Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins

Abstract

Lumican is a member of the small leucine-rich proteoglycan family. It is present in numerous extracellular matrices of different tissues, such as muscle, cartilage, and cornea. In skin, lumican is present as a glycoprotein. It plays a critical role in collagen fibrillogenesis, as shown by knocking out of its gene in mice. A direct link between lumican expression and melanoma progression and metastasis has been demonstrated. Lumican was shown to impede tumour cell migration and invasion by directly interacting with the a 2 b 1 integrin. In addition, an active sequence of the lumican core protein, called lumcorin, was identified as being responsible for inhibition of melanoma cell migration. Lumican was also shown to exert angiostatic properties by downregulating the proteolytic activity associated with endothelial cell membranes, particularly matrix metalloproteinase (MMP)-14 and MMP-9. Globally, lumican appears to be a potent agent for inhibiting tumour progression rather than tumorigenesis. However, progressive changes in proteoglycans occur in the tumour environment. The complexity and diversity of proteoglycan structure might be responsible for a variety of functions that regulate cell behaviour. Through their core protein and their glycosaminoglycan chains, proteoglycans can interact with growth factors and chemokines. These interactions affect cell signalling, motility, adhesion, growth, and apoptosis. This review summarizes recent data concerning lumican control of tumour progression in different cancers, with a particular focus on its interactions with MMPs and integrins. Its potential therapeutic implications are discussed.

Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition

“…This decrease of the significantly induced transmembrane MMP-14 by lumican in MCF-7/SP10+ could possibly explain the decreased level of invasion in the MCF-7/SP10+ cells treated with lumican, since a prerequisite for the invasive procedure of cells, is the localisation of MMP-14 within the filopodia. It was previously established that the altered activity of MMP-14 can serve as a potential mechanism of action of the anti-tumourigenic lumican163233. Specifically, it was proven that the cell migration of the EMT-like B16F1 cells, induced by elevated level of Snail expression, was altered by lumican34.…”

“…Besides the existing reports concerning the anticancer effect of lumican, the mechanism of action has not been fully elucidated. The effects of lumican discussed up to date may be due to different levels of action, concerning either its interactions with ECM molecules or intermediation in the activity of membrane receptors1627.…”

“…The human lumican gene encodes a protein of 338 amino acids15. Regarding ECM remodelling, lumican is involved in the inhibition of cancer invasion and metastasis, in the suppression of cell proliferation, in the inhibition of angiogenesis and in the inflammatory response16171819202122. Lumican is also a key regulator of the tumour matrix organisation and the cancer cell-matrix interactions due to its effects on collagen fibrillogenesis and degradation, binding to cell membrane integrins and receptors and eventually modulation downstream signalling pathways, as well as regulation of tumour cell functions23.…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…Lumican is a member of the SLRP family and can regulate diverse essential processes, such as cell proliferation, adhesion, and invasion, and is critical to control tumor progression and development [175]. Its expression, both positive and negative, has been associated with tumor growth, depending on the tissue [176-179].…”

Le stroma tumoral

“…Il existe des récepteurs pour certains de ces fragments à la surface des cellules cancéreuses. Ainsi, la lumcorine, un fragment actif du lumican (un protéoglycane à kératane sulfate), est capable d'inhiber la migration de cellules de mélanomes [19]. À l'inverse, l'endotrophine, un fragment du collagène de type VI, possède des propriétés procancéreuses dans les cancers du sein [20].…”