Downregulation of a newly identified laminin, laminin‐3B11, in vascular basement membranes of invasive human breast cancers

Abstract

Laminins present in the basement membranes (BM) of blood vessels are involved in angiogenesis and other vascular functions that are critical for tumor growth and metastasis. Two major vascular laminins, the a4 (laminin-411 ⁄ 421) and a5 (laminin-511 ⁄ 521) types, have been well characterized. We recently found a third type of vascular laminin, laminin-3B11, consisting of the a3B, b1 and c1 chains, and revealed its biological activity. Laminin-3B11 potently stimulates vascular endothelial cells to extend lamellipodial protrusions. To understand the roles of laminin-3B11 in blood vessel functions and tumor growth, we examined localization of the laminin a3B chain in normal mammary glands and breast cancers, in comparison with the a4 and a5 laminins. In the immunohistochemical analysis, the a3B laminin was co-localized with the a4 and a5 laminins in the BM of venules and capillaries of normal breast tissues, but a3B was scarcely detected in vessels near invasive breast carcinoma cells. In contrast, the a4 laminin was overexpressed in capillaries of invasive carcinomas, where a large number of macrophages were found. The a5 laminin appeared to be weakly downregulated in cancer tissues, especially in capillary vessels. Furthermore, our in vitro analysis indicated that TNF-a significantly suppressed the laminin a3B expression in vascular endothelial cells, while it, as well as IL-1b and TGF-a, upregulated the a4 expression. These results suggest that Lm3B11 ⁄ 3B21 may be required for normal mature vessels and interfere with tumor angiogenesis. (Cancer Sci 2011; 102: 1095-1100 T he vascular system is critically involved in tumor growth and metastasis.(1) New blood vessel formation, or angiogenesis, is required to sufficiently supply nutrients and oxygen to growing tumor cells. Invasion of tumor cells into the vascular system, that is, intravasation, is an essential step for tumor metastasis to distant organs. It has been accepted that blood vessels in tumor tissues are structurally and functionally different from those in normal tissues.(2-4) Such structure and function of blood vessels are regulated by a variety of extracellular matrix (ECM) components and soluble factors, both of which are produced by endothelial cells themselves, tumor cells, inflammatory cells and stromal cells.(5) Basement membranes (BM) are specialized ECM structures that directly support tissue architectures and functions in various types of tissues including endothelial and epithelial tissues.(6) Basement membranes also function as a physical barrier for molecular transportation and cell migration. Therefore, the BM and its components, especially laminins, have great effects on tumor growth and metastasis, as well as vascular functions.(5-7)Laminins are major cell adhesion proteins that are localized in the BM of various tissues.(8) Cells are stabilized on the BM matrix by adhering to the laminins through integrin receptors. Combinations of five a, three b and three c chains give rise to over 15 laminin isoforms. (9) Of the three laminin chains...

Angiomodulin, a marker of cancer vasculature, is upregulated by vascular endothelial growth factor and increases vascular permeability as a ligand of integrin αvβ3

“…These structural and functional changes of blood vessels are thought to have significant effects on tumor growth and metastasis. Recently we found that a novel form of laminin, laminin‐3B11, is present in the vascular basement membranes of various normal tissues, but its expression is lost in cancer tissues . Both AGM and laminin‐3B11 are cell adhesion ligands assembled into the basement membrane structure, but their expression patterns are completely opposite as shown in this and previous studies.…”

“…Five‐ μ m serial frozen sections were obtained from (KCRIA) and subjected to immunohistochemistry as described previously . The sections were treated with the first antibody, biotin‐conjugated second antibody (Vector; CA) and then streptoavidin‐conjugated peroxidase (Vector).…”

Elevated expression of angiomodulin (AGM/IGFBP‐rP1) in tumor stroma and its roles in fibroblast activation

“…Five-lm serial frozen sections were obtained from KCRIA and subjected to immunohistochemistry as described previously. (25) The sections were treated with the first antibody, biotin-conjugated second antibody (Vector, Burlingame, CA, USA) and then streptoavidin-conjugated peroxidase (Vector). The resultant immunocomplexes were visualized with 3,3-diaminobenzidine (DAB) using the Histofine kit (Nichirei, Tokyo, Japan).…”

“…Five‐μm serial frozen sections were obtained from KCRIA and subjected to immunohistochemistry as described previously . The sections were treated with the first antibody, biotin‐conjugated second antibody (Vector, Burlingame, CA, USA) and then streptoavidin‐conjugated peroxidase (Vector).…”

Extracellular Superoxide Dismutase, the Endothelial Basement Membrane, and the WNT Pathway: New Players in Vascular Normalization and Tumor Infiltration by T-Cells

“…For example, Lm111 is modified by ectokinases secreted by immune cells during extravasation, which alters the properties of the EC-BM barrier ( 46 ). In breast carcinomas, pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, suppress laminin α3B (LAMA3B) but enhances LAMA4 expression ( 47 ). In the breast tumors this changes the highly crosslinked and organized LAMA3B-rich EC-BM structure of the mammary gland ( 48 ) to a highly dynamic LAMA4-rich structure.…”