Temporal Exposure of Cryptic Collagen Epitopes within Ischemic Muscle during Hindlimb Reperfusion

Gagne, Paul J.; Tihonov, Nikita; Li, Xialou; Glaser, Joseph; Qiao, Jhenrong; Silberstein, M J; Yee, Herman; Gagne, Elizabeth; Brooks, Peter C.

doi:10.1016/s0002-9440(10)61222-9

Cited by 23 publications

(42 citation statements)

References 42 publications

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“…Importantly, previous studies have indicated that proteolytic enzymes, such as matrix metalloproteinase, can contribute to generation of the HU177 epitope in vivo. 16 We provide evidence that this cryptic collagen epitope played a role in SKOV-3 tumor growth, and these findings are consistent with a clinical trial that assessed tolerability and toxicity of mAb D93/TRC093. 20 Results of this study suggested no dose-limiting toxic effects and evidence of antitumor activity because a patient with an ovarian cancer had a reduction in metastatic liver lesions.…”

Section: Discussionsupporting

confidence: 85%

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Caron

Ames

Contois

et al. 2016

The American Journal of Pathology

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Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of a-smooth muscle actineexpressing stromal cells. Integrin a10b1 can serve as a receptor for the HU177 epitope in a-smooth muscle actineexpressing stromal cells and subsequently regulates Erkdependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized a 10 b 1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors. (Am J Pathol 2016 http://dx

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Section: Discussionsupporting

confidence: 85%

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Caron

Ames

Contois

et al. 2016

The American Journal of Pathology

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“…MMPmediated remodeling of extracellular matrix creates a permissive microenvironment for endothelial cell invasion and migration and thereby new blood vessel formation. Recently, it was shown that cryptic collagen epitope (Hu177) is present in both interstitial collagen type 1 and basement membrane collagen type IV and that selective exposure of these epitopes within ischemic muscle correlates with the enhanced MMP activity (42). Our findings reveal that 7 days after the initiation of ischemia, increased exposure of Hu177-positive staining was observed in the adductor muscles of WT mice suggesting increased MMP activity.…”

Section: Discussionsupporting

confidence: 56%

“…Cryosections (5 m) were made using Leica Kryostat (Model CM3050S, Leica, Wetzlar, Germany). After blocking in normal goat serum, the cryosections were incubated with rabbit anti-mouse von Willebrand Factor (vWF) antibodies and rat anti-mouse CD31 antibodies or monoclonal Hu177 antibodies (42) and rat anti-mouse CD31 for 1 h (1:500). After washing in phosphate-buffered saline, all slides were incubated with goat anti-rabbit secondary antibodies conjugated with Alexa Fluor 568 or goat anti-rat secondary antibodies conjugated with Alexa Fluor 488 or goat anti-rat secondary antibodies conjugated with Alexa Fluor 568 or goat anti-mouse secondary antibodies conjugated with Alexa Fluor 488.…”

Section: Methodsmentioning

confidence: 99%

“…Consistent with a lack of effect on MMP-2 levels, ischemia also had no significant effect on MMP-2 activity in 12/15-Lox Ϫ/Ϫ mice. HU177 was selectively exposed in the interstitial matrix of tumors as well as in the extracellular matrix of angiogenic blood vessels as a result of extracellular matrix degradation by MMPs (42). To confirm the role of MMP-2 in ischemia-induced neovascularization, we also performed double immunofluorescence staining for Hu177 and CD31 in ischemic adductor muscles of both WT and 12/15-Lox Ϫ/Ϫ mice.…”

Section: Lack Of a Neovascularization Response In 12/15-loxmentioning

confidence: 99%

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AP-1 (Fra-1/c-Jun)-mediated Induction of Expression of Matrix Metalloproteinase-2 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Angiogenesis

Singh

Quyền

Kundumani‐Sridharan

et al. 2010

Journal of Biological Chemistry

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To understand the involvement of matrix metalloproteinases (MMPs) in 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE)-induced angiogenesis, we have studied the role of MMP-2. 15(S)-HETE induced MMP-2 expression and activity in a timedependent manner in human dermal microvascular endothelial cells (HDMVECs). Inhibition of MMP-2 activity or depletion of its levels attenuated 15(S)-Angiogenesis has been implicated in the pathogenesis of cancer, diabetic retinopathy, and atherosclerosis (1). On the other hand, a therapeutic role for angiogenesis in the treatment of coronary artery disease and wound healing has been identified (2). In the initiation of new capillaries, endothelial cells of existing blood vessels degrade the underlying basement membrane and invade into the stroma of the neighboring tissue (3, 4). The endothelial cell invasion and migration require the cooperative activity of the plasminogen activator system and the matrix metalloproteinases (MMPs) 2 (3). MMPs were initially discovered in 1962 as collagenolytic activity degrading extracellular matrix protein during tadpole tail resorption (5). Since then, more than 23 members of the MMP family of matrix-degrading enzymes have been identified, characterized, and sub-classified based on their ability to degrade a specific extracellular matrix protein (6). Besides their role in extracellular matrix protein degradation, MMPs have been reported to play a role in the activation of cell surface receptors (7). MMPs not only have been shown to play a role in a number of physiological processes such as embryogenesis (8) and angiogenesis (9, 10), but also have been reported to contribute to the pathogenesis of various diseases, including tumor metastasis (11) and inflammation (12). Among many MMPs, MMP-2 and -9 (also known as gelatinase A and gelatinase B, respectively) have been identified as important players in several cardiovascular diseases, including atherosclerosis, ischemic heart disease, heart failure, aneurysm, and stroke (13-17). MMP-2 is expressed ubiquitously in various cell types, including cardiomyocytes, endothelial cells, fibroblasts, and vascular smooth muscle cells, and plays a crucial role in the regulation of angiogenesis (18 -20). Despite the importance of MMPs in cardiovascular development and diseases (21-23), relatively very little is known in regard to the role of these enzymes in eicosanoid-mediated vascular wall remodeling. It is well established that lipoxygenases, particularly 12/15-lipoxygenase (12/15-Lox), play an important role in the pathogenesis of various vascular diseases and cancers (24 -28). One of the initial mechanisms by which 12/15-Lox is implicated in atherosclerosis is its capacity to oxidize low density lipoprotein particles (24). However, many studies also provided clues for additional mechanisms of 12/15-Lox involvement in the pathogenesis of atherosclerosis, restenosis, and cancer. Of these, its role in the regulation of cell growth, migration, and apoptosis have received much attention (29 -32). Besides, one of the...

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“…In addition, other studies have shown the expression of the HU177 cryptic epitope within the medial wall of aortic explants from mice following ischemic injury and within the extracellular matrix of developing murine papillary membranes during angiogenesis (24,25). We recently showed the selective temporal exposure of the HU177 epitope within ischemic muscle tissue, and this expression correlated with enhanced matrix metalloproteinase levels (26). However, to date, no evidence exists that the HU177 cryptic epitope plays a functional role in regulating invasive cellular behavior, or whether this epitope represents a clinically useful therapeutic target.…”

mentioning

confidence: 80%

Disruption of Endothelial Cell Interactions with the Novel HU177 Cryptic Collagen Epitope Inhibits Angiogenesis

Cretu

Roth

Caunt

et al. 2007

Clinical Cancer Research

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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 tumorassociated 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.

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Temporal Exposure of Cryptic Collagen Epitopes within Ischemic Muscle during Hindlimb Reperfusion

Cited by 23 publications

References 42 publications

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

AP-1 (Fra-1/c-Jun)-mediated Induction of Expression of Matrix Metalloproteinase-2 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Angiogenesis

Disruption of Endothelial Cell Interactions with the Novel HU177 Cryptic Collagen Epitope Inhibits Angiogenesis

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