Basement membrane is a thin layer of specialized extracellular matrix. Its main components include collagen IV, laminins, heparan sulfate proteoglycan (perlecan) and nidogens. It can be found under sheets of epithelial and endothelial cells and surrounding muscle, fat and muscle cells. It is essential for tissue compartmentalization and maintenance of cell phenotypes; it also supplies stimuli for tissue development and remodeling [1, 2].
Among its components, nidogen binds and forms ternary complex with collagen IV and laminin, connecting the two networks and stabilizing the tri-dimensional structure of the basement membrane . Nidogen thus serves the important role of establishing and maintaining basement membrane and tissue architecture.
Nidogen also interacts with cell receptor molecules and controls cell polarization, migration and invasion. Nidogen-1, in particular, interacts with β1 family of integrin receptors and with αvβ3 integrin [4–7]. Through interactions with the leukocyte response integrin, nidogen favors neutrophil chemotaxis during the inflammation process. The interactions between cells and basement membranes regulate various cellular processes, including differentiation, proliferation and apoptosis.
In human, two nidogen proteins, nidogen-1 (150 kDa) and nidogen-2 (200 kDa), have been identified. The two proteins share a 46% primary sequence identity and a very similar three dimensional structure, consisting of three globular domains connected by a flexible link and a rod [8, 9].
Both nidogens are co-expressed in various tissues and interact with collagens I and IV and perlecan at comparable level. Differently, in vitro binding of nidogen-2 to laminin γ1 is weaker than for nidogen-1. Also, nidogen-2, differently from nidogen-1, does not interact with fibulins. Both nidogens are also cell-adhesive. The above features indicate that the two proteins might fulfill similar if not identical functions, may be interchangeable in many, but not all the cases and may compensate each other deficiency [10, 11]. This suggestion is confirmed by the findings that both nidogen-1 and nidogen-2 are ubiquitous components of basement membranes underneath epithelia of most of the major organ systems . Furthermore, while deficient mice for either nidogen-1 or nidogen-2 [12, 13] have no overt phenotypic abnormalities and basement membranes appear to be normal, preliminary reports of double mutants indicate a perinatal lethal phenotype and altered basement membrane ultrastructure . At least in the case of nidogen-1 knock-out, nidogen 2 compensation was demonstrated. An increase in nidogen-2 expression and unexpected high affinity of nidogen-2 for laminin γ1 was discovered, thus explaining the lack of phenotype of the NID1-null mice .
In spite of the fact that it is established that abnormal stromal microenvironment contributes to tumor formation and progression and nidogens play a key role in the maintenance of the structural integrity of basement membranes, which establish a barrier for cell movement, migration and invasion, nidogen defects have not been linked to human cancer. Here, we report that methylation of nidogen 1 and 2 promoters is responsible for loss of their gene expression and is frequent in human gastrointestinal tumors.