[Show abstract][Hide abstract] ABSTRACT: Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.
American Journal Of Pathology 06/2011; 178(6):2866-78. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanisms of host defense can form an unwitting alliance with tumor cells to promote tumor progression, invasion, and dissemination to distant sites. By secreting TGF-beta, an immunoregulatory molecule designated for both promoting inflammation and dampening immune responses, the tumor tricks the host into supporting its expansion and survival. TGF-beta not only recruits leukocytes to secrete chemokines, growth factors, cytokines, and proteases in support of a tumor-friendly niche but also in a context-specific manner, incapacitates the emergent immune response. As a profound immunosuppressant, TGF-beta, both directly and through the generation of regulatory T cells, blunts immune surveillance, favoring tumor escape. Collectively, the ability of the tumor to hijack these host defense pathways can tip the balance in favor of the tumor.
Current Opinion in Immunology 05/2008; 20(2):234-40. · 7.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tonsil epithelium has been implicated in human immunodeficiency virus (HIV) pathogenesis, but its role in oral transmission remains controversial. To study characteristics of this tissue, which may influence susceptibility or resistance to HIV, we performed microarray analysis of the tonsil epithelium. Our data revealed that genes related to immune functions such as antibody production and antigen processing were increasingly expressed in tonsil compared with the epithelium of another oropharyngeal site, the gingival epithelium. Importantly, tonsil epithelium highly expressed genes associated with HIV entrapment and/or transmission, including the HIV co-receptor CXCR4 and the potential HIV-binding molecules FcRgammaIII, complement receptor 2, and various complement components. Immunohistochemical staining confirmed the increased presence of CXCR4 in the tonsil epithelium compared with multiple oral epithelial sites, particularly in basal and parabasal layers. This increased expression of molecules involved in viral recognition, binding, and entry may favor virus-epithelium interactions in an environment with reduced innate antiviral mechanisms. Specifically, secretory leukocyte protease inhibitor, an innate molecule with anti-HIV activity, was minimal in the tonsil epithelium, in contrast to oral mucosa. Collectively, our data suggest that increased expression of molecules associated with HIV binding and entry coupled with decreased innate antiviral factors may render the tonsil a potential site for oral transmission.
American Journal Of Pathology 09/2007; 171(2):571-9. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functionally barricaded immune responses or sites of immune privilege are no longer considered dependent on specific anatomical considerations, but rather, they can develop in any location where immunoregulatory cells congregate and express or release products capable of deviating the host response to foreign antigens. Among the pivotal molecules involved in orchestrating these ectopic sites of immune suppression is transforming growth factor-beta (TGF-beta), a secreted and cell-associated polypeptide with a multiplicity of actions in innate and adaptive immunity. While beneficial in initiating and controlling immune responses and maintaining immune homeostasis, immunosuppressive pathways mediated by TGF-beta may obscure immune surveillance mechanisms, resulting in failure to recognize or respond adequately to self, foreign, or tumor-associated antigens. CD4+CD25+Foxp3+ regulatory T cells represent a dominant purveyor of TGF-beta-mediated suppression and are found in infiltrating tumors and other sites of immune privilege, where they influence CD8+ T cells; CD4+ T-helper (Th)1, Th2, and Th17 cells; natural killer cells; and cells of myeloid lineage to choreograph and/or muck up host defense. Defining the cellular sources, mechanisms of action, and networking that distinguish the dynamic establishment of localized immune privilege is vital for developing strategic approaches to diminish or to embellish these tolerogenic events for therapeutic benefit.
[Show abstract][Hide abstract] ABSTRACT: An intimate but deadly encounter between natural killer (NK) cells and transformed cells results in the delivery of cytotoxic molecules into tumor cells. New evidence reveals another intimate association, this time between NK cells and regulatory T cells, but this encounter opposes NK-cell tumoricidal activity. Through a contact-dependent mechanism involving transforming growth factor-beta, regulatory T cells provide an escape mechanism from NK-cell-mediated tumor surveillance.
Trends in Immunology 05/2006; 27(4):161-4. · 12.03 Impact Factor