Abstract 1905: Galectin-3 and -4 as signature markers of lung, colon, pancreatic and bladder tumor progression and chemopreventive interventions

Abstract

Abstract Galectins, a family of glycan-binding proteins, interact with cell-surface glycoconjugates and influence tumor progression by triggering a cascade of transmembrane signaling events which influence pathogenesis of cancer or tumor outcome. Despite considerable progress in identifying the involvement of individual galectins in tumor biology, an integrated portrait of the galectin network in different organ-site tumors or its microenvironments is not fully established. To understand the role of each galectin in lung, colon, pancreas and urinary bladder tumors and their relevance as markers of tumor progression; chemoprevention intervention trials was evaluated. Lung adenoma and adenocarcinomas were induced by tobacco specific carcinogen, NNK and colon adenomas and adenocarcinomas by azoxymethane (AOM). Whereas, pancreatic ductal tumors were induced by KrasG12D activation in p48Cre.KrasG12D mice and bladder tumors were induced by SV40 activation in UPII-SV40T mice. Expression profiling of galectins was obtained by whole genome-transcriptome analysis with SOLiD methodology from RNAs of tumors and normally appearing tissues from each organ-site. Further profiling and characterization of each galectin (Gal) was carried by RT-PCR, western blotting, and immunohistochemcial analysis. Data from transcriptome suggest that Gal-1, Gal-3, Gal-4, and Gal-12 are significantly associated with tumor progression. Particularly, Gal-1, Gal-3, and Gal-4 expressions were positively correlated with tumor progression in all the above cancers compared to their respective normal tissues and early lesions. Gal-12 was significantly increased in pancreatic and bladder tumor tissues but not in lung and colonic tumors. To understand prognostic value of galectins for chemoprevention interventions, we tested well-established and highly efficacious agents, difluoromethyl ornithine (DFMO), an inhibitor of ODC), and Licofelone, a dual COX-LOX inhibitor in above organ site cancers. DFMO (up to 2,000 ppm) and Licofelone (up to 500 ppm) was administered in the diet to mice after initiation of preneoplastic lesions or adenomas and continued until malignant tumor formations. As anticipated, both agents significantly inhibited malignant tumor formation. Importantly, intervention of tumor growth with mice fed with chemopreventive agents (DFMO and licofelone) showed a significant decrease in expression of Gal-3 and Gal-4 in tumor tissues and correlated with progression of tumor growth inhibition. Overall, these data provide impetus for further studies to delineate the role of Gal-3 and Gal-4 in various cancers and their usefulness as prognostic markers of chemoprevention interventions. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Jagan M. r. Patolla, Naveena B. Janakiram, Qian Li, Yuting Zhang, Laura Biddick, Allison Gillaspy, Stanley Lightfoot, Chinthalapally V. Rao. Galectin-3 and -4 as signature markers of lung, colon, pancreatic and bladder tumor progression and chemopreventive interventions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2015-1905