Expression of matrix metalloproteinase-2 and mutant p53 is increased in hydatidiform mole as compared with normal placenta

Matrix metalloproteinases (MMPs) are group of enzymes thought to play an important role in trophoblastic and tumor invasion. The aim of our study was to investigate the trophoblastic expression of MMPs and p53 in normal trophoblast and hydatidiform moles (HM). Paraffin sections of 45 specimens, including 14 complete hydatidiform moles (CM), 15 partial hydatidiform moles (PM), 8 atypical partial hydatidiform moles (aPM), and 8 controls were selected. Classification of HM was established on histologic criteria and supported by the DNA ploidy results. Tissue sections from each case were immunostained with monoclonal antibodies, cytokeratin-7, MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, and p53 wild type (p53wt) and mutant types (mutp53). Staining for cytokeratin-7 revealed a positive reaction in 93% of the samples. MMP-2 was mainly expressed in the syncytiotrophoblast of HM and found in 62% of aPM, 60% PM, and 93% CM. The mutp53 was mainly and focally expressed in syncytiotrophoblastic cells and was found in 63% of aPM, 80% PM, and 93% CM. Expression of MMP-2 and mutp53 was both significantly greater in HM vs control group (P < 0.05) and greater in CM vs PM and aPM (P < 0.05). No significant difference was observed for cytokeratin-7, MMP-9, TIMP-1, and p53wt between the HM subgroups and between HM and control group. MMP-2 and mutp53 are overexpressed in HM as compared with normal trophoblast and might participate in the invasive behavior of the HM.     

COX-2 基因与基质金属蛋白酶在星形细胞瘤中的表达及二者相关性研

 目的 探讨COX-2基因与基质金属蛋白酶在星形细胞瘤中的表达及二者相关性。方法 用原位杂交的方法检测星形细胞瘤组织中COX-2 mRNA的表达；用Ultrasensitive S-P法(链霉素抗生物素蛋白-过氧化物免疫组化染色)检测同等标本中基质金属蛋白酶-2和基质金属蛋白酶-9蛋白的表达；并将COX-2 mRNA与基质金属蛋白酶的表达作相关性分析。结果 COX-2 mRNA及MMP2、MMP9在星形细胞瘤中高度表达，表达阳性率分别为62．69％、56．70％和58．20％；COX-2 mRNA与MMP2和MMP9均有正相线性关系，Pearson积距相关系数分别为0．260、0．347，P<0．05。结论 COX-2基因和基质金属蛋白酶在星形细胞瘤组织中的表达密切相关，说明它在星形细胞瘤向周围组织侵袭中起重要作用。     

RECK、MMP 9在三阴性乳腺癌组织芯片中的表达及临床意义

【摘要】 目的 探讨基质金属蛋白酶抑制剂(RECK)、基质金属蛋白酶 9(MMP 9)在三阴性乳腺癌（TNBC）组织、癌旁组织中的表达及与TNBC临床病理的关系。方法 选择绵阳市中心医院乳腺外科2011年5月~2013年7月经病理证实为TNBC的72例石蜡标本及同 患者癌旁组织,利用免疫组化组织芯片技术检测其RECK、MMP 9蛋白的表达。结果 RECK在TNBC组织及癌旁组织中阳性表达率分别为4306%、8056%（P=0000）。TNBC中RECK的表达与临床分期（P=0009）、组织学分级（P=0010）、腋窝淋巴结转移情况（P=0000）相关。MMP 9在TNBC组织及癌旁组织中阳性表达率分别为625%、1528%（P=0000）。TNBC中MMP 9的表达与肿瘤大小（P=0017）、临床分期（P=0001）、组织学分级（P=0001）、腋窝淋巴结转移状况（P=0001）、Ki 67表达情况（P=0034）相关。TNBC中RECK与MMP 9表达呈负相关(r= 0195,P＜005)。结论 RECK的表达缺失与MMP 9过度表达与TNBC浸润、转移有关,有望成为TNBC的预后指标,并且有可能成为TNBC治疗的靶点。     

Increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP10, MMP23 in inflammatory bowel disease: Cross‐sectional study

It has been reported that EMMPRIN is involved in the regulation of immune response and the induction of MMPs production by fibroblasts. The aim of this study was to describe the intestinal gene expression and protein production of EMMPRIN, MMP23 and MMP10 in patients with ulcerative colitis (UC) and Crohn’s disease (CD) and compared them with a control group. Gene expression of EMMPRIN, MMP10 and MMP23B was measured by RT‐PCR. In order to determine EMMPRIN and MMP protein expression, colonic tissues were immunostained. The results of the study showed EMMPRIN gene expression was upregulated in rectal mucosa from active (a)UC versus aCD patients (P = .045), remission (r)CD group (P = .0009) and controls (P < .0001). We detected differences between rUC and aCD (P = .004), rCD (P < .0001) or control group (P < .0001). EMMPRIN showed a higher expression in mucosa (intraepithelial lymphocytes), submucosa and adventitia (endothelial cells) from aCD patients. MMP23 levels were increased in aUC and aCD compared to rUC and rCD and the control group (P = .0001). EMMPRIN+/MMP23+─expressing cells were localized mainly in mucosa, muscular and adventitia from active UC patients. MMP10 gene expression was increased in aUC versus CD patients and the control group (P = .0001). MMP10 gene expression is associated with inflammation in UC patients (P = .0001, r² = .585). EMMPRIN+/MMP10+─producing cells were found mainly in all intestinal layers and perivascular inflammatory infiltrates from aUC patients. In conclusion, EMMPRIN, MMP23 and MMP10 were upregulated in patients with active UC versus remission UC , CD and control groups suggesting that, they are involved in the inflammatory process.     

Stage-specific prognostic biomarkers in melanoma

The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression.Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients).Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.     

Microenvironment and tumor cell plasticity: An easy way out

Cancer cells undergo genetic changes allowing their adaptation to environmental changes, thereby obtaining an advantage during the long metastatic route, disseminated of several changes in the surrounding environment. In particular, plasticity in cell motility, mainly due to epigenetic regulation of cancer cells by environmental insults, engage adaptive strategies aimed essentially to survive in hostile milieu, thereby escaping adverse sites. This review is focused on tumor microenvironment as a collection of structural and cellular elements promoting plasticity and adaptive programs. We analyze the role of extracellular matrix stiffness, hypoxia, nutrient deprivation, acidity, as well as different cell populations of tumor microenvironment.     

Plasminogen activator inhibitor-1 is an aggregate response factor with pleiotropic effects on cell signaling in vascular disease and the tumor microenvironment

In hemostasis, the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) functions to stabilize clots via inhibition of tissue plasminogen activator (tPA) with subsequent inhibition of fibrinolysis. In tissues, PAI-1 functions to inhibit extracellular matrix degradation via inhibition of urokinase plasminogen activator (uPA). Elevated levels of PAI-1 in the vasculature and in tissues have long been known to be associated with thrombosis and fibrosis, respectively. However, there is emerging evidence that PAI-1 may participate in the pathophysiology of a number of diseases such as atherosclerosis, restenosis, and cancer. In many of these disease states, the canonical view of PAI-1 as an inhibitor of tPA and uPA cannot fully account for a mechanism whereby PAI-1 contributes to the disease. In these cases, one must consider recent data, which indicates PAI-1 can directly promote pro-proliferative and anti-apoptotic signaling in a variety of cell types. Given the wide variety of inflammatory, hormonal, and metabolic signals that increase PAI-1 expression, it is important to consider mechanisms by which PAI-1 can directly participate in disease etiology.     

Investigational drugs for the treatment of osteoarthritis

Introduction: Osteoarthritis (OA) is a common joint disease with multiple pathophysiological processes, affecting the whole joint. Current therapeutic options such as NSAIDs can provide a palliative effect on symptoms but have limited effect on disease progression. New drugs targeting OA structures may retard disease progression at an earlier stage and delay the need for joint replacement.

Areas covered: Some drugs have entered into clinical trials and a few, such as strontium ranelate, do have improvements in both pain and structure changes. However, most of them have failed in clinical trials largely due to increased side effects or the failure to identify the right OA phenotype for the right drug in clinical design. This review describes various investigational drugs developed for the treatment of OA covering those at stages from preclinical experiments to early phase clinical trials. They include drugs for slowing cartilage degradation, regulating cartilage metabolism, targeting subchondral bone, controlling inflammation and relieving pain.

Expert opinion: Treatment options for OA remain limited. However, with the emergence of sensitive tools to detect early disease progression and identification of different OA phenotypes, disease-modifying anti-OA drugs with increased benefit and reduced risks will become available for OA treatment in the near future.