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Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2801-2810. https://doi.org/10.1172/JCI24813.
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Research Article Angiogenesis Article has an altmetric score of 9

Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin

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Abstract

Human noncollagenous domain 1 of the α1 chain of type IV collagen [α1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo; however, the mechanisms involved are not known. In the present study we demonstrate that human α1(IV)NC1 binds to α1β1 integrin, competes with type IV collagen binding to α1β1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, α1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway. In contrast, α1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in α1 integrin receptor knockout ECs. Consistent with this, α1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in α1 integrin receptor knockout mice. This suggests a highly specific, α1β1 integrin–dependent antiangiogenic activity of α1(IV)NC1. In addition, α1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1α and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human α1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that α1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.

Authors

Akulapalli Sudhakar, Pia Nyberg, Venkateshwar G. Keshamouni, Arjuna P. Mannam, Jian Li, Hikaru Sugimoto, Dominic Cosgrove, Raghu Kalluri

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Figure 7

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Tumor burden studies using WT and α1 integrin–/– mice. (A) SCC-PSA1 tumo...
Tumor burden studies using WT and α1 integrin–/– mice. (A) SCC-PSA1 tumor growth in WT and α1 integrin–/– mice. Ten male mice in each group, age-matched WT and α1 integrin–/– mice, were used in this experiment. Recombinant α1(IV)NC1 protein was injected i.v. into 5 WT and 5 α1 integrin–/– mice daily (30 μg) for 14 days in sterile PBS, while only PBS was injected into the other 5 WT and 5 α1 integrin–/– mice. Data are representative of 3 such independent experiments. The results are shown as the mean ± SEM; P < 0.001 compared with WT mice with and without injection. (B) Frozen sections (4 μm) from tumor tissue were stained with anti-CD31 antibody, and the numbers of CD31-positive blood vessels (arrows) were counted in 6 fields at ×200 magnification. Scale bar: 50 μm. The blood vessel quantification results are shown as the mean ± SEM. *P = NS versus α1 integrin–/– mice with and without treatment. **P < 0.001 versus WT mice with and without treatment. (C) VEGFR2-positive circulating ECs from tumor-bearing mouse peripheral blood were stained with VEGFR2 antibody, and the numbers of positive cells (arrows) were counted. Scale bar: 50 μm. The results are shown as the mean ± SEM. *P = NS between α1 integrin–/– mice with and without treatment. **P < 0.001 versus WT mice with and without injection.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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