The role of aortic carboxypeptidase-like protein in epithelial-mesenchymal transition

Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Communication from stromal cells to tumors contributes to the progression of several carcinomas. Stromal fibroblasts, also referred to as cancer associated fibroblasts, in part through their production of secreted factors, promote epithelial-mesenchymal transition (EMT). EMT contributes to cancer progression by disseminating cells from the primary tumor and increasing these cells migratory capacity, an initial step in metastasis. Recently, several microarray studies have identified aortic carboxypeptidase-like protein (ACLP) as being significantly up-regulated in cancers, including prostate cancer and breast cancer, leading to the hypothesis that ACLP may regulate tumor progression and metastasis. To begin to test this hypothesis, this study first examined ACLP expression in a mouse mammary ductal carcinoma model and detected abundant ACLP expression in the cells surrounding the tumor. Cultured fibroblasts, derived from these tumors, readily expressed and secreted ACLP. To explore the functional contribution of ACLP to EMT in vitro we treated normal murine mammary gland epithelial cells (NMuMG) with recombinant ACLP (rACLP). In NMuMG cells, rACLP modulated the expression of epithelial-mesenchymal transition markers, Snail, fibronectin, occludin, and a-smooth muscle actin. Furthermore, rACLP treatment resulted in E-cadherin dissolution from the cell surface when compared with controls. These studies indicate that fibroblasts within a breast carcinoma express and may secrete ACLP, and in vitro data demonstrate that rACLP is capable of promoting EMT in normal epithelial cells. Therefore, ACLP may serve as an important mediator in the progression of cancer