title: Cell-cell and cell-matrix adhesion in survival and metastasis: Stat3 versus Akt.
abstract: Both cell-cell and cell-matrix adhesion are important for epithelial cell differentiation and function. Classical cadherins mediate cell to cell interactions and are potent activators of the signal transducer and activator of transcription (Stat3), thereby offering survival signaling. While the epithelial (E)-cadherin is required for cells to remain tightly associated within differentiated epithelial tissues, cadherin-11 promotes invasion and metastasis, preferentially to the bone. Cell adhesion to the extracellular matrix is mediated through the integrin receptors that bind to the focal adhesion kinase (FAK)/Src complex, thus activating downstream effectors such as Ras/Erk1/2 and PI3k/Akt, but not Stat3. Therefore, at high densities of cultured cells or in epithelial tissues, co-ordinate activation of the complementary cadherin/Stat3 and integrin/FAK pathways can greatly enhance survival and growth of tumor cells. In neoplastically transformed cells on the other hand, a variety of oncogenes including activated Src or receptor tyrosine kinases, activate both pathways. Still, most single-agent therapies directed against these signaling pathways have proven disappointing in the clinic. Combined targeting of the Src/FAK and Stat3 pathways with inhibitory drugs would be expected to have greater efficacy in inhibiting tumor cell survival, and enhancing sensitivity to conventional cytotoxic drugs for treatment of metastatic disease.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Niit
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoskin
authors.forename: Esther
authors.initials: E
authors.lastname: Carefoot
authors.forename: Mulu
authors.initials: M
authors.lastname: Geletu
authors.forename: Rozanne
authors.initials: R
authors.lastname: Arulanandam
authors.forename: Bruce
authors.initials: B
authors.lastname: Elliott
authors.forename: Leda
authors.initials: L
authors.lastname: Raptis
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002470:Cell Survival; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D050796:STAT3 Transcription Factor