High mobility group box 1 can be used to monitor perioperative course in patients with liver cancer

ObjectiveHigh mobility group box 1 (HMGB1) is produced by inflammation. Regarding liver injuries, HMGB1 is reportedly involved in liver regeneration. The present study investigated the use of HMGB1 as a postoperative marker of surgical course in patients with liver cancer.MethodsPatients were enrolled if they had liver cancer, had undergone liver surgery, and did not develop postsurgical complications. Patients who received emergency surgery or patients with unresectable cancerous lesions were excluded. Blood samples were preoperatively obtained as well as at 1 day, 1 week, and 4 weeks following surgery; white blood cell count, serum C-reactive protein, serum albumin, and serum HMGB1 levels were measured.ResultsA total of 36 patients were included in this study. HMGB1 levels significantly changed over time, increasing from a median of 7.1 ng/ml (preoperatively) to 13.9 ng/ml at 1 week postoperatively, and then decreased to 6.3 ng/ml at 4 weeks postoperatively. Peak HMGB1 levels were delayed, and elevated HMGB1 levels persisted as compared with the changes in conventional markers.ConclusionsHMGB1 indicates a unique perioperative inflammatory state in patients with liver cancer. Serum HMGB1 may serve as a marker for monitoring surgical course in patients undergoing surgery for liver cancer.     

May the Neutrophil/Lymphocyte Ratio Be a Predictor in the Differentiation of Different Thyroid Disorders?

Background: The neutrophil/lymphocyte ratio (NLR) is a simple index of systemic inflammatory response,and has been shown to be a prognostic indicator in some types of cancer. Inflammation has been implicatedin the initiation and progression of thyroid cancer. The aim of this study was to examine the relationship ofNLR with papillary thyroid cancer (PTC) and different benign thyroid pathologies like multinodular goiter(MNG) and lymphocytic thyroiditis (LT). Materials and Methods: We retrospectively evaluated the neutrophil,lymphocyte counts and NLR calculated from these parameters of 232 patients with histologically confirmed asmultinodular goiter (group MNG) (n=70), lymphocytic thyroiditis (group LT) (n=97), LT with PTC (group LTPTC)(n=25) and PTC (group PTC) (n=40). The optimal cut-off value for NLR was determined. Results: NLRlevel was significantly higher in groups LT-PTC and PTC as compared to groups MNG and LT (p<0.05). NLRof LT subgroups according to TSH levels were not different (p>0.05). When we grouped the patients as benignand malignant according to PTC presence, the optimum NLR cut-off point obtained from ROC analysis was 1.91(sensitivity 89.0% and specificity 54.5%). Conclusions: Since NLR was significantly elevated in group LT-PTCand group PTC, NLR value may give an opinion as a potential marker in differentiation of benign and malignthyroid disorders. For this purpose a cut-off value of 1.91 for NLR may be accepted.     

Lymphocytic infiltration in juvenile thyroid carcinoma

In this study, the significance of lymphocytic infiltration in juvenile thyroid carcinoma is clarified. We examined nine patients younger than 20 years of age. Histopathologically, there was good correlation between lymphocytic infiltration and the development and spread of carcinoma. It is believed that lymphocytic infiltration around the tumor is an immunologic reaction induced by antigens from the carcinoma itself, and also that the reaction may progress according to tumor development. Immunocytochemically, we determined what type of inflammatory cells infiltrated the thyroid and demonstrated HLA-DR expression in the cancer cells. These findings are similar to autoimmune thyroiditis in which antibody-dependent cellular cytotoxicity (ADCC) works as a main immunomechanism.     

High-mobility group boxes mediate cell proliferation and radiosensitivity via retinoblastoma-interaction-dependent and -independent mechanisms

Our previous studies have shown that high-mobility group box 1 (HMGB1) could physically associate with the retinoblastoma (RB) protein via an LXCXE (leucine-X-cysteine-X-glutamic; X=any amino acid) motif. An identical LXCXE motif is present in the HMGB1-3 protein sequences, whereas a near-consensus LXCXD (leucine-X-cysteine-X-asparagine; X=any amino acid) motif is found in the HMGB4 protein. In this study, we have demonstrated that like HMGB1, HMGB2-3 also associated with the RB in vitro and in vivo, as evidenced by glutathione-s-transferase capture and immunoprecipitation-Western blot assays. A point mutation of the LXCXE or LXCXD motif led to disruption of RB:HMGB1-4 interactions. Enforced expression of HMGB1-3 or HMGB4 by adenoviral-vector-mediated gene transfer resulted in significant inhibition of breast cancer cell proliferation through an LXCXE- or LXCXD-dependent mechanism and an increased radiosensitivity through an LXCXE- or LXCXD-independent mechanism. These results suggest an important role of the LXCXE/D motif in RB:HMGB1-4 association and modulation of cancer cell growth, but not radiosensitivity.     

Irradiation‐induced polyploid giant cancer cells are involved in tumor cell repopulation via neosis

Tumor repopulation occurs when residual tumor cells surviving therapies tenaciously proliferate and re‐establish the tumor. The cellular and molecular mechanisms underlying this process remain poorly understood. In this study, we propose that polyploid giant cancer cells (PGCCs) are involved in tumor repopulation via neosis following radiotherapy. We found that although the majority of PGCCs induced by irradiation underwent cell death, some PGCCs exhibited proliferative capacity. Utilizing time‐lapse microscopy and single‐cell cloning assays, we observed that proliferating PGCCs underwent neosis, thereby contributing to tumor cell repopulation after irradiation. Notably, HMGB1 released from dying tumor cells rather than intracellular HMGB1 could promote neosis‐based tumor repopulation, and the latter could be suppressed by the use of HMGB1 inhibitors. Taken together, our results indicate that PGCC can initiate tumor repopulation via neosis following radiation therapy.     

Microsatellite Instability and k-ras, p53 Mutations in Thyroid Lymphoma

Patho-epidemiological studies showed that thyroid lymphoma (TL) arises in inflammatory lesions of chronic lymphocytic thyroiditis (CLTH). Replication error (RER) is found in inflammatory lesions and associated cancer, suggesting that chronic inflammation could be a risk factor for neoplastic development through causing RER. To clarify whether RER is involved in the pathogenesis of TL, we examined the microsatellite instability (MSI) in 9 cases with CLTH and 19 with TL, including 10 diffuse large B-cell lymphoma (DLBL), 4 follicle center cell lymphoma, 3 marginal zone B-cell lymphoma of extranodal (MALT) type, and 2 lymphoplasmacytic type. Sixteen distinct microsatellite repeats were analyzed. Mutations of p53 and k- ras genes were also examined. When alterations at 2 or more microsatellite loci were judged as positive, only 5 DLBL cases exhibited MSI. The frequency of MSI in DLBL was significantly higher than that in other types of TL and CLTH ( P < 0.05). Four of 19 cases (21.1%) showed point mutation of the k- ras gene. The k- ras mutations occurred in the cases with DLBL with RER, and four of five cases with RER had a k- ras mutation, indicating a close association between RER and k- ras mutation. p53 mutations were not found in the CLTH. Two of 19 TL cases showed mutations of p53 gene. There was no significant association between RER and p53 mutation. These findings indicate that genomic instability contributes to the progression of TL from low grade to high grade, but not to the development of low grade lymphoma in CLTH lesions.     

Microsatellite instability and k-ras, p53 mutations in thyroid lymphoma.

Patho-epidemiological studies showed that thyroid lymphoma (TL) arises in inflammatory lesions of chronic lymphocytic thyroiditis (CLTH). Replication error (RER) is found in inflammatory lesions and associated cancer, suggesting that chronic inflammation could be a risk factor for neoplastic development through causing RER. To clarify whether RER is involved in the pathogenesis of TL, we examined the microsatellite instability (MSI) in 9 cases with CLTH and 19 with TL, including 10 diffuse large B-cell lymphoma (DLBL), 4 follicle center cell lymphoma, 3 marginal zone B-cell lymphoma of extranodal (MALT) type, and 2 lymphoplasmacytic type. Sixteen distinct microsatellite repeats were analyzed. Mutations of p53 and k-ras genes were also examined. When alterations at 2 or more microsatellite loci were judged as positive, only 5 DLBL cases exhibited MSI. The frequency of MSI in DLBL was significantly higher than that in other types of TL and CLTH (P < 0.05). Four of 19 cases (21.1%) showed point mutation of the k-ras gene. The k-ras mutations occurred in the cases with DLBL with RER, and four of five cases with RER had a k-ras mutation, indicating a close association between RER and k-ras mutation. p53 mutations were not found in the CLTH. Two of 19 TL cases showed mutations of p53 gene. There was no significant association between RER and p53 mutation. These findings indicate that genomic instability contributes to the progression of TL from low grade to high grade, but not to the development of low grade lymphoma in CLTH lesions.     

Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti‐inflammatory phenotype

A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor‐associated macrophages (TAMs), which are polarized towards an anti‐inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti‐cancer strategies along this line. One potential immune modulating compound, sphingosine‐1‐phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P‐producing enzymes for tumor progression. The growth of SphK2‐deficient MCF‐7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2‐deficient and control tumors was comparable. However, TAMs from SphK2‐deficient tumors displayed a pronounced anti‐tumor phenotype, showing an increased expression of pro‐inflammatory markers/mediators such as NO, TNF‐α, IL‐12 and MHCII and a low expression of anti‐inflammatory IL‐10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. © 2009 UICC     

HMGB1 combining with tumor-associated macrophages enhanced lymphangiogenesis in human epithelial ovarian cancer

Within tumor microenvironment, high-mobility group box protein 1 (HMGB1) and tumor-associated macrophages (TAMs) are able to influence ovarian cancer development and progression via facilitating tumor lymphatic metastasis. However, little is known about the association between HMGB1 and TAMs on lymphangiogenesis in epithelial ovarian cancer (EOC). To investigate the effect of HMGB1 and TAMs on lymphangiogenesis in EOC, immunohistochemistry was performed to determine the expressions of HMGB1, TAMs, and lymphatic vessel density (LVD) in a total of 108 ovarian tissue specimens. Then, the relationships between HMGB1 or TAMs and LVD were assessed by correlation test. In our in vitro study, TAMs were isolated from ascites of EOC patients. Effects of HMGB1, TAMs, and HMGB1 combining with TAMs on lymphatic endothelial cell (LEC) proliferation, migration, and the capillary-like tube formation were measured. Results showed that the expression of HMGB1 and the number of TAMs infiltration were overexpressed in malignant ovarian tumors compared with that in normal ovarian and were closely associated with lymph node metastasis. Positive correlations existed between HMGB1 expression or TAMs count and LVD determination. In an in vitro study, data demonstrated that either HMGB1 or TAMs could facilitate lymphangiogenesis by inducing LEC proliferation, migration, and capillary-like tube formation. Meanwhile, HMGB1 combining with TAMs may augment the pro-lymphangiogenic property. Our data suggest that either HMGB1 or TAMs could facilitate lymphangiogenesis, while HMGB1 coculture with TAMs may strengthen the pro-lymphangiogenic potential, which may serve as a therapeutic target for ovarian cancer.     

高迁移率族蛋白B1在肿瘤中的作用

高迁移率族蛋白B1(HMGB1)是一种非组蛋白染色体蛋白质,它参与转录、DNA修复、V(D)J重组、分化、发生、细胞外信号转导.HMGB1与肿瘤细胞的生长、浸润和转移有密切关系.HMGB1过表达可抑制细胞凋亡,同时抑制抑癌基因,从而导致肿瘤的发生、生长.HMGB1与纤维蛋白酶原、基质金属蛋白酶的活化、细胞骨架重组等有关.HMGB1还可参与损伤DNA的修复,防止细胞癌变.HMGB1可以增加乳腺癌细胞对γ射线的放射敏感性.     

Immunogenic cell death biomarkers HMGB1, RAGE,and DNAse indicate response to radioembolization therapy and prognosis in colorectal cancer patients

Radioembolization therapy (RE) is an efficient locoregional treatment for liver metastases from colorectal cancer. Serum biomarkers involved in immunogenic cell death are potentially valuable for early predicting therapy response and estimating prognosis. In a prospective observation study, blood samples were taken from 49 consecutive colorectal cancer patients with extensive hepatic metastases before, 24 and 48 hr after RE. Serum levels of high mobility group box 1 (HMGB1), receptor of glycation end products (RAGE) and activity of desoxyribonuclease were compared with response to therapy regularly determined radiologically 3 months after therapy and with overall survival. Serum levels of HMGB1 were increased already 24 hr after RE, while RAGE levels were decreased and DNAse remained unchanged. In radiological staging, 35 patients demonstrated disease progression while 14 patients had stable disease or remission. Serum HMGB1 levels 24 hr after RE were significantly higher in progressive than in nonprogressive patients while for RAGE and DNAse no difference was observed between the response groups. Concerning overall survival, high pretherapeutic (0 hr) and 24 hr levels of HMGB1 were associated with poor outcome. Multivariate analysis including HMGB1, tumor, liver and inflammation markers revealed HMGB1 and CRP as independent prognostic parameters. HMGB1 is a valuable serum biomarker for early estimation of therapy response and prognosis in colorectal cancer patients with liver metastases undergoing RE therapy.     

恶性肿瘤代谢特点及其与炎性介质的相关性研究进展

 恶性肿瘤是一种高能量代谢疾病，因其本身的作用，人体对恶性肿瘤的应激反应以及抗癌治疗过程中的措施导致肿瘤患者的代谢特点具有特殊性，如脂肪分解、脂肪酸氧化增加、瘦组织群减少、胰岛素抵抗以及蛋白质代谢紊乱等。而大量代谢产物如脂多糖（LPS）、乳酸、花生四烯酸代谢物（PGE2）、游离脂肪酸（FFA）等常诱发慢性轻度炎症。而很多肿瘤多发生在感染、慢性刺激和炎性反应的部位，所以炎性微环境对肿瘤的影响已成为科研领域的研究重点。而在肿瘤机体代谢的过程中，许多炎性介质参与其中，故本文就肿瘤能量代谢特点、代谢异常与相关炎性介质的关系作一系统总结。     

Co-expression of RAGE and HMGB1 is associated with cancer progression and poor patient outcome of prostate cancer

Receptor for advanced glycation end products (RAGE), along with its ligand high mobility group box 1 (HMGB1), is believed to play an important role in prostate cancer. The aim of this retrospective study was to investigate the expression of RAGE and HMGB1 and their clinical impact on prostate cancer progression and prognosis. The expression of RAGE and HMGB1 was assessed by immunohistochemistry in cancer lesions from 85 confirmed prostate cancer cases. We determined the potential association between the expression level of these two proteins and the clinicopathological features and overall patient survival. RAGE and HMGB1 were expressed in 78.8% (67/85) and 68.2% (58/85) cases of prostate cancer, respectively, and in the majority (54/85) of cases, these two proteins were co-expressed. There was a strong correlation between RAGE and HMGB1 expressions (P<0.001). The expression of RAGE, HMGB1 and their co-expression were all associated with advanced tumor clinical stage (P<0.05 for all). RAGE expression was also associated with the prostate specific antigen (PSA) level (P=0.014). However, neither the individual expression of those genes nor their co-expression was significantly related with age or Gleason score. The co-expression of RAGE and HMGB1 was associated with poor overall survival in patients with stage III and IV prostate cancer (P=0.047). These results suggest that the expression of RAGE and HMGB1 is associated with the progression and poor prognosis of prostate cancer. RAGE and HMGB1 could be new prognostic biomarkers for prostate cancer as well as molecular target for novel forms of therapies.     

HMGB1与乳腺癌患者临床病理学特征及免疫指标的相关性研究

背景与目的:高迁移率族蛋白1(high mobility group box 1,HMGB1)参与DNA复制、转录及翻译过程,与恶性肿瘤的发生、发展、浸润及转移密切相关,并参与炎症、免疫、增殖、转移和自噬等多种信号转导通路的调节.探究HMGB1与乳腺癌患者临床病理学特征、免疫功能及新辅助化疗效果的相关性.方法:选取20...     

Riedel甲状腺炎诊治进展

Riedel甲状腺炎是一种原因不明的主要侵犯甲状腺组织的慢性侵袭性纤维化炎症,常合并全身其它组织或器官的纤维化炎症。临床表现复杂,诊断比较困难,容易和恶性肿瘤或其它自身免疫性疾病混淆。一般以类固醇治疗为主,抗纤维化治疗也有一定的效果,近期报道三苯氧胺治疗效果较好,手术治疗主要用于解除压迫症状。     

Phase IB trial for malignant melanoma using R24 monoclonal antibody, interleukin-2/α-interferon

The inflammatory tumor lymphocytic infiltrates and spontaneous tumor regressions seen in patients with metastatic malignant melanomas suggest a cellular immune involvement. Enhancement of such responses has been the goal of R24 (GD3 ganglioside-specific) monoclonal antibody trials, alone and in combination with other agents. This study reports the results of 21 patients treated in a phase IB trial employing R24 (0, 5, 25, 50 mg/m²) administered by continuous i.v. infusion on days 1–5 followed by 3mU each of interleukin-2 (IL-2) and alpha interferon (α-IFN) given subcutaneously on days 8–12, 15–19 and 22–26. R24-related toxicities occurred pre-dominantly at the 25 and 50 mg/m² doses. One patient (50 mg/m² R24) exhibited a dose-limiting Grade 4 anaphylaxis. Cytokine-related toxicities required IL-2/α-IFN dose reduction in two patients and early termination of treatment in five additional patients. Nine of 20 baseline biopsies showed chronic inflammation; six with lymphocytic tumor infiltration and three where inflammation was confined to the perivascular/ peritumoral spaces. No day 8 or 29 biopsies in the R24-treated groups demonstrated treatment-induced tumor lymphocytic infiltrates. However, one patient randomized to no R24 treatment, showed a significant inflammatory tumor lymphocytic infiltration at days 8 and 29. Eighteen of 21 treated patients were evaluable for response. One (5%) patient receiving IL-2/α-IFN alone had stable disease lasting 1.5 years. Five (28%) R24, IL-2/α-IFN-treated patients had stable disease ranging from 6 to 32 weeks, with one patient remaining alive 2.5 years post-treatment. Although this combined treatment program was generally well tolerated, no objective responses were seen and significant R24-induced tumor lymphocytic infiltrates were not demonstrated.     

HMGB1 is a key factor for tamoxifen resistance and has the potential to predict the efficacy of CDK4/6 inhibitors in breast cancer

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.