Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

Abstract

Chemokine receptor 7 (CCR7) upregulation, which mediates immune cell survival and migration to lymph nodes, has recently been associated with nodal metastasis of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of CCR7 in tumor progression, its downstream signaling mediators, and interactions with other pathways contributing to metastasis of SCCHN have not been determined. We hypothesized that inflammatory chemokine-mediated signals could also promote tumor proliferation and mitogenic effects. Functional assays showed that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospholipase Cc-1. In addition, treatment of CCR7 þ metastatic SCCHN cells with CCL19 (MIP-3b) showed rapid activation of the prosurvival, PI3K/Akt pathway. Transactivation of EGFR-mediated and mitogen-activated protein kinase signaling pathways, which can promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Thus, proinflammatory chemokine signals that mediate activation, trafficking and survival of tumor-infiltrating immune cells in the tumor microenvironment actually appear to induce signals for progression of cancer cells. The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis.

Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival

“…Wang et al (2004) reported upregulation of CCR7 expression in metastatic tumour lines from 14 patients with SSCHN. Furthermore, Wang et al (2005) have shown that CCR7-triggered signalling through the phosphoinositide-3-kinase (PI-3K/protein kinase B (PKB/AKT) signalling cascade is directly involved in chemotaxis and tumour cell invasion of matrigel in vitro in two SCCHN cell lines.…”

Chemokine receptor 7 promotes cell migration and adhesion in metastatic squamous cell carcinoma of the head and neck by activating integrin αvβ3

“…The results are representative of three independent experiments. Expression relative to β-actin is shown as the mean ± Sd ( ccR7 has been shown to interact with chemokines (ccL19, ccL21) and modulate migration, invasion and proliferation of metastatic SccHN (10,11,28). However, the mechanisms and the signaling pathways underlying ccR7-mediated adhesion and migration remain poorly understood.…”

“…PcI-37B cells were cultured as previously described (10,11,28) in Dulbecco's modified eagle's medium (DMeM) (Invitrogen, carlsbad, cA, USA), supplemented with 10% fetal bovine serum (FBS) (gibco, carlsbad, cA, USA), 100 U/ml penicillin g, and 100 U/ml streptomycin in an atmosphere of 95% air/5% cO 2 at 37˚C. When inhibitors were used, inhibitor treatment at the dose used did not affect the viability or expression of ccR7 by the cells.…”

CCR7: Roles in cancer cell dissemination, migration and metastasis formation

“…Interestingly, under inflammatory conditions, CCL19 and CCL21 were found to be up-regulated in endothelial cells of the blood-brain barrier (Alt et al, 2002) enabling acute T cell leukemia cells to infiltrate into the central nervous system in a CCR7-dependent manner (Buonamici et al, 2009). Furthermore, CCR7 also contributes to tumor cell survival by activating the PI3K/Akt signaling pathway (Wang et al, 2005).…”