The Walter Herbert Lecture. Control of cell motility and tumour invasion by extracellular matrix interactions.

Integrins are heterodimeric transmembrane proteins with large ectodomains and a short cytoplasmic tail inside the cell. They mediate cell adhesion to extracellular matrix proteins and to the surfaces of other cells. In many cases the sequence recognised by the integrins in the extracellular matrix proteins is the tripeptide Arg-Gly-Asp (RGD). Short synthetic peptides containing this sequence can inhibit invasion in vitro and tumour dissemination in vivo. Thus, the alpha 5 beta 1 fibronectin binding integrin appears to be the key integrin in the invasion of at least melanoma, osteosarcoma and glioblastoma cells. Modulation of the level and activities of this integrin can suppress invasion, whereas the alpha v beta 3 vitronectin binding integrin appears to be associated with increased invasiveness. There is increasing evidence that some of these effects are mediated through signals elicited by the binding of integrins to their target proteins. This possibility has generated a great deal of interest in the cytoplasmic molecules that might mediate the integrin-associated signalling.

[1]  Y. Nakamura,et al.  Allelotype of colorectal carcinomas. , 1989, Science.

[2]  W. Birchmeier,et al.  Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion , 1989, The Journal of cell biology.

[3]  M. Hemler.  VLA proteins in the integrin family: structures, functions, and their role on leukocytes. , 1990, Annual review of immunology.

[4]  E. Ruoslahti,et al.  An alternative form of the integrin beta 1 subunit with a variant cytoplasmic domain. , 1992, The Journal of biological chemistry.

[5]  K. Sugimura,et al.  The inhibition of murine lung metastasis by synthetic polypeptides [poly(arg-gly-asp) and poly(tyr-ile-gly-ser-arg)] with a core sequence of cell adhesion molecules. , 1989, British Journal of Cancer.

[6]  E Ruoslahti,et al.  Influence of stereochemistry of the sequence Arg-Gly-Asp-Xaa on binding specificity in cell adhesion. , 1987, The Journal of biological chemistry.

[7]  L. Rohrschneider,et al.  Phosphorylation of the fibronectin receptor complex in cells transformed by oncogenes that encode tyrosine kinases. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[8]  E. Bossy‐Wetzel,et al.  Characterization of the integrin alpha 8 subunit: a new integrin beta 1‐associated subunit, which is prominently expressed on axons and on cells in contact with basal laminae in chick embryos. , 1991, The EMBO journal.

[9]  R. Hynes,et al.  An MBoC Favorite: Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein , 1991, Molecular biology of the cell.

[10]  T. Springer,et al.  The cytoplasmic domain of the integrin lymphocyte function-associated antigen 1 beta subunit: sites required for binding to intercellular adhesion molecule 1 and the phorbol ester-stimulated phosphorylation site , 1991, The Journal of experimental medicine.

[11]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[12]  T. Kupper,et al.  Two integrin-binding peptides abrogate T cell-mediated immune responses in vivo. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Y. Shimizu,et al.  Lymphocyte interactions with extracellular matrix , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  M. Humphries,et al.  A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. , 1986, Science.

[15]  Erkki Ruoslahti,et al.  Proteoglycans as modulators of growth factor activities , 1991, Cell.

[16]  K. Sugimura,et al.  Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules. , 1989, Cancer research.

[17]  E. Ruoslahti,et al.  Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides [published erratum appears in J Cell Biol 1989 Jun;108(6):following 2546] , 1988, The Journal of cell biology.

[18]  L. Liotta,et al.  Modulation of the metastatic activity of melanoma cells by laminin and fibronectin. , 1984, Science.

[19]  R. Juliano,et al.  Increased tumorigenicity of fibronectin receptor deficient Chinese hamster ovary cell variants. , 1991, Cancer research.

[20]  R L Juliano,et al.  Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. Lechene,et al.  Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin alpha 5 beta 1, independent of cell shape. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Richard O. Hynes,et al.  Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor α 4 β 1 , 1990, Cell.

[23]  R. Timpl,et al.  Laminin-binding integrin α7β1 : functional characterization and expression in normal and malignant melanocytes , 1991 .

[24]  W. Bodmer,et al.  Integrin‐receptor‐mediated differentiation and growth inhibition are enhanced by transforming growth factor‐β in colorectal tumour cells grown in collagen gel , 1989, International journal of cancer.

[25]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[26]  Z. Werb,et al.  Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression , 1989, The Journal of cell biology.

[27]  B. Obrink,et al.  Cell-cell contacts mediated by E-cadherin (uvomorulin) restrict invasive behavior of L-cells , 1991, The Journal of cell biology.

[28]  G. Nicolson,et al.  Correlation of inhibition of adhesion of large cell lymphoma and hepatic sinusoidal endothelial cells by RGD-containing peptide polymers with metastatic potential: role of integrin-dependent and -independent adhesion mechanisms. , 1989, Cancer communications.

[29]  E Ruoslahti,et al.  New perspectives in cell adhesion: RGD and integrins. , 1987, Science.

[30]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.