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The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers.

Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S, Stein I, Singh SP, Bedolla RB, Peled A, Troyer DA, Pikarsky E, Karin M, Farber JM - PLoS ONE (2009)

Bottom Line: Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine.Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells.We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. meravd@hadassah.org.il

ABSTRACT
Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.

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Related in: MedlinePlus

CXCL16 and CXCR6 establish positive feedback loops contributing to the progression of inflammation-associated cancers.Secretion of CXCL16 from pre-cancer or cancer cells leads to CXCR6-mediated recruitment of leukocytes. Cytokines such as TNF-α and IFN-γ produced by these cells in turn induce expression of CXCL16 and CXCR6, creating a positive feedback loop that enhances tumorigenesis – directly, through effects on the growth of pre-cancer and cancer cells, and indirectly, by increasing the migration and proliferation of the inflammatory cells, together leading to the increased growth of inflammation-associated cancers.
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pone-0006695-g008: CXCL16 and CXCR6 establish positive feedback loops contributing to the progression of inflammation-associated cancers.Secretion of CXCL16 from pre-cancer or cancer cells leads to CXCR6-mediated recruitment of leukocytes. Cytokines such as TNF-α and IFN-γ produced by these cells in turn induce expression of CXCL16 and CXCR6, creating a positive feedback loop that enhances tumorigenesis – directly, through effects on the growth of pre-cancer and cancer cells, and indirectly, by increasing the migration and proliferation of the inflammatory cells, together leading to the increased growth of inflammation-associated cancers.

Mentions: Taken together, our data suggest that CXCL16 and CXCR6, expressed by both inflammatory cells and cancer cells in human cancers, may be components of inter-related paracrine and autocrine positive feedback loops involving these cells, pleiotropic cytokines and chemokines. CXCL16 could enhance tumor growth directly through CXCR6-mediated effects on the proliferation/survival of cancer cells and indirectly through enhanced recruitment and proliferation/survival of cytokine-producing T cells (Figure 8). Our data correlating CXCL16 and CXCR6 with stage and grade of prostate cancer provide additional evidence that, in the prostate, inflammation is tumorigenic, and should stimulate the increasing interest in a possible tumor-promoting role specifically for CD4+ T cells [52]. Although we have focused on prostate cancer, our findings that multiple inflammation-associated human cancers express high levels of CXCL16 and CXCR6 suggest that this chemokine/receptor pair may serve as a marker of current or prior inflammation within cancers, thereby providing a tool that can be broadly applied to studying the relationships between inflammation and the behaviors of various malignancies.


The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers.

Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S, Stein I, Singh SP, Bedolla RB, Peled A, Troyer DA, Pikarsky E, Karin M, Farber JM - PLoS ONE (2009)

CXCL16 and CXCR6 establish positive feedback loops contributing to the progression of inflammation-associated cancers.Secretion of CXCL16 from pre-cancer or cancer cells leads to CXCR6-mediated recruitment of leukocytes. Cytokines such as TNF-α and IFN-γ produced by these cells in turn induce expression of CXCL16 and CXCR6, creating a positive feedback loop that enhances tumorigenesis – directly, through effects on the growth of pre-cancer and cancer cells, and indirectly, by increasing the migration and proliferation of the inflammatory cells, together leading to the increased growth of inflammation-associated cancers.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2723911&req=5

pone-0006695-g008: CXCL16 and CXCR6 establish positive feedback loops contributing to the progression of inflammation-associated cancers.Secretion of CXCL16 from pre-cancer or cancer cells leads to CXCR6-mediated recruitment of leukocytes. Cytokines such as TNF-α and IFN-γ produced by these cells in turn induce expression of CXCL16 and CXCR6, creating a positive feedback loop that enhances tumorigenesis – directly, through effects on the growth of pre-cancer and cancer cells, and indirectly, by increasing the migration and proliferation of the inflammatory cells, together leading to the increased growth of inflammation-associated cancers.
Mentions: Taken together, our data suggest that CXCL16 and CXCR6, expressed by both inflammatory cells and cancer cells in human cancers, may be components of inter-related paracrine and autocrine positive feedback loops involving these cells, pleiotropic cytokines and chemokines. CXCL16 could enhance tumor growth directly through CXCR6-mediated effects on the proliferation/survival of cancer cells and indirectly through enhanced recruitment and proliferation/survival of cytokine-producing T cells (Figure 8). Our data correlating CXCL16 and CXCR6 with stage and grade of prostate cancer provide additional evidence that, in the prostate, inflammation is tumorigenic, and should stimulate the increasing interest in a possible tumor-promoting role specifically for CD4+ T cells [52]. Although we have focused on prostate cancer, our findings that multiple inflammation-associated human cancers express high levels of CXCL16 and CXCR6 suggest that this chemokine/receptor pair may serve as a marker of current or prior inflammation within cancers, thereby providing a tool that can be broadly applied to studying the relationships between inflammation and the behaviors of various malignancies.

Bottom Line: Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine.Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells.We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. meravd@hadassah.org.il

ABSTRACT
Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.

Show MeSH
Related in: MedlinePlus