Chemokine Signals in Head and Neck Cancer Progression

Summary

Principal Investigator: Robert Ferris
Affiliation: National Cancer Institute
Country: USA
Abstract: Chemokines are small molecules secreted by cells at inflammatory sites that mediate homing and recruitment of immune cells, through G-protein linked receptors. Recently, tumor cells have been shown to express chemokine receptor (CCR)7 that may facilitate lymph node metastasis, and we have shown upregulation of functional CCR7 on metastatic squamous cell carcinoma of the head and neck (SCCHN), compared to nonmetastatic tumors. Our data suggest that NF-?B mediates downstream CCR7-induced activities, as well as the expression of CCR7, itself, and its ligands in an autocrine loop. However, the mechanism and functional importance of CCR7 upregulation in vivo are not well understood. Our central hypotheses are that i) inflammatory signals in the tumor microenvironment lead to upregulation and activation of CCR7 by SCCHN cells, and ii) CCR7-mediated signals promote tumor progression, survival and metastasis. To test these hypotheses, in AIM 1 the effect of inflammatory autocrine/paracrine cytokines on CCR7 expression and activation of NF-?B will be analyzed in SCCHN cells, and the prognostic value of CCR7 expression as a biomarker of clinical disease status in SCCHN specimens will be analyzed by immunohistochemistry. AIM 2, we will elucidate the intracellular CCR7-mediated signals promoting invasion, survival and cis-platinum resistance of metastatic SCCHN cells. Because inhibition of a single signaling pathway is unlikely to have significant clinical benefit, combination targeting strategies are needed. Thus, the antitumor effect of CCR7 inhibition will be evaluated in vitro, and combined with another important signaling pathway in SCCHN, EGFR, to enhance the translational therapeutic potential. In AIM 3, the importance CCR7 activity on tumor progression in vivo will be tested in preclinical murine SCCHN model systems. We have observed that CCR7 overexpression increased migratory capacity of a poorly metastatic murine SCCHN tumor cell line. Using this model, the antitumor efficacy of CCR7 inhibition, in modulating tumor growth and metastasis will be tested alone or in combination with EGFR blockade. These data will be compared to tumor formation in plt/plt mice, which are deficient in CCR7 ligands. Overall these studies are designed to identify the EGFR-independent, CCR7-mediated pathways relevant to invasion and survival of SCCHN and to use this information to facilitate the development of CCR7 targeted therapeutic strategies.
Funding Period: 2006-04-21 - 2011-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?
    Michael R Shurin
    Department of Pathology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, PA 15213, USA
    Cancer Metastasis Rev 25:333-56. 2006
  2. ncbi Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling
    Faina Linkov
    Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Cancer Epidemiol Biomarkers Prev 16:102-7. 2007
  3. doi Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy
    Jun Wang
    Department of Otolaryngology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
    J Natl Cancer Inst 100:502-12. 2008
  4. doi Recurrence in head and neck squamous cell carcinoma. Editorial
    Michael S Leibowitz
    Cancer 113:671-3. 2008

Scientific Experts

  • Michael Shurin
  • Robert L Ferris
  • Jun Wang
  • Michael S Leibowitz
  • Faina Linkov
  • Carter Van Waes
  • Qing Zhang
  • William Gooding
  • Raja R Seethala
  • Hitoshi Hasegawa
  • Lyudmila Velikokhatnaya
  • William Bigbee
  • Adele Marrangoni
  • Jill Siegfried
  • Alex Lisovich
  • Matthew Winans
  • Anna Lokshin
  • Brian Nolen
  • Zoya Yurkovetsky

Detail Information

Publications4

  1. ncbi Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?
    Michael R Shurin
    Department of Pathology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, PA 15213, USA
    Cancer Metastasis Rev 25:333-56. 2006
    ..This review is limited to discussing the role of intratumoral cytokine network in the understanding immunobiology of tumor-associated dendritic cells, which seems to possess different regulatory functions at the tumor site...
  2. ncbi Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling
    Faina Linkov
    Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Cancer Epidemiol Biomarkers Prev 16:102-7. 2007
    ..The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer...
  3. doi Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy
    Jun Wang
    Department of Otolaryngology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
    J Natl Cancer Inst 100:502-12. 2008
    ..Constitutive prosurvival signaling by the phosphoinositide-3 kinase/Akt pathway has been observed in SCCHN cells independent of epidermal growth factor receptor (EGFR) signaling...
  4. doi Recurrence in head and neck squamous cell carcinoma. Editorial
    Michael S Leibowitz
    Cancer 113:671-3. 2008