keratan-sulfate and Neoplasms

Keratan sulphate (KS) is a bioactive glycosaminoglycan (GAG) of some complexity composed of the repeat disaccharide D-galactose β1→4 glycosidically linked to N-acetyl glucosamine. During the biosynthesis of KS, a family of glycosyltransferase and sulphotransferase enzymes act sequentially and in a coordinated fashion to add D-galactose (D-Gal) then N-acetyl glucosamine (GlcNAc) to a GlcNAc acceptor residue at the reducing terminus of a nascent KS chain to effect chain elongation. D-Gal and GlcNAc can both undergo sulphation at C6 but this occurs more frequently on GlcNAc than D-Gal. Sulphation along the developing KS chain is not uniform and contains regions of variable length where no sulphation occurs, regions which are monosulphated mainly on GlcNAc and further regions of high sulphation where both of the repeat disaccharides are sulphated. Each of these respective regions in the KS chain can be of variable length leading to KS complexity in terms of chain length and charge localization along the KS chain. Like other GAGs, it is these variably sulphated regions in KS which define its interactive properties with ligands such as growth factors, morphogens and cytokines and which determine the functional properties of tissues containing KS. Further adding to KS complexity is the identification of three different linkage structures in KS to asparagine (N-linked) or to threonine or serine residues (O-linked) in proteoglycan core proteins which has allowed the categorization of KS into three types, namely KS-I (corneal KS, N-linked), KS-II (skeletal KS, O-linked) or KS-III (brain KS, O-linked). KS-I to -III are also subject to variable addition of L-fucose and sialic acid groups. Furthermore, the GlcNAc residues of some members of the mucin-like glycoprotein family can also act as acceptor molecules for the addition of D-Gal and GlcNAc residues which can also be sulphated leading to small low sulphation glycoforms of KS. These differ from the more heavily sulphated KS chains found on proteoglycans. Like other GAGs, KS has evolved molecular recognition and information transfer properties over hundreds of millions of years of vertebrate and invertebrate evolution which equips them with cell mediatory properties in normal cellular processes and in aberrant pathological situations such as in tumourogenesis. Two KS-proteoglycans in particular, podocalyxin and lumican, are cell membrane, intracellular or stromal tissue-associated components with roles in the promo

Topics: Humans; Keratan Sulfate; Neoplasms; Proteoglycans; Tumor Microenvironment

The consecutive steps of tumor growth, local invasion, intravasation, extravasation and invasion of anatomically distant sites are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Lumican, a class II small leucine-rich proteoglycans (SLRP) has been designated key roles both in extracellular matrix (ECM) organization and as an important modulator of biological functions. This review will critically discuss lumicans' roles in tumor development and progression. We will especially focus on correlating lumicans' expression and distribution in tumor tissues with: (1) the organization of the tumor matrices; (2) tumor cell signaling and functions; (3) tumor cell-matrix interface; (4) tumor angiogenesis; and (5) lumicans' potential roles in tumor-associated inflammatory response. Present knowledge of lumicans' biology provides a fundamental platform upon which to build and deepen our understanding of lumican function in tumorigenesis in order to be able to design credible anti-tumor approaches.

Topics: Animals; Carcinogenesis; Chondroitin Sulfate Proteoglycans; Extracellular Matrix; Humans; Inflammation; Keratan Sulfate; Lumican; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Microenvironment

Lumican belongs to the family of small leucine-rich repeat proteoglycans. Recent studies have shown that lumican participates in the maintenance of tissue homeostasis and modulates cellular functions including cell proliferation, migration, and differentiation. The expression of lumican has been correlated to the growth and metastasis of various malignancies; however, its exact role in tumorogenesis remains elusive. This review focuses upon the role of lumican in cell biology, providing insights into molecular mechanisms that lumican likely utilizes to control processes relevant to tumorogenesis.

Topics: Animals; Chondroitin Sulfate Proteoglycans; Humans; Keratan Sulfate; Leucine; Lumican; Neoplasms; Signal Transduction

The roles of lumican, a member of the small-leucine-rich-proteoglycan (SLRP) family, in pathological fibrosis, cancer tissues and tumor cell growth were reviewed. Lumican is predominantly localized in the areas of pathological fibrosis including the thickened intima of human coronary arteries, ischemic and reperfused hearts, and acute pancreatitis and chronic pancreatitis (CP)-like lesions adjacent to pancreatic cancer nests. In these lesions, lumican mRNA and protein were transiently and ectopically overexpressed in most of the vascular smooth muscle cells (VSMCs) that migrated into the thickened intima, myocardial cells adjacent to an ischemic lesion, acinar cells, islet cells and fibroblasts of pathological pancreatic tissues. The low expression level of lumican in breast cancer is associated with rapid progression and poor survival. Lumican mRNA in breast cancer is overexpressed in fibroblasts adjacent to cancer cells but not in cancer cells. Furthermore, the high expression level of lumican is associated with a high pathological tumor grade, a low estrogen receptor level in the cancer tissues, and young age of patients. The suppression of lumican expression in culture cells induces their cell growth. Lumican-transfected tumor cells are characterized by a strong suppression of their anchorage-independent growth and capacity of invasion. Lumican significantly suppressed subcutaneous tumor formation in syngenic mice, with a concomitant decrease in cyclin D1 expression level, and induced and/or enhanced the apoptosis of these cells. The autocrine mechanism in cancer cells and the paracrine mechanism in cancer cells and fibroblasts via transforming growth factor (TGF)-beta and Smad signals may play important roles in the regulation of tumor growth by SLRPs.

Topics: Animals; Apoptosis; Cell Communication; Cell Division; Chondroitin Sulfate Proteoglycans; DNA-Binding Proteins; Fibrosis; Gene Expression; Humans; Keratan Sulfate; Lumican; Mice; Muscle, Smooth, Vascular; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms; RNA, Messenger; Smad Proteins; Trans-Activators; Transforming Growth Factor beta

Topics: Animals; Basement Membrane; Cartilage; Chemical Phenomena; Chemistry; Chondroitin Sulfate Proteoglycans; Dermatan Sulfate; Extracellular Matrix; Glycosaminoglycans; Heparan Sulfate Proteoglycans; Heparin; Heparitin Sulfate; Humans; Hyaluronic Acid; Keratan Sulfate; Lumican; Models, Biological; Neoplasms; Proteoglycans; Staining and Labeling

Topics: Animals; Chondroitin Sulfates; Electrophoresis, Cellulose Acetate; Glycosaminoglycans; Heparitin Sulfate; Humans; Keratan Sulfate; Neoplasms; Nitrous Acid