Abstract LB-032: Soluble E-cadherin as a microenvironmental factor that enhances tumor progression

Abstract

Abstract During malignant transformation of epithelial cells, their well-organized architecture is disrupted. A key event observed during epithelial cancer progression is down regulation of E-cadherin (E-cad), a central adherens junction protein that plays a crucial role in directing cell polarity, epithelial architecture and cell-cell adhesion. One mechanism by which tumor cells downregulate E-cad is by the proteolytic cleavage of its extracellular domain by proteases such as the matrix metalloproteinases (MMPs). This proteolytic cleavage results in the shedding of the E-cad ectodomain as an 80 kDa fragment known as soluble E-cadherin (sE-cad). Elevated levels of sE-cad are found in the serum and urine of cancer patients. In tumor cells physiological consequences include enhanced tumor cell migration and invasion, induction of MMP secretion, and increased cell signaling; all of which ultimately result in tumor progression. sE-cad also causes morphological changes in epithelial cells, including disruption of the adherens junction. However, the influence of elevated sE-cad levels on normal tissue architecture is not well understood. Specifically, the mechanism by which sE-cad in the tumor microenvironment interacts with cellular E-cad in normal epithelium is yet to be elucidated. We used a three-dimensional (3D) cell-culture system to determine the effects of sE-cad on normal epithelial cyst morphology. In this study, we show that recombinant, purified sE-cad can induce lumen-filling in normal non-tumorigenic Madin-Darby canine kidney (MDCK) epithelial cysts. The acinar luminal filling and multiple lumen formation induced by purified sE-cad represent changes in epithelial tissue structure that are characteristic of premalignant lesions reported in human epithelial glandular tumors. We further demonstrate that co-culturing of tumor cells with epithelial MDCK cysts results in disruption of 3D epithelial architecture and filling up of the hollow lumen. Our results also show that tumor cell-induced lumen filling is trigged by sE-cad shedding, with a concomitant increase in MMP-9. Using an inhibitor of MMP-9, we provide evidence that MMP-9 is crucial for lumen filling. Together, these novel findings indicate that invasive carcinoma cells can induce structural alterations in adjacent normal epithelium, and that elevated sE-cad levels disrupt epithelial architecture and activate signaling pathways in normal epithelial cells. Citation Format: Pratima Patil, Robert W. Mason, Julia D' Ambrosio, Ayyappan K. Rajasekaran. Soluble E-cadherin as a microenvironmental factor that enhances tumor progression. [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 LB-032. doi:10.1158/1538-7445.AM2015-LB-032