Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

Johnson, Sara D.; Costa, Anna-Maria A. De; Young, Matthew R.

doi:10.3390/cancers6020756

Cited by 47 publications

(49 citation statements)

References 36 publications

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“…Previously, our lab had shown that premalignant lesion cells established from the 4-NQO murine model of oral carcinogenesis secrete increased levels of several immune modulating factors, including PGE 2 , compared to HNSCC cells (27). The current study shows that treatment of premalignant lesion cells with indomethacin, a pan-COX inhibitor, increased their induction of spleen cell production of Th1-associated cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Primary cell lines were established, as previously described (27) by excising 4-NQO-induced premalignant lesions or HNSCC from the tongues of premalignant lesion- or HNSCC-bearing mice at the appropriate stage, as defined through histopathological analysis by the oral pathology section in the Center for Oral Health Research at the Medical University of South Carolina. Briefly, excised premalignant lesions or HNSCC tumors were placed into culture and, once adherent cells became established, non-adherent cells were removed.…”

Section: Methodsmentioning

confidence: 99%

“…These studies suggest that an activated T cell response is occurring at the premalignant lesion stage that wanes as the immunosuppressive environment of HNSCC is established. The premalignant lesion cells contribute to the inflammatory phenotype by their production of G-CSF, RANTES, MCP-1, and PGE 2 (27). Because of the progressive nature of this model, which spans from premalignant oral lesions to HNSCC, investigation into the immune environment during the course of progression is possible.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer

Johnson

Young

2016

Front. Immunol.

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Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE2, compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8+ T cells expressing IFN-γ compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer

Johnson

Young

2016

Front. Immunol.

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“…The stromal microenvironment within the colon is comprised of extracellular matrix components, secreted factors, and stromal cells, which include fibroblasts as well as resident and infiltrating immune cells. Previous studies of premalignant changes associated with cancer, including head and neck (21), breast (22) and ovarian (23) cancers, have found evidence for a pro-inflammatory stromal microenvironment. Characteristic changes include increased cytokine signaling and immune cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

Distinct Transcriptional Changes and Epithelial–Stromal Interactions Are Altered in Early-Stage Colon Cancer Development

Jackson

Varma

et al. 2016

Molecular Cancer Research

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While the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here the development of an ultra-sensitive laser-capture microdissection (LCM)/RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci (ACF) is described. ACF are the earliest identifiable pre-neoplastic lesion found within the human colon and are detected using high-definition endoscopy with contrast dye-spray. The current analysis focused on the epithelium of ACF with somatic mutations to either KRAS, BRAF, or APC, with expression patterns compared to normal mucosa from each patient. By comparing gene expression patterns between groups, an increase in a number of pro-inflammatory NF-κB target genes were identified that were specific to ACF epithelium, including TIMP1, RELA and RELB. Distinct transcriptional changes associated with each somatic mutation were observed and a subset display a BRAFV600E-mediated senescence-associated transcriptome characterized by increased expression of CDKN2A. Finally, LCM-captured ACF-associated stroma was found to be transcriptionally distinct from normal stroma, with an up-regulation of genes related to immune cell infiltration and fibroblast activation. Immunofluorescence confirmed increased CD3+ T cells within the stromal microenvironment of ACF and an abundance of activated fibroblasts. Collectively, these results provide new insight into the cellular interplay that occurs at the earliest stages of colonic neoplasia, highlighting the important role of NF-kB, activated stromal fibroblasts and lymphocyte infiltration. Implications Fibroblasts and immune cells in the stromal microenvironment play an important role during the earliest stages of colon carcinogenesis.

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“…In head and neck cancer for example, the premalignant microenvironment elicits pro-inflammatory cytokine production, in contrast to the tumor microenvironment, which is less immune stimulatory [15]. Alterations in the microenvironment can be present early before changes in the epithelial cells or these changes may be a reaction to excess proliferation of premalignant or malignant cells [16].…”

Section: The Molecular Basis For Cancer Preventionmentioning

confidence: 99%

The hallmarks of premalignant conditions: a molecular basis for cancer prevention

Ryan

Faupel-Badger

2016

Seminars in Oncology

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The hallmarks of premalignant lesions were first described in the 1970s, a time when relatively little was known about the molecular underpinnings of cancer. Yet it was clear there must be opportunities to intervene early in carcinogenesis. A vast array of molecular information has since been uncovered, with much of this stemming from studies of existing cancer or cancer models. Here, examples of how an understanding of cancer biology has informed cancer prevention studies are highlighted and emerging areas that may have implications for the field of cancer prevention research are described. A note of caution accompanies these examples, in that while there are similarities, there are also fundamental differences between the biology of premalignant lesions or premalignant conditions and invasive cancer. These differences must be kept in mind, and indeed leveraged, when exploring potential cancer prevention measures.

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Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

Cited by 47 publications

References 36 publications

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer

Distinct Transcriptional Changes and Epithelial–Stromal Interactions Are Altered in Early-Stage Colon Cancer Development

The hallmarks of premalignant conditions: a molecular basis for cancer prevention

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