Abstract 3808: The functional role of extracellular keratin complexes in cancer

Abstract

Research in our group is focused on identifying improved predictive molecular markers for cancer, specifically, lung and prostate cancers. Unlike other cancers, there are no molecular markers for either the diagnosis or prognosis of lung cancer; biopsy and imaging modalities are the only available options. For prostate cancer, serum PSA, Gleason score, stage, and surgical margins are used for diagnosis and prognosis; however, these criteria are less than precise in predicting disease outcome, with only 10% specificity at the 90% sensitivity level. We are investigating the appearance of a particular antibody present in the sera of lung cancer and prostate cancer patients through an ELISA-based test. This antibody binds to an epitope of the C-terminus of keratin 8 (K8). In ongoing clinical trials at M. D. Anderson Cancer Center Orlando, we are able to identify serum samples from patients diagnosed with cancer when compared to control samples. These observations have led us to investigate the mechanism by which this K8 antibody appears in cancer patients. We hypothesize that the antibody is produced in response to K8 that aberrantly appears on the surface of epithelial cancer cells. Keratins are intermediate filament proteins that are contained within normal epithelia, including prostate and lung. Published reports, however, have placed epitopes of K8 on the surfaces of a variety of epithelial cancer cell lines. Our results from flow cytometry and immunofluorescence experiments demonstrate the extracellular expression of K8 (eK8) on some, but not all, cancer cell lines. This differential expression of eK8 may be an important marker of cancer prognosis. We have also found that K8 expression in primary human prostate tumors and lung tumors differs significantly from normal tissue. These observations led us to investigate the functional role of K8 in cancer. Due to a terminal lysine, eK8 is a potential binding site for plasminogen, the activation of which is implicated in tumor progression and metastasis. We found that plasminogen exhibited a specific binding interaction with the C-terminus of K8. We also confirmed that K8 interacts with urokinase plasminogen activator (uPA), which suggests that K8 may serve as a docking site for plasminogen activation system (PAS) components, facilitating the activation of plasmin. We found that the presence of K8 accelerated the activation rate of plasminogen by urokinase plasminogen activator (uPA). Furthermore, the presence of K8 accelerated activated plasmin-mediated degradation of extracellular matrix proteins. We hypothesize that eK8 present on epithelial prostate and lung cancer cells works in conjunction with components of the plasminogen activation system, thereby playing an integral role in tumor migration and in vivo dissemination. The results of this work may help distinguish lethal from indolent cancer, as well as enabling effective monitoring of treatment response, thus improving patient outcome. 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 3808. doi:10.1158/1538-7445.AM2011-3808