Chemokine receptor (CCR) 7 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 related 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 show that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospho-PLCγ-1. In addition, protection of CCR7+ metastatic SCCHN cells from cis-platinum-induced apoptosis was conferred by treatment with its ligand MIP-3β, and showed that PI3K/Akt activation is important for tumor growth and survival. Transactivation of EGFR-mediated and mitogen activated protein (MAP)-kinase signaling pathways, which promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Combined blockade of CCR7 and EGFR mediated signaling indicated a potential therapeutic role for combined pathway antagonism. Thus, pro-inflammatory chemokine signals intended for 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.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]