Author

Emma Ehrlich

Date of Award

2012

First Advisor

Patricia Dooley

Second Advisor

Erin McMullin

Third Advisor

Scott Coonrod

Abstract

Recent cancer research has increasingly begun to recognize the power of physical, chemical, and cellular aspects of the tissue microenvironment to suppress or to support tumor growth and progression. In particular, localized inflammation, marked by the inflammatory mediator COX2, and consequent immune cell infiltration are thought to support the growth of many cancers. Interleukin 8 (CXCL8) is a pro-inflammatory, growth-promoting, neutrophil chemotactic cytokine that is up-regulated in mammary tissue in response to estrogen receptor and HER2 signalling. Citrullination of CXCL8 by the post-translational modification enzyme PADI2 prevents truncation of CXCL8 that is normal and necessary for it to assume full neutrophil chemotactic ability, suggesting that this citrullination may be a co-optive mechanism by which mammary tumors may limit anti-tumor neutrophil invasion while continuing to promote their own growth. Our preliminary observations indicate that CXCL8 is expressed sporadically and in association with necrosis in human tumors from an in vivo mouse xenograft model. We fine-tuned a technique for immunostaining in vitro human tumor spheroids, which recapitulate key aspects of the in vivo tumor microenvironment, and our additional preliminary observations using these model systems suggest that PADI2 activity may have a role in promoting inflammation.

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