Are peroxiredoxins tumor suppressors?

It has been known for many years that free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), promote diseases such as cancer. Peroxiredoxins (Prdxs) are small H(2)O(2) scavenging proteins that appear to have tumor preventive functions since loss of Prdx1 in mice leads to premature death from cancer. However, as Prdxs are antioxidants they also scavenge the H(2)O(2) in cancer cells that way supporting survival and tumor maintenance. This suggests that Prdxs function as tumor 'preventers' rather than as tumor suppressors since they do not induce cell death when re-expressed in cancer cells, as it occurs with the tumor suppressor p53. Therefore, the knowledge of Prdx function and regulation may help provide a fuller understanding of the role of ROS in tumorigenesis.     

Graying anatomy? Toward molecular tumor characterization

Will anatomical tumor classification become history as we make way for molecular characterization in oncology? Howard McLeod, Fred Eshelman Distinguished Professor of Pharmacy and Professor of Medicine at the University of North Carolina (NC, USA), is internationally recognized for his work on the pharmacogenomic analysis of cancer treatments. Here, he offers Pharmacogenomics his perspectives on the prospects for practical implementation of PGx in clinical care and the corresponding timescales. He and colleagues have already identified specific genetic components of several drugs that have lead to the US FDA changing the drug package inserts to identify patient groups that are genetically predisposed to risk of severe side effects or inadequate benefit. He is currently working with the large national clinical trials groups--such as Cancer and Leukemia Group B--to confirm that findings from small institutional studies will actually translate into better therapy across the USA.     

Therapeutic targeting of tumor–stroma interactions

Introduction: Cancers exist within a complex microenvironment populated by diverse cell types within a protein-rich extracellular matrix. It is becoming increasingly apparent that molecular interactions between epithelial cells and cells in the surrounding stroma promote growth, invasion and spread of the tumor itself and thus represents a crucial underlying driving force in tumorigenesis.

Areas covered: This article reviews how key interactions between tumor epithelial cells and surrounding mesenchymal and immune cells can promote tumor progression and highlights molecular elements that might represent novel therapeutic targets.

Expert opinion: The tumor microenvironment is increasingly being viewed as a potential therapeutic target with a number of strategies being developed to disrupt tumor–stroma interactions, in order to delay or circumvent tumor progression. Targeting elements of the tumor microenvironment, or signaling pathways in tumor cells activated as a consequence of stromal interactions, may prove a useful therapeutic strategy to prevent tumor development and progression. However, given the tumor cells' ability to circumvent various therapeutic agents when given as monotherapy, the success of these agents is likely to be seen when used in combination with existing treatments.     

N-acetyl-L-cysteine protects endothelial cells but not L929 tumor cells from tumor necrosis factor-α-mediated cytotoxicity

Summary The effect of N-acetyl-L-cysteine on the cytotoxicity of tumor necrosis factor- was investigated in cultured bovine pulmonary artery endothelial cells and L929 mouse tumor cells. In endothelial cells, a 72-h incubation with tumor necrosis factor- (100 ng/ml) reduced the number of viable cells to 27% of control. Simultaneous incubation with N-acetyl-Lcysteine (0.5–5 mmol/l) protected endothelial cells from tumor necrosis factor--mediated cytotoxicity and increased viability in a concentration-dependent fashion to 69% of control. Under the same conditions, a 72-h incubation with tumor necrosis factor- (100 ng/ml) reduced the number of viable L929 tumor cells to 31% of control. However, this cytotoxic response remained unaltered in the presence of N-acetyl-Lrcysteine (0.5–5 mmol/l). Similar results were obtained when using a lower concentration of tumor necrosis factor- (50 ng/ml). These findings demonstrate protection from tumor necrosis factor--mediated toxicity by N-acetyl-L-cysteine in endothelial cells but not in a tumor cell line. It is concluded that N-acetyl-L-cysteine might serve as a therapeutic agent to limit the vascular toxicity of tumor necrosis factor- without affecting its antineoplastic activity.Correspondence to H. Schröder at the above address     

α(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by α(2)-adrenoceptor (α(2)-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. α(2)-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [(3)H]-Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two α(2)-AR subtypes and α(2)-adrenergic agonists enhanced fibroblast proliferation. In vivo, the α(2)-adrenergic agonist clonidine significantly enhanced tumor growth. The α(2)-adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblast-enriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors. These experiments show that fibroblasts from tumor stroma are also influenced by α(2)-adrenergic compounds through the α(2)-ARs expressed in these cells. Moreover, the α(2)-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients.     

Depressive-like behavior induced by tumor necrosis factor-α in mice

Pro-inflammatory cytokines are implicated in the pathogenesis of depression. However, few animal models of cytokine-induced depression well characterized regarding its response to antidepressants are available. Hence, the aim of this study was to propose a model of depressive-like behavior induced by the administration of tumor necrosis factor-α (TNF-α) responsive to antidepressant treatments. TNF-α administered by i.c.v. route produced a depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1-1 fg/site and 0.001 fg/site, respectively), without altering the locomotor activity in the open-field test. In addition, anti-TNF-α antibody (0.1-1 pg/site, i.c.v.), but not the inhibitor of TNF-α synthesis thalidomide (3-30 mg/kg, s.c.) produced an antidepressant-like response in the FST. Moreover, either anti-TNF-α antibody (0.01 pg/site, i.c.v) or thalidomide (30 mg/kg, s.c.) reversed the depressive-like behavior induced by TNF- (0.1 fg/site, i.c.v.) in the FST. TNF-α receptor 1 (TNFR1) knockout mice exhibited an antidepressant-like behavior in the FST and in the TST as compared with the wild type mice. Treatment with fluoxetine (32 mg/kg, i.p), imipramine (15 mg/kg, i.p.) and desipramine (16 mg/kg, i.p) prevented the depressant-like effect induced by TNF-α (0.1 fg/site, i.c.v.) in the FST. In addition, TNF-α (0.1 fg/site, i.c.v.) administration produced an anhedonic response in a sucrose intake test, which was prevented by anti-TNF-α antibody (0.01 pg/site, i.c.v) or fluoxetine (32 mg/kg, i.p). Taken together, these results indicate that TNF-α produces a depressive-like state in mice, reinforcing the notion that an inflammatory component may play an important role in the pathophysiology of depression and suggesting that the central administration of TNF-α may be a novel approach to study the inflammatory component of depressive disorder. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Does p53 status influence tumor response to anticancer therapies?

Abnormalities in the tumor suppressor gene p53 have been identified in over 60% of human cancers. Since it plays such a pivotal role in cell growth regulation and apoptosis, the status of the p53 gene has been proposed as one of the major determinants of a tumor's response to anticancer therapies. In this review we examine the relationship between functional p53 and sensitivity/resistance to both chemotherapy and radiotherapy, and discuss the potential use of some of the current gene therapy approaches to restore functional p53 to tumors as a means of modulating the effects of radiation and chemotherapy.     

Recombinant human tumor necrosis factor-α covalently conjugated to long-circulating liposomes

Recombinant tumor necrosis factor-α (rHuTNF) was covalently conjugated to a phospholipid, N-glutaryl phosphatidylethanolamine (NGPE). The resultant rHuTNF-NGPE conjugates were incorporated into liposomes composed of phosphatidylcholine (PC) and cholesterol (Chol) with or without polyethyleneglycol conjugated to phosphatidylethanolamine (PEG3000-PE). Efficient incorporation (35–50%) of rHuTNF-NGPE conjugates into liposomes was obtained for both PC/Chol and PC/Chol/PEG3000-PE liposomes. An in vitro cytotoxicity assay showed that rHuTNF-NGPE conjugates incorporated into liposomes exhibit a reduced biological activity as compared to the free rHuTNF. Biodistribution studies using ¹²⁵I-labeled rHuTNF showed a significant increase in the circulation time of rHuTNF by incorporation into PC/Chol/PEG3000-PE liposomes, but not conventional PC/Chol liposomes. However, studies using a radioactive lipid as a liposome marker showed that incorporation of rHuTNF-NGPE conjugates resulted in increased clearance from the blood and accumulation in the spleen and liver of both liposomal formulations. The liposome clearance from the blood depends on the protein/lipid ratio of liposomes. The higher the protein/lipid ratio, the higher the liposome clearance from the blood and accumulation in the spleen and liver, suggesting that accumulation of rHuTNF-bound liposomes in the spleen and liver involves interactions with TNF-receptors in these organs.     

Research progress of microtubule inhibitor-induced tumor cell mitotic catastrophe北大核心CSCD

Microtubule inhibitor has been a hot area of anticancer drugs research. Microtubule inhibitor exert an anti-tumor effect by promoting or inhibiting the microtubule aggregation to break the dynamic balance of microtubule, hindering the spindle formation of tumor cells, and then blocking the process of cell division. Mitotic catastrophe is a cell death phenomenon that is caused by abnormal cell division and damage of spindle structure in cell mitosis phase. In recent years more and more attention has been paid to mitotic catastrophe cell death because it has been confirmed clinically that microtubule inhibitors can induce mitotic catastrophe death of tumor cells. This paper reviews the latest research progress of microtubule inhibitors, and discusses the molecular mechanisms of mitotic catastrophe cell death tumor cells induced by microtubule inhibitors.     

Threshold dose of liver tumor promoting effect of β-naphthoflavone in rats

To determine the threshold dose of β-Naphthoflavone (BNF) that induces hepatocellular tumor promoting effects, reactive oxygen species (ROS) generation and thiobarbituric acid-reactive substance (TBARS) formation, and drug-metabolizing enzymes that protect against ROS generation, two-stage liver carcinogenesis model was used. Partial hepatectomized rats (n = 11 to 12) were fed diets containing 0, 0.03, 0.06, 0.125 or 0.25% BNF for 6 weeks after an intraperitoneal injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Histopathologically, glutathione S-transferase placental form (GST-P)-positive foci significantly increased in rats given 0.25% BNF. No marked changes in ROS production and TBARS contents were observed between the BNF treated and DEN alone groups. Real-time RT-PCR showed that the expression of Cyp1a1, Cyp1a2, Cyp1b1 and Nqo1 significantly increased in the groups given 0.03% BNF or more, but Ugt1a6, Akr7a3 and Gstm1 significantly increased in the groups given 0.125% BNF or more. Gpx2 and Yc2 significantly increased in the groups given 0.06% BNF or more and 0.25% BNF, respectively. Inflammation-related genes such as Ccl2, Mmp12, Serpine1 and Cox-2 significantly increased in the 0.25% BNF group. In immunohistochemistry, the number of cyclooxygenase-2 (COX-2)-positive cells increased in rats given 0.25% BNF. These results suggest that 0.25% BNF is the threshold dose for liver tumor promotion, and the fact that inflammation-related genes and COX-2 protein increased in the 0.25% BNF group strongly suggests that inflammation is involved in the liver tumor promoting effect of BNF in rats.     

Targeting TGF-β in prostate cancer: therapeutic possibilities during tumor progression

Background: TGF-β regulates prostate growth by inhibiting epithelial cell proliferation and inducing apoptosis through eliciting a dynamic signaling pathway. In metastatic prostate cancer, however, TGF-β serves as a tumor promoter. TGF-β engages Smad-dependent and Smad-independent mechanisms to exert its action. During prostate tumorigenesis, prostate cells exhibit loss or mutation of TGF-β transmembrane receptors. Increased production of TGF-β causes immunosuppression, extracellular matrix degradation, epithelia to mesenchymal transition and angiogenesis that promotes tumor cell invasion and metastasis. Objective: The molecular basis for effective therapeutic targeting of TGF-β must be directed towards the double-edge-sword nature of the cytokine: Inhibiting the TGF-β tumor promoter capabilities in advanced metastatic prostate cancer, although retaining the growth-inhibitory abilities exhibited in early stages of prostate tumorigenesis. Results/conclusion: The current understanding of the therapeutic possibilities of targeting TGF-β signaling during prostate tumor progression is built on preclinical studies. Studies targeting TGF-β signaling pathway for the treatment of several human malignancies include the use of neutralizing antibodies, antisense oligonucelotides and small molecule inhibitors of kinase activity of the receptor complex. This review focuses on exploiting the therapeutic potential of targeting TGF-β signaling in the context of its contribution to prostate cancer initiation and progression to metastasis.     

Long-term toxicity of modified recombinant human tumor necrosis factor in Macaca mulata

目的：研究新型重组人肿瘤坏死因子（ｒｈＴＮＦＮＣ）ｉｖ对恒河猴的长期毒性，并与重组人肿瘤坏死因子（ｒｈＴＮＦ）作比较．方法：１６只恒河猴分４组分别每日ｉｖｒｈＴＮＦＮＣ９３和９３ＧＵ／ｍ２１个月和ｒｈＴＮＦ６３ＧＵ／ｍ２１０ｄ，检测其一般症状，血液学，血液化学和尿液生化指标，心电图，特异性抗体，骨髓，对组织器官作病理检查等．结果：ｉｖｒｈＴＮＦＮＣ后除大剂量组出现纳差和部分动物眼睑水肿之外，未见明显的药物性毒性反应，而ｒｈＴＮＦ组除上述反应外，还伴有肝肾受损，红系降低，注射局部有静脉炎及血栓形成等病理改变．此外两种ＴＮＦ均能使猴产生特异性抗体．结论：ｒｈＴＮＦＮＣ对恒河猴的毒性比ｒｈＴＮＦ要小得多．     

Effects of tumor necrosis factor-alpha on calcium movement in rat ventricular myocytes

AIM: To study the effects of tumor necrosis factor-alpha (TNF-α) on calcium movement in rat ventricular myocytes. METHODS: Intracellular free Ca~(2+) concentration was measured with calcium fluorescent probe Fluo-3/AM and laser confocal microscope. L-type calcium current (I_(Ca.L)) was recorded with the whole-cell configuration of the patch-clamp techniques. RESULTS: At 2, 20 and 200μg/L, TNF-α was found to increase intracellular free Ca~(2+) concentration in a dose-dependent manner illustrated by the increment of calcium fluorescence density with laser confocal microscope. Nicardipine 0.5μtmol/L slightly attenuated TNF-α-induced response. When the cardiac myocytes were exposed to caffeine (100mmol/L) for 30 rain, TNF-α failed to induce any change of intracellular free calcium. However, it was found that TNF-α inhibited I_(Ca.L) in whole-cell patch-clamp experiments. At 2, 20, and 200μg/L, TNF-α decreased peak I_(Ca.L) by 3.9％ (-5.1 pA/pF±0.3 pA/pF vs -4.9 pA/pF±0.2 pA/pF, n=9, P>0.05), 15.7     

Clear cell ��sugar�� tumor of the lung �� case report

Background

The clear cell ??sugar?? tumor of the lung is an extremely rare benign mesenchymal tumor. Aim: To report a case of the sugar tumor and discuss diagnostic differentiation of the tumor.

Case report

A 53-year female presented with persisting cough. A CT scan revealed a round, 10 mm nodule located within the right lower lobe. The nodule was easily removed during thoracotomy. On the gross examination, the tumor was well circumscribed, and had a homogenous grayish-white appearance on the cut surface. The tumor consisted of round and oval cells with abundant clear cytoplasm, showing PAS pozitive abundant glycogen granules, which were removed by diastase pre-treatment before further staining with PAS. Immunohistochemical studies revealed the tumor cells were positive for HMB-45, vimentin, S-100 protein and very few cells for CD-117. The tumor cells were negative for ??SMA, CK-7, AE1/AE3, CD-10, chromogranin and TTF-1.

Conclusion

Based on the clinical, pathohistological and immunohistochemical data, the diagnosis of the primary clear cell sugar tumor of the lung was established.