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Inflammatory Mechanisms of Chemokine Receptor 7 expression in Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Mburu, Yvonne K. (2011) Inflammatory Mechanisms of Chemokine Receptor 7 expression in Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN). Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    The microenvironment of aerodigestive cancers contains tumor promoting inflammatory signals often involved in innate immunity. SCCHN is an epithelial malignancy characterized by the secretion of inflammatory mediators that can promote tumorigenesis and lymph node metastasis. The chemokine receptor CCR7 is a key molecule whose aberrant expression in SCCHN has been linked to pro-survival, invasive and metastatic pathways. Indeed, the selective upregulation of CCR7 in metastatic SCCHN tumors has been previously described. However, the mechanisms of CCR7 expression have not yet been elucidated. Inflammatory cytokines are known to upregulate CCR7 in immune cells through downstream NF-κB dependent mechanisms. In addition, antimicrobial peptides such as human β-defensin 3 (HBD3) are capable of promoting an inflammatory microenvironment and may possess tumor-promoting properties. Given the frequent overexpression NF-κB in SCCHN and its association with a more aggressive SCCHN phenotype, I hypothesized that NF-κB may be a key mediator of invasive and metastatic disease by promoting CCR7 expression in SCCHN tumors. Indeed, I identified and studied four potential NF-κB binding sites in the promoter region upstream of the CCR7 gene and report on their relative contribution to CCR7 expression in metastatic SCCHN. Furthermore, I demonstrate that HBD3 induces CCR7 expression in dendritic cells as well as primary SCCHN tumors in an NF-κB-dependent fashion. Interestingly, HBD3 stimulation provides anti-apoptotic signals to SCCHN cells, as evidenced by tumor resistance to cisplatin-induced cell death. As presented in this dissertation, these findings suggest that HBD3 represents a novel, NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their growth, survival and evolution into a metastatic phenotype. NF-κB appears to be a key regulator of basal and inducible CCR7 expression. The observed NF-κB induction of CCR7 and its subsequent downstream pathways provide clinically important therapeutic targets to control the progression and metastasis of SCCHN tumors.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairFerris, Robert Lferrisrl@upmc.edu
    Committee MemberSiegfried, Jill Mjsiegfr@pitt.edu
    Committee MemberKane, Lawrence Plkane@pitt.edu
    Committee MemberShurin, Michael Rshurinmr@upmc.edu
    Committee MemberWalker, William Hwalkerw@pitt.edu
    Title: Inflammatory Mechanisms of Chemokine Receptor 7 expression in Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)
    Status: Unpublished
    Abstract: The microenvironment of aerodigestive cancers contains tumor promoting inflammatory signals often involved in innate immunity. SCCHN is an epithelial malignancy characterized by the secretion of inflammatory mediators that can promote tumorigenesis and lymph node metastasis. The chemokine receptor CCR7 is a key molecule whose aberrant expression in SCCHN has been linked to pro-survival, invasive and metastatic pathways. Indeed, the selective upregulation of CCR7 in metastatic SCCHN tumors has been previously described. However, the mechanisms of CCR7 expression have not yet been elucidated. Inflammatory cytokines are known to upregulate CCR7 in immune cells through downstream NF-κB dependent mechanisms. In addition, antimicrobial peptides such as human β-defensin 3 (HBD3) are capable of promoting an inflammatory microenvironment and may possess tumor-promoting properties. Given the frequent overexpression NF-κB in SCCHN and its association with a more aggressive SCCHN phenotype, I hypothesized that NF-κB may be a key mediator of invasive and metastatic disease by promoting CCR7 expression in SCCHN tumors. Indeed, I identified and studied four potential NF-κB binding sites in the promoter region upstream of the CCR7 gene and report on their relative contribution to CCR7 expression in metastatic SCCHN. Furthermore, I demonstrate that HBD3 induces CCR7 expression in dendritic cells as well as primary SCCHN tumors in an NF-κB-dependent fashion. Interestingly, HBD3 stimulation provides anti-apoptotic signals to SCCHN cells, as evidenced by tumor resistance to cisplatin-induced cell death. As presented in this dissertation, these findings suggest that HBD3 represents a novel, NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their growth, survival and evolution into a metastatic phenotype. NF-κB appears to be a key regulator of basal and inducible CCR7 expression. The observed NF-κB induction of CCR7 and its subsequent downstream pathways provide clinically important therapeutic targets to control the progression and metastasis of SCCHN tumors.
    Date: 28 April 2011
    Date Type: Completion
    Defense Date: 19 November 2010
    Approval Date: 28 April 2011
    Submission Date: 24 April 2011
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-04242011-234925
    Uncontrolled Keywords: Cancer Metastasis; CCR7; Chemokines; Head and Neck Cancer; Human Beta Defensins; Inflammation; NFkappaB
    Schools and Programs: School of Medicine > Immunology
    Date Deposited: 10 Nov 2011 14:42
    Last Modified: 05 Jun 2012 09:54
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-04242011-234925/, etd-04242011-234925

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