*2.1.5 Epidermal growth factor receptor-integrin crosstalk*

EGFR is a cell surface RTK, the activation of which initiates cell proliferation and survival pathways including PI3K/Akt and Ras/Raf/MEK/ERK [83]. High expression of EGFR is associated with an aggressive and invasive phenotype in multiple cancer types including ovarian cancer [84–88]. Interestingly, integrin-mediated ECM adhesion can induce tyrosine phosphorylation of EGFR in the absence of EGF, and if both EGF and activated integrins are present, they can promote sustained EGFR signaling [89, 90]. For example, EGFR expression in OV-MZ-6 cells is correlated with αvβ<sup>3</sup> integrin levels [34]. In the same cells, the activity of MAPK and FAK was increased upon stimulation of αvβ3 integrins and EGFR by vitronectin and EGF, respectively, demonstrating that both MAPK and FAK play key roles in αvβ3-mediated regulation of EGFR activity. A cooperative effect of EGFR and integrins has also been reported in JAK2/STAT3 signaling, which is associated with EMT in cancer [91]. Colomiere *et al.* reported that EGF exposure initiates an EMT-associated increase in N-cadherin and vimentin levels, as well as cell motility in OVCA 433 and SKOV3 cells. Ovarian cancer cells also showed increased activation of JAK2/STAT3 and expression of α2, α6, and β<sup>1</sup> integrin subunits when treated with EGF. Blocking integrin subunits α6 and β1 significantly inhibited EGF-induced migration, suggesting an interaction between EGFR, α6β1 integrins, and JAK2/STAT3 signaling in ovarian cancer cells that increases EMT and cell motility. The crosstalk between EGFR and β1 integrin was also studied by Lau *et al.* in the context of invasion and metastasis in ovarian cancer [35]. The authors found that EGF stimulation induces β1 expression in OVCAR5 and SKOV3 cells, and that blocking the MAPK/ERK pathway inhibited EGF-enhanced β1 expression. β1 is downstream of the MAPK/ERK pathway and EGF-induced β1 expression is mediated by MAPK/ERK signaling. In summary, EGFR plays a key role in multiple cell survival pathways and its overexpression is associated with a poor prognosis in ovarian cancer [84–88]. These studies suggest that EGFR-integrin crosstalk can lead to the potentiation and cooperative stimulation of intracellular pathways that contribute to cell survival and drug resistance.
