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Published on: October 4, 2019
Disruption of endothelial cell interactions with the novel HU177 cryptic collagen epitope inhibits angiogenesis
Alexandra Cretu1, Jennifer M Roth, Maresa Caunt
1Department of Radiation Oncology, The New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Purpose:
The importance of cellular communication with the extracellular matrix in regulating cellular invasion is well established. Selective disruption of communication links between cells and the local microenvironment by specifically targeting non-cellular matrix-immobilized cryptic extracellular matrix epitopes may represent an effective new clinical approach to limit tumor-associated angiogenesis. Therefore, we sought to determine whether the HU177 cryptic collagen epitope plays a functional role in regulating angiogenesis in vivo.
Experimental Design:
We examined the expression and characterized the HU177 cryptic collagen epitope in vitro and in vivo using immunohistochemistry and ELISA. We examined potential mechanisms by which this cryptic collagen epitope may regulate angiogenesis using in vitro cell adhesion, migration, proliferation, and biochemical assays. Finally, we examined the whether blocking cellular interactions with the HU177 cryptic epitope plays a role in angiogenesis and tumor growth in vivo using the chick embryo model.
Results:
The HU177 cryptic epitope was selectively exposed within tumor blood vessel extracellular matrix, whereas little was associated with quiescent vessels. An antibody directed to this cryptic site selectively inhibited endothelial cell adhesion, migration, and proliferation on denatured collagen type IV and induced increased levels of cyclin-dependent kinase inhibitor p27(KIP1). Systemic administration of mAb HU177 inhibited cytokine- and tumor-induced angiogenesis in vivo.
Conclusions:
We provide evidence for a new functional cryptic regulatory element within collagen IV that regulates tumor angiogenesis. These findings suggest a novel and highly selective approach for regulating angiogenesis by targeting a non-cellular cryptic collagen epitope.
Insights
Targeting the HU177 cryptic collagen epitope inhibits tumor angiogenesis. This approach selectively disrupts cellular communication with the extracellular matrix, offering a novel strategy to limit tumor growth by blocking blood vessel formation.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Cellular communication with the extracellular matrix (ECM) is crucial for regulating cell invasion.
- Targeting cryptic ECM epitopes presents a potential strategy to limit tumor angiogenesis.
Purpose of the Study:
- To determine the functional role of the HU177 cryptic collagen epitope in regulating angiogenesis in vivo.
- To investigate if blocking cellular interactions with HU177 can inhibit tumor growth.
Main Methods:
- Examined HU177 epitope expression in vitro and in vivo using immunohistochemistry and ELISA.
- Assessed mechanisms of angiogenesis regulation via cell adhesion, migration, and proliferation assays.
- Utilized the chick embryo model to evaluate the effect of blocking HU177 interactions on angiogenesis and tumor growth.
Main Results:
- HU177 epitope was selectively exposed in tumor blood vessel ECM, not quiescent vessels.
- An antibody to HU177 inhibited endothelial cell adhesion, migration, and proliferation on collagen IV, increasing p27(KIP1) levels.
- Systemic administration of mAb HU177 inhibited both cytokine- and tumor-induced angiogenesis.
Conclusions:
- Identified a novel functional cryptic regulatory element within collagen IV that controls tumor angiogenesis.
- Targeting non-cellular cryptic collagen epitopes offers a highly selective approach for regulating angiogenesis.
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