Laminin-332-rich tumor microenvironment for tumor invasion in the interface zone of breast cancer

Abstract

Dense fibrosis, which is caused by desmoplastic reaction, is usually found in invasive ductal carcinoma (IDC) and may represent the alteration of the tumor microenvironment (TME) preceding tumor invasion. Thus, the dense fibrotic zone around IDC can be considered to be the actual tissue site of TME, where the precedent alterations for tumor invasion occur. To characterize the dense fibrotic zone, we classified IDC tissue into a tumor zone (TZ), a normal zone (NZ), and the novel interface zone (IZ), which shows dense fibrosis. The postulated IZ is a 5-mm-wide belt that circles the tumor margin and overlaps with normal tissue. Of the extracellular matrix (ECM) components, laminin-332 was specifically overexpressed in the IZ. Events that appear to be similar to the epithelial-mesenchymal transition (EMT), a novel source of myofibroblast formation from epithelial cells, were observed in the IZ, according to the following characteristics: overexpression of MMP3, MT1-MMP, Snail, and ZEB1, and the gain of N-cadherin expression, as well as the downregulation of miR200c. The myofibroblasts isolated from the IZ, which were designated InF (interface zone-fibroblast), displayed laminin-332 and MT1-MMP overexpression, in contrast with both CAF (cancer-associated fibroblast) and NBF (normal breast fibroblast). Taken together, our results suggest that the IZ, which shows dense fibrosis, may provide a specialized microenvironment for guiding tumor invasion: the fibrosis caused by laminin-332 overexpressing myofibroblast formation (InF) via EMT.