Laminins are strong promoters of cell attachment and they influence a variety of important biological processes including cell attachment, cell migration, inflammation, wound healing, angiogenesis and tumor invasion. The tissue specificity of laminin functions is achieved through the diversity of different combination of laminin chains. It has been recently found that laminin-8 and laminin-10, which contain newly identified laminin alpha4 and alpha5 chains, are the laminins produced by microvascular endothelial cells. It is hypothesized that these two laminins confer tissue specific functions to the endothelial basement membrane zone (BMZ) and play critical roles in cell adhesion, spreading and angiogenesis. Also, these laminins may be utilized by other cells which come in contact with endothelial BMZ including metastatic tumor cells and inflammatory cells. The biomedical importance of these molecules is emphasized by the discovery that alpha5 chain of laminin-10 is a major laminin alpha chain produced by three most common types of skin cancer, melanoma, basal cell carcinoma and squamous cell carcinoma.
The aim of this proposal is to determine the functions of laminins-8 and laminin-10. Specifically, their ability to promote cell attachment and migration will be examined by cell binding and migration assays. Their interactions with other extracellular matrix components will be measured through ligand binding assays. Recombinant laminin alpha4 and alpha5 subdomains will be used to pinpoint locations of these functions. An in vitro model of endothelial cell tubule formation/BMZ formation, and an in vivo system of human endothelial BMZ formation/tumor angiogenesis model will be utilized to further elucidate the significance of these laminins in angiogenesis. In addition, the role of alpha5 laminin chain in skin tumors will be studied by Matrigel invasion assay in vitro and transgenic human skin model or SCID mouse tumor model in vivo.
| Li, Jie; Zhou, Lisa; Tran, Hoang T et al. (2006) Overexpression of laminin-8 in human dermal microvascular endothelial cells promotes angiogenesis-related functions. J Invest Dermatol 126:432-40 |
