We will test the hypothesis that cellular interaction with cryptic collagen epitopes play unique roles in regulating tumor growth and angiogenesis.
The aims of this proposal are based on experiments with two novel reagents that selectively bind cryptic epitopes within collagen-IV. Proteolytic remodeling of the extracellular matrix (ECM) plays important roles in angiogenesis and tumor growth. However, little is known concerning the mechanisms by which these cryptic ECM epitopes function. Our studies have identified the HUIV26 cryptic epitope that regulates endothelial and tumor cell adhesion and migration in vitro and angiogenesis and tumor growth in vivo. Interestingly, cellular interactions with denatured collagen-IV can be partially inhibited by antagonists of avb3 or Mab HUIV26. Antagonists of b1 integrins can also partially inhibit interactions while a combination of both avb3 and b1 antagonists completely inhibit cellular interactions with denatured collagen-IV. These observations suggest that at least one other cryptic epitope, in addition to the HUIV26 cryptic site is exposed within denatured collagen-IV. Our new studies suggest that a second cryptic epitope recognized by a synthetic peptide is exposed within the denatured collagen-IV. Blocking interactions with this second cryptic epitope may inhibit adhesion, migration and proliferation. Taken together, our studies suggest that at least two distinct cryptic epitopes recognized by different integrin receptors are present within collagen type-IV and that these epitopes may represent novel therapeutic targets for the treatment of malignant tumors. Based on our findings, the studies were designed to examine four central objectives. First, we will define the amino acid sequence of the HUIV26 cryptic epitope and examine potential mechanisms by which this epitope regulates TSP-1. Second, we will determine the functional consequences of interactions with the second cryptic epitope have on invasive cellular behavior in vitro and identify receptors for the second cryptic epitope and examine mechanisms by which interactions with this epitope regulates cellular behavior. Third, we will determine whether soluble forms of the cryptic epitope are released in the circulation and whether these soluble forms correlate with tumor progression Finally, we will determine whether the second cryptic epitope plays a role in angiogenesis, tumor growth and metastasis in vivo. These studies may result in the development of novel strategies for the treatment of human tumors.
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