Tg(Ins2-cre)25Mgn Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(Ins2-cre)25Mgn Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(Ins2-cre)25Mgn Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans lesion Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Vegfatm2Gne Pancreas - Islet of Langerhans lesion Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans tumor Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans tumor
  • Tumstatin
Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans tumor
  • endostatin
Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas - Islet of Langerhans tumor
  • Thrombospondin-1
Pancreas - Islet of Langerhans

observed

C57BL/6-Tg(RIP1-Tag)2Dh Pancreas tumor Pancreas

observed

C57BL/6-Col4a3tm1Dec Tg(RIP1-Tag)2Dh Pancreas tumor Pancreas

observed

C57BL/6-Col18a1tm1Hms Tg(RIP1-Tag)2Dh Pancreas tumor Pancreas

observed

C57BL/6-Tg(RIP1-Tag)5Dh Thbs1tm1Hyn Pancreas tumor Pancreas

observed

C57BL/6-Itgb3tm1Hyn Tg(RIP1-Tag)5Dh Pancreas tumor Pancreas

observed

C57BL/6-Trp53tm1Brd (Unspecified organ) angiosarcoma (Unspecified organ)

observed

C57BL/6-Col4a3tm1Dec Trp53tm1Brd (Unspecified organ) angiosarcoma (Unspecified organ)

observed

C57BL/6-Col4a3tm1Dec Thbs1tm1Hyn Trp53tm1Brd (Unspecified organ) angiosarcoma (Unspecified organ)

observed

C57BL/6-Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

25

C57BL/6-Col4a3tm1Dec Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

43

C57BL/6-Col4a3tm1Dec Thbs1tm1Hyn Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

50