Journal of the National Cancer Institute Advance Access originally published online on March 25, 2008
JNCI Journal of the National Cancer Institute 2008 100(7):502-512; doi:10.1093/jnci/djn059
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ARTICLES |
Autocrine and Paracrine Chemokine Receptor 7 Activation in Head and Neck Cancer: Implications for Therapy
Affiliations of authors: Departments of Otolaryngology (JW, QZ, RLF) and Immunology (RLF), University of Pittsburgh Medical School, Pittsburgh, PA; Biostatistics Facility (WG), University of Pittsburgh Cancer Institute (JW, RLF), Pittsburgh, PA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA (RS); Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD (CvW); First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Ehime, Japan (HH)
Correspondence to: Robert L. Ferris, MD, PhD, Departments of Otolaryngology and Immunology, University of Pittsburgh Cancer Institute, Hillman Cancer Center—Research Wing, Rm 2.26b, 5117 Centre Ave, Pittsburgh, PA 15213 (e-mail: ferrisrl{at}upmc.edu).
Background: The chemokine receptor 7 (CCR7) mediates survival and invasiveness of metastatic squamous cell carcinoma of the head and neck (SCCHN) to regional lymph nodes. Constitutive prosurvival signaling by the phosphoinositide-3 kinase/Akt pathway has been observed in SCCHN cells independent of epidermal growth factor receptor (EGFR) signaling.
Methods: Human SCCHN cell lines were treated with agents that block or activate CCR7-mediated signaling, and Akt activation, cell viability in the presence or absence of EGFR inhibition, and cisplatin-induced apoptosis (in the presence or absence of Akt inhibition) were assessed by immunoblotting, the MTT assay, and the detection of annexin V, respectively. Expression and secretion of chemokines by primary tumors, metastatic nodes, and benign nodes of patients with SCCHN were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The role of paracrine activation of CCR7 on tumor growth was analyzed by comparing the growth of orthotopic tumors derived from B7E3 murine oral carcinoma cells in wild-type BALB/c mice, in paucity of lymphoid T cell (plt, deficient in CCL19 and CCL21 expression) mice, and in plt mice in which the implanted B7E3 cells overexpressed CCR7 (n = 14 mice per group).
Results: In the absence of exogenous ligand treatment, blockade of CCR7 signaling reduced levels of phosphorylated (activated) Akt and decreased SCCHN cell viability by up to 59% (95% confidence interval [CI] = 58.2% to 59.8%), enhancing the effect of EGFR inhibition. CCR7 stimulation protected metastatic SCCHN cells from cisplatin-induced apoptosis in an Akt-dependent manner. Metastatic nodes expressed and secreted higher levels of CCL19 than benign nodes or primary tumors. CCR7-positive murine SCCHN tumors grew more slowly in plt mice than in control BALB/c mice (mean average tumor volume on day 20 = 12.2 and 26.5 mm3, respectively; difference = 14.3 mm3, 95% CI = 12.3 to 17.1 mm3).
Conclusions: Secretion of CCL19 and CCL21 by SCCHN cells and by paracrine sources combine to promote activation of CCR7 prosurvival signaling associated with tumor progression and disease relapse. CCR7 and its cognate chemokines may be useful biomarkers of SCCHN progression, and blockade of CCR7-mediated signaling may enhance the efficacy of platinum- and EGFR-based therapies.
| CONTEXT AND CAVEATS Prior knowledge The expression of chemokine receptor CCR7 in metastatic squamous cell carcinoma of the head and neck (SCCHN) cells and the fact that CCR7 activation stimulated prosurvival signaling in SCCHN cells in vitro suggested that chemokine-mediated activation of CCR7 may play an important role in progression of SCCHN. Study design The role of CCR7-mediated signaling pathways in mediating cell survival and resistance to apoptosis was analyzed in human SCCHN cell lines, and the expression of chemokines that activate CCR7 was measured in metastatic nodes and normal tissue from SCCHN patients. The contribution of paracrine and autocrine activation of CCR7 to tumor growth was analyzed using a mouse model deficient in expression of CCR7 ligands. Contribution Prosurvival signaling initiated by the binding of chemokines to CCR7 may contribute to the progression and treatment resistance of SCCHN. Implications Further study of the role of chemokine signaling in survival and proliferation of SCCHN cells may furnish insight into the mechanisms that underlie resistance to chemotherapies. Limitations Insights into prosurvival mechanisms obtained from cell lines and mouse models may not apply to the behavior of human cancer cells in vivo.
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Manuscript received July 6, 2007; revised January 8, 2008; accepted February 15, 2008.
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J Natl Cancer Inst 2008 100: 447.