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CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.

Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K - BMC Cancer (2014)

Bottom Line: Silencing of IRF8 significantly decreased TNF-α-induced apoptosis.Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.

View Article: PubMed Central - PubMed

Affiliation: Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kkoizumi@inm.u-toyama.ac.jp.

ABSTRACT

Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients.

Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages.

Results: CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.

Conclusions: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.

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Related in: MedlinePlus

Tumor-derived CXCL16 inhibited liver metastasis by metastatic CRC cells. (A) Liver metastasis of SL4 cells. (B) Number of nodules on liver metastasis. Horizontal bar is the mean of the data points/group. (C) Tumor weight of liver metastasis. Similar results were obtained from three independent experiments (n = 8). *P <0.05. All experiments were repeated at least three times.
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Fig5: Tumor-derived CXCL16 inhibited liver metastasis by metastatic CRC cells. (A) Liver metastasis of SL4 cells. (B) Number of nodules on liver metastasis. Horizontal bar is the mean of the data points/group. (C) Tumor weight of liver metastasis. Similar results were obtained from three independent experiments (n = 8). *P <0.05. All experiments were repeated at least three times.

Mentions: The liver is a major metastatic organ of CRC and no specific therapeutic method is available for liver metastasis other than surgical resection [2]. Our finding that CXCL16 expression enhanced the sensitivity of SL4-CXCL16 to TNF-α led us to hypothesize that enhanced sensitivity to TNF-α by CXCL16 expression inhibits in vivo liver metastasis. As shown in Figure 5A, intraportal vein injection of cells into C57BL/6 mice significantly inhibited liver metastasis in the SL4-CXCL16 group compared with the SL4-Cont group (Figure 5B). The difference in tumor weight was evaluated after dividing the resected liver into normal and tumor parts. Tumor weight was significantly lower in the SL4-CXCL16 group than in the SL4-Cont group (Figure 5C).Figure 5


CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.

Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K - BMC Cancer (2014)

Tumor-derived CXCL16 inhibited liver metastasis by metastatic CRC cells. (A) Liver metastasis of SL4 cells. (B) Number of nodules on liver metastasis. Horizontal bar is the mean of the data points/group. (C) Tumor weight of liver metastasis. Similar results were obtained from three independent experiments (n = 8). *P <0.05. All experiments were repeated at least three times.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4300614&req=5

Fig5: Tumor-derived CXCL16 inhibited liver metastasis by metastatic CRC cells. (A) Liver metastasis of SL4 cells. (B) Number of nodules on liver metastasis. Horizontal bar is the mean of the data points/group. (C) Tumor weight of liver metastasis. Similar results were obtained from three independent experiments (n = 8). *P <0.05. All experiments were repeated at least three times.
Mentions: The liver is a major metastatic organ of CRC and no specific therapeutic method is available for liver metastasis other than surgical resection [2]. Our finding that CXCL16 expression enhanced the sensitivity of SL4-CXCL16 to TNF-α led us to hypothesize that enhanced sensitivity to TNF-α by CXCL16 expression inhibits in vivo liver metastasis. As shown in Figure 5A, intraportal vein injection of cells into C57BL/6 mice significantly inhibited liver metastasis in the SL4-CXCL16 group compared with the SL4-Cont group (Figure 5B). The difference in tumor weight was evaluated after dividing the resected liver into normal and tumor parts. Tumor weight was significantly lower in the SL4-CXCL16 group than in the SL4-Cont group (Figure 5C).Figure 5

Bottom Line: Silencing of IRF8 significantly decreased TNF-α-induced apoptosis.Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.

View Article: PubMed Central - PubMed

Affiliation: Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kkoizumi@inm.u-toyama.ac.jp.

ABSTRACT

Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients.

Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages.

Results: CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.

Conclusions: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.

Show MeSH
Related in: MedlinePlus