Signal transduction therapy: a new paradigm

  • E. C. Kohn


The advent of molecular medicine has brought new approaches to the treatment, diagnosis and evaluation of malignant disease. The molecular medicine of cancer has gone from cytotoxic chemotherapy to immunotherapy and now has entered into gene therapy interventions. Through recent scientific advances, immunotherapy has been brought from the laboratory bench to the clinic in the form of biological response modification, treatment with directed antibodies and combinations of cytokines and activated lymphocytes primed against the tumor. The optimal use and outcome of these forms of immunotherapy for ovarian cancer are still under investigation. The explosion in knowledge of how specific genes are involved in the process of cancer growth and metastasis has led to the areas of transgenic animal experimentation and human gene therapy. The concept of gene therapy for general cancer treatment is in the early stages of investigation and specific applications to ovarian cancer have not yet been introduced clinically. The last new target to be identified is that of signal transduction.


Tyrosine Phosphorylation Calcium Influx Pertussis Toxin Ovarian Cancer Cell Line Inositol Phosphate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Spiegel, A. (1988) G proteins in clinical medicine. Hosp. Pract. June 93–111.Google Scholar
  2. 2.
    Rink, T.J. (1990) Receptor-mediated calcium entry. FEBS Lett. 268, 381–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Bean, B.P. (1989) Classes of calcium channels in vertebrate cells.Ann. Rev. Physiol 51 367–84.CrossRefGoogle Scholar
  4. 4.
    Simon, M.I., Strathmann, M.P., and Gautam, N. (1991) Diversity of G proteins in signal transduction. Science 252 802–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Aaronson, S.A. (1991) Growth factors and cancer. Science 2541146–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Tanaabe, T., Tadeshima, H., Mikami, A. et al. (1987) Primary structure of the receptor for calcium-channel blockers from skeletal muscle. Nature 328 313–18.CrossRefGoogle Scholar
  7. 7.
    Zernig, G. (1990) Widening potiential for Ca2+ antagonists: non-L-type Ca2+ channel interaction. TiPS 11 38–44.PubMedGoogle Scholar
  8. 8.
    Kim, D., Lewis, D.L., Graziafei, L. et al (1989) G-protein βγ-subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature 337 557–60.CrossRefGoogle Scholar
  9. 9.
    Brooks, R.C., McCarthy, K.D., Lapetina, E.G. and Morell, P. (1989) Receptor-stimulated phospholipase A2 activation is coupled to influx of external calcium and not to mobilization of intracellular calcium in C62B glioma cells, J.Biol Chem. 264 20147–53.PubMedGoogle Scholar
  10. 10.
    Felder, C.C., Dieter, P., Kinsella, J. et al (1990) A transfected m5 muscarinic acetylcholine receptor stimulates phospholipse A2 by inducing both calcium influx and activation of protein kinase C. J. Pharm. Exp. Ther. 255 1140–7.Google Scholar
  11. 11.
    Marks, P.W., and Maxfield, F.R. (1990) Transient increases in cytosolic free calcium appear to be required for the migration of adherent human neutrophils.J. Cell Biol 110 43–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Hamachi, T., Hirata, M. and Koga, T. (1986) Origin of intracellular calcium and quantitation of mobilizable calcium in neutrophils stimulated with chemotactic peptide. Biochem. Biophys. Acta 889136–48.PubMedCrossRefGoogle Scholar
  13. 13.
    Gusovsky, P., Leuders, J.E., Kohn, E.G. and Felder, C.C. (1993) Muscarinic receptor-mediated tyrosine phosphorylation of phospholipase C-gamma: alternative mechanism for cholinergic receptor-induced phosphoinosi-tide breakdown, J. Biol Chem. 268 7768–72.PubMedGoogle Scholar
  14. 14.
    Bianchini, L., Todderud, G. and Grinstein, S. (1993) Cytosolic [Ca2+] homeostasis and tyrosine phosphorylation of phospholipase Cgamma2 in HL60 granulocytes. J. Biol Chem. 268, 3357–63.PubMedGoogle Scholar
  15. 15.
    Tanaguchi, T., Kitagawea, H., Yasue, S. et al (1993) Protein-tyrosine kinase P72syk is activated by thrombin and is negatively regulated through Ca2+ regulation in platelets, J. Biol Chem. 268, 2277–9.Google Scholar
  16. 16.
    Guirguis, R., Margulies, I., Taraboletti, G. et al (1987) Cytokine-induced pseudopodial protrusion is coupled to tumor cell migration. Nature 329 261–3.PubMedCrossRefGoogle Scholar
  17. 17.
    Kohn, E.G., Francis, E.A., Liotta, L.A. and Schiffmann, E. (1990) Heterogeneity of the motility responses in malignant tumor cells: a biological basis for the diversity and homing of metastatic cells. Int.J. Cancer 46287–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Aznavoorian, S.A., Stracke, M.L., Krutzsch, H. et al (1990) Signal transduction for Chemotaxis and haptotaxis by matrix molecules in tumor cells. J. Cell Biol 1101427–38.PubMedCrossRefGoogle Scholar
  19. 19.
    Bar-Sagi, D. and Feramisco, J.R. (1986) Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 2331061–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Brown, P.D., Levy, A.T., Margulies, I.M.K. et al (1990) Independent expression and cellular processing of Mr 72,000 type IV collage-nase and interstitial collagenase in human tumorigenic cell lines. Cancer Res. 50 6184–91.PubMedGoogle Scholar
  21. 21.
    Ojcius, D.M., Zychlinsky, A., Zheng, L.M. and Young, J.D.E. (1991) lonophore-induced apop-tosis: role of DNA fragmentation and calcium fluxes. Exp. Cell Res. 19743–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Klee, C.B. (1988) Ca2+-dependent phospholipid (and membrane-) binding proteins. Biochemistry 27 6645–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Kojima, I., Matsunaga, H., Kurokawa, K. et al (1988)Calcium influx: an intracellular message of the mitogenic action of insulin-like growth factor-I. J.Biol Chem. 26316561–7.PubMedGoogle Scholar
  24. 24.
    Kadowski, T., Koyasu, S., Nishida, E. et al (1987) Tyrosine phosphorylation of common and specific sets of cellular proteins rapidly induced by insulin, insulin-like growth factor I, and epidermal growth factor in an intact cell. J. Biol Chem. 262, 7342–50.Google Scholar
  25. 25.
    Nishibe, S., Wahl, M.I., Hernandez-Sotomayor, al (1990) Increase of the catalytic activity of phospholipase C-yl by tyrosine phosphorylation.Science 2501253–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim, H.K., Kim, J.W., Zilberstein, A. et al (1991) PDGF stimulation of inositol phospholipid hydrolysis requires PLC-gammal phosphorylation on tyrosine residues 783 and 1254. Cell 65435–41.PubMedCrossRefGoogle Scholar
  27. 27.
    Wahl, M.I., Nishibe, S., Suh, P.G. et al (1989) Epidermal growth factor stimulates tyrosine phosphorylation of phospholipase C-II independently of receptor internalization and extracellular calcium.Proc. Natl Acad. Sci. USA 86,1568–72.PubMedCrossRefGoogle Scholar
  28. 28.
    Kurachi, H., Morishige, K., Amemiya, K. et al (1991) Importance of transforming growth factor alpha/epidermal growth factor receptor autocrine growth mechanism in an ovarian cancer cell line in vivo. Cancer Res. 51, 5956–9.PubMedGoogle Scholar
  29. 29.
    Blay, J. and Brown, K.D. (1985) Epidermal growth factor promotes chemotactic migration of cultured rat intestinal epithelial cells. J. Cell Physiol 124107–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Berchuck, A., Kamel, A., Whitaker, R. et al (1990) Overexpression of HER-2/ neu is associated with poor survival in advanced epithelial ovarian cancer.Cancer Res. 50,4087–91.PubMedGoogle Scholar
  31. 31.
    Kornberg, L.J., Earp, H.S., Turner, C.E. et al (1991) Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of ßl integrins. Proc. Natl Acad. Sci. USA 88, 8392–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Hynes, R.O. (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 6911–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Savarese, D.M.F., Russel, J.T., Fatatis, A. and Liotta, L.A. (1992) Type IV collagen stimulates an increase in intracellular calcium: potential role in tumor cell motiUty. J. Biol Chem. 267 21928–35.PubMedGoogle Scholar
  34. 34.
    McCarthy, J.B., Hagen, S.T. and Furcht, L.T. (1986) Human fibronectin contains distinct adhesion and motility-promoting domains for metastatic melanoma cells J. Cell Biol 102, 179–88.PubMedCrossRefGoogle Scholar
  35. 35.
    Jaconi, M.E.E., Theler, J.M., Schlegel, W. et al (1991) Multiple elevations in cytosoHc-free Ca2+ in human neutrophils: initiation by adherence receptors of the integrin family. J. Cell Biol 112,1249–57.PubMedCrossRefGoogle Scholar
  36. 36.
    Julius, D., Livelli, T.J., Jessell, T.M. and Axel, R. (1989) Ectopic expression of the serotonin Ic receptor and the triggering of malignant transformation. Science 2441057–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Allen, L.F., Lefkowitz, R.J., Caron, M.G. and Cotecchia, S. (1991) G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alphalB-adrenergic receptor enhances mitogenesis and tumori-genicity.Proc. Natl Acad. Sci. USA 88,11354–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Bonner, T.I. (1989) The molecular basis of muscarinic receptor diversity. TINS 12, 148–51.PubMedGoogle Scholar
  39. 39.
    Felder, C.C., MacArthur, L., Ma A.L. et al (1993) Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx. Proc. Natl Acad. Sci USA 901706–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Gutkind, J.S., Novotny, E.A., Brann, M.R., and Robbins, K.C. (1991) Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.Proc. Natl Acad. ScL USA 88,4703–7.CrossRefGoogle Scholar
  41. 41.
    Liotta, L.A. (1986) Tumor invasion and metastases-role of the extracellular matrix. Cancer Res. 46,1–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Furcht, L.T. (1986) Critical factors controUing angiogenesis: cell products, cell matrix, and growth factors. Lab. Invest. 55 505–9.PubMedGoogle Scholar
  43. 43.
    Liotta, L.A., Steeg, P.S. and Stetler-Stevenson, W.G. (1991) Cancer metastasis and angiogenesis; an imbalance of positive and negative regulation. Cell 64, 327–36.PubMedCrossRefGoogle Scholar
  44. 44.
    Tandon, A.K., Clark, G.M., Chamness, G.C. et al (1990) Cathepsin-D and prognosis in breast cancer. N. Engl J. Med. 322297–302.PubMedCrossRefGoogle Scholar
  45. 45.
    Hollas, W., Blasi, F. and Boyd, D. (1991) Role of urokinase receptor in facilitating extracellular matrix invasion by cultured colon cancer. Cancer Res. 51 3690–5.PubMedGoogle Scholar
  46. 46.
    Takeichi, M. (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 2511451–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Vleminck, K., Vakaet, L., Mareel, M. et al. (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role.Cell 66107–19.CrossRefGoogle Scholar
  48. 48.
    Oka, H., Shiozaki, H., Kobayashi, K. et al (1993) Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and 57. its relationship to metastasis.Cancer Res. 53 1696–701.PubMedGoogle Scholar
  49. 49.
    Shimoyama, Y., Nagafuchi, A., Fujita, S. et al.(1992) Cadherin dysfunction in a human cancer cell line: possible involvement of loss of 58. alpha-catenin expression in reduced cell-cell adhesiveness. Cancer Res. 52 5770–4.PubMedGoogle Scholar
  50. 50.
    Stetler-Stevenson, W., Krutzsch, H.C., Wacher, M.P. et al. (1989) The activation of human type IV collagenase proenzyme, J.Biol. Chem. 264 59. 1353–6.PubMedGoogle Scholar
  51. 51.
    Keski-Oja, J., Lohi, J., Tuuttila, A. et al. (1992) Proteolytic processing of the 72,000 Da type IV 60. collagenase by urokinase plasminogen activator. Exp. Cell. Res. 202 471–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Stossel, T.P. (1989) From signal to pseudopod. J. Biol. Chem. 26418261–4.PubMedGoogle Scholar
  53. 53.
    Lester, B.R., McCarthy, J.B., Sun, Z. et al. (1989) G-protein involvement in matrix-mediated motility and invasion of high and low experimental metastatic B16 melanoma clones. Cancer Res. 49 5940–8.PubMedGoogle Scholar
  54. 54.
    Liotta, L.A., Mandler, R., Murano, G. et al. (1986) Tumor cell autocrine motility factor. Proc. Natl Acad. Sci. USA 83 3302–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Stracke, M.L., Krutzsch, H.C., Unsworth, E.J. et al. (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J. Biol. Chem. 267 2524–9.PubMedGoogle Scholar
  56. 56.
    Stracke, M.L., Guirguis, R., Liotta, L.A. and Schiffmann, E. (1987) Pertussis toxin inhibits stimulated motility independently of the adenylate cyclase pathway in human melanoma cells. Biochem. Biophys. Res. Commun. 146339–45.PubMedCrossRefGoogle Scholar
  57. 57.
    Kohn, E.C., Liotta, L.A. and Schiffmann, E. (1990) Autocrine motility factor stimulates a three-fold increase in inositol trisphosphate in human melanoma cells. Biochem. Biophys. Res. Commun. 166 757–64.PubMedCrossRefGoogle Scholar
  58. 58.
    Evans, C.P., Walsh, D.S., and Kohn, E.G. (1991) An autocrine motility factor secreted by the Dunning R-3327 rat prostatic adenocarcinoma cell subtype AT2.1. Int. J. Cancer 49 109–13.PubMedCrossRefGoogle Scholar
  59. 59.
    Bochis, R., Ghabala, J.G. and Fisher, M.H. 5-amino or substituted amino 1,2,3-triazoles. US Patent 4,590,201, May 1986.Google Scholar
  60. 60.
    Kohn, E.G. and Liotta, L.A. (1990) L651582, anovel antiproliferative and antimetastasis agent. J. Natl Cancer Inst., 82 54–60.PubMedCrossRefGoogle Scholar
  61. 61.
    Kohn, E.G., Sandeen, M.A. and Liotta, L.A. (1992) In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates. Cancer Res. 523208–12.PubMedGoogle Scholar
  62. 62.
    Felder, G.G., Ma A.L., Liotta, L.A. and Kohn, E.G. (1991) The antiproliferative and anti-metastatic compound L6511582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release. J. Pharm. Exp. Ther. 257 967–71Google Scholar
  63. 63.
    Kohn, E.G., Felder, G.G., Jacobs, W. et al. (1994) Structure-function analysis of signal and growth inhibition by carboxyamido-triazole, GAL Cancer Res. 54 935–42.Google Scholar

Copyright information

© Chapman & Hall 1995

Authors and Affiliations

  • E. C. Kohn

There are no affiliations available

Personalised recommendations