Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles

Shahar, Ehud; Gorodetsky, Raphael; Aizenshtein, É. M.; Lalush, Lior; Pitcovski, Jacob

doi:10.1007/s00262-015-1719-z

Cited by 2 publications

(2 citation statements)

References 58 publications

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“…We next analyzed the mechanism by which RIPK1-mediated inflammation might promote HCC in Tak1 ΔHEP mice. CD45 is an important marker for infiltrating lymphocytes in the tumor microenvironment (48,49). We found that TAK1 deficiency in Tak1 ΔHEP mice caused the prominent increases in the liver recruitment of CD45 + cells, which was suppressed by RIPK1 D138N mutation (Fig.…”

Section: Hepatocytic Tak1 Deficiency Promotes Liver Infiltration Ofmentioning

confidence: 77%

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Tan

Zhao

Cao

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 inTak1ΔHEPmice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation inTak1ΔHEPmice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

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Section: Hepatocytic Tak1 Deficiency Promotes Liver Infiltration Ofmentioning

confidence: 77%

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Tan

Zhao

Cao

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…In many instances, tumor formation is driven by the activation, recruitment, and accumulation of immune cells in the tumor milieu (12,34). Thus we next examined nonexclusive conventional immune cell markers to further our understanding of the role of this microRNA in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer

Velázquez

Enos

McClellan

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155(-/-) mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-β/SMAD pathway in miR-155(-/-) mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer.

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Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles

Cited by 2 publications

References 58 publications

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer

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