Abstract 1549: Regulation of inflammation and tumor growth by the novel XL313 cryptic ECM element

Abstract

Abstract Experimental evidence suggests that multiple cell types within the tumor microenvironment such as fibroblast, endothelial cells and inflammatory cells contribute to tumor growth. Recent evidence indicates that biomechanical alterations in the structural integrity of ECM proteins may result in exposure of cryptic regulatory elements that play roles in differentially controlling cell signaling pathways. Therefore, exposure of cryptic regulatory sites may function as biomechanical switches, allowing various cell populations to respond in distinct ways to localized structural alterations within the tumor microenvironment. Thus, identifying and characterizing biomechanical ECM switches may provide selective new therapeutic targets to regulate tumor progression. In this regard, triple helical collagen has numerous RGD containing cryptic integrin binding sites. However, it is not known whether all these cryptic RGD elements are functionally redundant or whether distinct flanking sequences may convey differential control of cellular behavior. To examine potential functional differences between distinct RGD containing cryptic sites, we generated a series of Mabs directed to synthetic RGD containing peptides found within type-I collagen. One Mab termed XL313 selectively recognized a cryptic element containing the amino acid sequence RGDKGE, but failed to bind other RGD containing sites. Mab XL313 failed to recognize intact triple helical collagen, but did bind proteolytically cleaved collagen. Importantly, Mab XL313 significantly (P<0.05) inhibited B16F10 melanoma tumor growth by greater than 50%. Given the possibility that inflammation may contribute to tumor development, we examined the impact of the XL313 epitope on growth factor induced inflammation. Our studies suggest that the XL313 cryptic site may regulate inflammation as Mab XL313 significantly (P<0.05) inhibited inflammation / CAM thickening in the chick embryo model. Collectively, our studies suggest that the XL313 biomechanical ECM switch may represent an important new therapeutic target for the control of tumor growth and inflammation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1549. doi:10.1158/1538-7445.AM2011-1549