TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma

Yang, Pengyuan; Li, Qi Jing; Feng, Yuxiong; Zhang, Yun; Markowitz, Geoffrey J.; Ning, Shanglei; Deng, Yuezhen; Zhao, Jiang-Sha; Jiang, Shan; Yuan, Yufeng; Wang, Hong Yang; Cheng, Shu; Xie, Dong; Wang, Xiao Fan

doi:10.1016/j.ccr.2012.07.023

Cited by 488 publications

(439 citation statements)

References 43 publications

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“…Indeed, it has been reported previously that, in HCC, CCL22 promotes tumor growth and the formation of portal vein thrombosis through the recruitment of Treg. 35 High numbers of Treg have also been found in the tumor tissue of PDAC patients and, as in HCC patients, correlate with poor clinical outcome. 22,25 In pancreatic cancer, tissue accumulation of Treg has so far been associated mainly with expression of TGF-b.…”

Section: Discussionmentioning

confidence: 98%

“…39 This may, however, be explained by the addition of IFNg in incubation protocols of that study, which is known to induce CCL22 in epithelial cells. 41,42 Although the regulation of CCL22 has been investigated in several further studies, 3,6,35,43 we describe here for the first time its induction through IL-1a by cancer cells. Further, we show that IL-1a-induced CCL22 leads to the recruitment of Treg and this can be blocked by the IL-1 receptor antagonist anakinra.…”

Section: Discussionmentioning

confidence: 99%

“…40 In HCC, CCL22 upregulation was shown in HBVinfected HCC cell lines and HBVC primary HCC tumors on mRNA level. 35 In HCC, using immunohistology, we did not observe any CCL22 expression by tumor cells in vivo. Thus, our data indicate that in vivo, in HCC, CCL22 expression is restricted to tumor-infiltrating immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

et al. 2016

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In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1a). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1a as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumorinduced immunosuppression.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

et al. 2016

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“…While Yang et al (2012a) explained how the HBV chronic infection increases the expression of TGF-␤, which reduces the miR-34a expression. This event increases the expression of the chemokine CCL22 that stimulates T regulatory cells and favours the immune escape.…”

Section: Mir-34amentioning

confidence: 99%

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Bronte

Fanale

et al. 2016

Critical Reviews in Oncology/Hematology

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“…96,97 Tregs promote immunosuppression in the tumor microenvironment, and their accumulation in the tumor milieu promotes tumor progression and enables metastasis. [98][99][100] Tregs express galectin-1, a mediator of the immunosuppressive activity of these cells. 101,102 In normal tissues, Tregs function to maintain immune homeostasis limiting autoimmune responses; however, cancer cells highjack these cells to avoid the immune attack.…”

Section: Inflammation and Metastasismentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma

Cited by 488 publications

References 43 publications

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Inflammation and skeletal metastasis

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