Masquerader: High Mobility Group Box-1 and Cancer

Ellerman, Jessica; Brown, Charles K.; Vera, Michael de; Zeh, Herbert J.; Billiar, Timothy R.; Rubartelli, Anna; Lotze, Michael T.

doi:10.1158/1078-0432.ccr-06-1953

Cited by 326 publications

(300 citation statements)

References 117 publications

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“…31,32 Conversely viable mesothelioma cells actively secrete HMGB1: interference with HMGB1 or with the RAGE receptors limits the growth of human xenografts in immunodeficient mice, 33 supporting the contention that the molecule can play cancer-supporting actions in the extracellular environment. 34 Cell death occurring after chemotherapy with cytotoxic agents substantially increases the extent of HMGB1 released from MC-38 cells. 14 Some HMGB1 is released even in the absence of elicited cell necrosis, possibly as a consequence of normal MC-38 cell turnover (not shown).…”

Section: Discussionmentioning

confidence: 99%

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

et al. 2016

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The factors that determine whether disseminated transformed cells in vivo yield neoplastic lesions have only been partially identified. We established an ad hoc model of peritoneal carcinomatosis by injecting colon carcinoma cells in mice. Tumor cells recruit inflammatory leukocytes, mostly macrophages, and generate neoplastic peritoneal lesions. Phagocyte depletion via clodronate treatment reduces neoplastic growth. Colon carcinoma cells release a prototypic damage-associated molecular pattern (DAMP)/alarmin, High Mobility Group Box1 (HMGB1), which attracts leukocytes. Exogenous HMGB1 accelerates leukocyte recruitment, macrophage infiltration, tumor growth and vascularization. Lentiviral-based HMGB1 knockdown or pharmacological interference with its extracellular impair macrophage recruitment and tumor growth. Our findings provide a preclinical proof of principle that strategies based on preventing HMGB1-driven recruitment of leukocytes could be used for treating peritoneal carcinomatosis.

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Section: Discussionmentioning

confidence: 99%

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

et al. 2016

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“…HMGB1 is significantly increased in pancreatic cancer, breast cancer and colon cancer, and this increase can promote activation of TLR4 on immune cells and induce cancer progression and metastasis. 19 We hypothesized that TLR4 on M2-polarized TAMs promotes EMT, which leads to the aggressive behaviors of pancreatic cancer cells. To test this hypothesis, we induced knockdown or inhibition of TLR4 signaling in M2-polarized TAMs.…”

Section: Discussionmentioning

confidence: 99%

“…Previous study has implicated that TLR4 on macrophages induced pancreatic cancer progression and metastasis, 18,19 but it is still unknown whether TLR4 has a role in EMT. In the present study, we examined the role of TLR4 in EMT.…”

Section: Tlr4 Signaling Has An Essential Role In Emt Of Pancreatic Camentioning

confidence: 99%

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

Liu

Shi

et al. 2013

Laboratory Investigation

389

290

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M2-polarized tumor-associated macrophages (TAMs) are key regulators of the link between inflammation and cancer. A negative correlation between infiltration intensity of M2-polarized TAMs and prognosis of pancreatic cancer has been reported. Epithelial-mesenchymal transition (EMT) is an important biological process in the progression of primary tumors toward metastasis. Inflammation-induced EMT has been previously shown, therefore, we hypothesized M2-polarized TAMs could induce EMT in pancreatic cancer. Toll-like receptor 4 (TLR4) signaling has an active role in tumor progression during chronic inflammation and the receptor is primarily expressed on macrophages. Activation of TLR4 on M2-polarized TAMs stimulates an increase in the cytokine interleukin-10 (IL-10); consequently, another aim was to investigate the potential role of TLR4/IL-10 signaling in the EMT of pancreatic cancer. Treatment with IL-4 (20 ng/ml) for 24 h successfully induced the polarization of macrophage cell line RAW 264.7 to M2 phenotype, IL-10 high , IL-12 low , and IL-23 low , and high expression of CD204 and CD206. A coculture system allowed investigation of the roles of M2-polarized TAMs and TLR4/IL-10 signaling in the EMT of Panc-1 and BxPC-3 pancreatic cancer cell lines. Our results showed that coculture with M2-polarized TAMs increased fibroblastic morphology, upregulated mesenchymal markers vimentin and snail at the mRNA and protein levels, and increased proliferation, migration, and metalloproteinase (MMP)2 and MMP9 proteolytic activity in pancreatic cancer cells. Simultaneously, coculture with M2-polarized TAMs decreased the expression of the epithelial marker E-cadherin. Coculture with pancreatic cancer cells increased TLR4 mRNA and protein expression in M2-polarized TAMs. Application of TLR4 siRNA and neutralizing antibodies against TLR4 and IL-10 markedly inhibited E-cadherin reduction and the upregulation of snail and vimentin. Furthermore, activation of TLR4 signaling by lipopolysaccharide profoundly increased the EMT of pancreatic cancer cells. In conclusion, M2-polarized TAMs promoted EMT in pancreatic cancer cells partially through TLR4/IL-10 signaling, suggesting novel therapeutic strategies and enhancing our understanding of M2-polarized TAMs. Pancreatic ductal adenocarcinoma is highly malignant and is resistant to chemo-and radiotherapeutics. 1 Recent evidence suggests the inflammatory environment of the tumor is critical for its progression. 2 Tumor-associated macrophages (TAMs) are derived from circulating monocytes, which are highly abundant within the tumor and provide a key link between inflammation and cancer. 3 TAMs develop a phenotype similar to M2-polarized macrophages and respond to recruitment to the tumor microenvironment. 4 Previous studies have commonly associated elevated numbers of TAMs with tumor progression and poor patient outcome. 5 This association is likely linked to the typical presence of M2-polarized TAMs during cancer invasion, 6 however, the exact mechanisms by which these cells influence the pr...

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“…HMGB1 protein binds to minor groove of DNA and promotes the assembly of site-specific transcriptional proteins (Bonaldi et al, 2002). In addition to its well-established nuclear functions, HMGB1 protein functions as a extracellular signalling molecule which plays a criticle role in inflammation and carcinogenesis (Scaffidi et al, 2002;Ellerman et al, 2007). The HMGB1 protein, secreted actively by NK cells, monocytes and macrophage, functions as an inflammatory cytokine (Wang et al, 1999;Lotze et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background:The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.

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Masquerader: High Mobility Group Box-1 and Cancer

Cited by 326 publications

References 117 publications

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

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