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 and may represent the alteration of the tumor microenvironment preceding tumor invasion. Thus, the dense fibrotic zone around invasive ductal carcinoma can be considered to be the actual tissue site of tumor microenvironment, where the precedent alterations for tumor invasion occur. To characterize the dense fibrotic zone, we classified invasive ductal carcinoma tissue into a tumor zone, a normal zone, 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 components, laminin-332 was specifically overexpressed in the IZ. Events that appear to be similar to the epithelial-mesenchymal transition, a novel source of myofibroblast formation from epithelial cells, were observed in the IZ, according to the following characteristics: overexpression of matrix metalloproteinase 3, membrane type 1؊matrix metalloproteinase, snail, and zinc finger E-box-binding homeobox 1, and the gain of N-cadherin expression, as well as the down-regulation of miR200c. The myofibroblasts isolated from the IZ, which were designated interface zone-fibroblast, displayed laminin-332 and membrane type 1؊matrix metalloproteinase overexpression, in contrast with both cancer-associated fibroblasts and normal breast fibroblasts. 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 (interface zone-fibroblast) via epithelialmesenchymal transition.

Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines

“…Secreted proteins of the microenvironment, including type I collagen and laminin, are important in the invasiveness and progression of breast cancer cells (27). The results of the present study reveal that type I collagen may be one of the ECM proteins which stimulates breast cancer cell metastasis, which is a result that is consistent with other studies (28–30).…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Laminin-111/Ln-1 has three head domains which can crosslink into a soft cohesive 3D network, whereas other laminin isoforms with truncated head domains, such as laminin-332/Ln-5, laminin-511/Ln-10 or laminin-521/Ln-11, cannot form a network [22,29], and do not support normal epithelial cell function in vitro, despite the fact that all these isoforms present similar tail domains to cells [16]. Furthermore, some evidence suggests that laminin-332, or collagen IV may support tumor invasion or aggressiveness [30][31][32].…”

Galectin-3 Binding Protein Secreted by Breast Cancer Cells Inhibits Monocyte-Derived Fibrocyte Differentiation

“…In response to some tumors, the immune system also initiates a desmoplastic response, attempting to contain the tumor (9, 28). This desmoplastic sheath is a dynamic, responsive tissue that adjusts to changing conditions in the tumor microenvironment (29, 30). …”

“…To metastasize through this desmoplastic tissue, cancer cells must find a way to remove scar tissue or to prevent scar tissue from forming (29–34). As cancer progresses towards metastasis and a more mesenchymal phenotype, it interacts with the immune system in different ways.…”