Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment (Nat Med, 2010, 16:1009-1017)

報告日期: 2011/03/25
報告時間: 17:10/18:00
報告學生: 林岳德 (英文報告)
講評老師: 張南山

Full Text:

Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment
Vivian Barry-Hamilton and Victoria Smith et al.
Nature Medicine 16, 1009–1017, 2010
Commentator: 張南山 Ph.D.
Date2011/03/25 3:10 pm
Place: room 602
  Carcinoma cells are like epithelial cells that live in a complicated microenvironment, including extracellular matrix (ECM), growth factors, cytokines, and various non-epithelial cells that include fibroblasts, vasculature (pericytes, endothelial cells and smooth muscle cells etc.) and immune cells (lymphocytes, macrophages and mast cells) that respond to inflammation and tissue injury. Carcinoma cells can induce stromal modification, facilitate adjacent fibroblasts proliferation, promote angiogenesis and recruit inflammation-associated cells. The major cells around epithelium are fibroblasts that can produce stromal ECM proteins such as transforming growth factors (TGF-β1), fibroblast growth factors (FGF), hepatocyte growth factors (HGF), and vascular endothelial growth factors (VEGF) etc. Activated fibroblasts induce pathological signaling pathway, tissue remodeling and carcinoma initiation or progression. Lysyl oxidase (LOX) and LOXL2 are enzymes that promote cross-linking of fibrillar collagen, and LOXL2 expression is described in tumor and liver fibrosis, with a potential for promoting invasion. In this paper, the authors used AB0023 antibody specific to LOXL2 in both primary and metastatic xenograft models. Inhibition of LOXL2 resulted in a marked reduction of activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors pathway (TGF-β1 pathway) and cytokines. AB0023 also outperform the small-molecule LOX inhibitor β-aminoproprionitrile (βAPN). The authors pretreated AB0023 to chemical-induced liver and lung fibrotic models and they found AB0023 inhibit and reverse fibrosis. The monoclonal LOXL2-specific antibody AB0023 presents a new approach in clinical therapy.
1. Bhowmick, N.A., Neilson, E.G. & Moses, H.L. Stromal fbroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).
2. Rodriguez, H.M. et al. Modulation of lysyl oxidase–like 2 enzymatic activity by an allosteric antibody inhibitor. J. Biol. Chem. 285, 20964–20974 (2010).