Osteopontin is linked to p65 and MMP-9 expression in pulmonary adenocarcinoma but not in malignant pleural mesothelioma

AIMS: Osteopontin (OPN) is a matricellular protein involved in tissue remodelling, cell-mediated immunity and malignant transformation. High OPN serum levels predict poor prognosis in non-small cell carcinoma and set patients with malignant pleural mesothelioma (MM) apart from disease-free asbestos-exposed individuals. Yet neither the spectrum of tissue expression nor the signalling pathways of OPN in MM and pulmonary adenocarcinoma have been characterized, although in vitro evidence links OPN to the epidermal growth factor receptor (EGFR) pathway. The aim of this study was to address these deficiencies. METHODS AND RESULTS: OPN expression was investigated immunohistochemically in 104 adenocarcinomas and 38 MM and correlated with histological features, including tumour type, grade and proliferation and with expression of activated intermediary EGFR signalling pathway molecules p65, p-AKT, p-ERK, p-STAT-3, and of metalloproteinase (MMP)-1, MMP-2 and MMP-9. In MM, OPN expression was widespread (36/38) and independent of the molecular parameters studied. In adenocarcinoma, high OPN expression was correlated with expression of p65, p-ERK and MMP-9. CONCLUSIONS: Frequent OPN expression is typical of, but not specific for MM, whereas it appears to select adenocarcinoma cases with p65 and MMP-9 expression, suggesting a link with EGFR signalling pathways.     

Immunolocalization of MMP-2 and MMP-9 in human rheumatoid synovium

Matrix metalloproteinase (MMP)-2 and MMP-9, two important members of the matrix metalloproteinase family, have been shown critical contributions in intra-tumor angiogenesis and invasion of tumor progression, and they might also play important roles in the angiogenesis as well as the pannus formation of rheumatoid arthritis (RA). In the present study, we used the immunohistochemistry, the immunofluorescence staining and the con-focal scanning methods to characterize the immunolocalization of MMP-2 and MMP-9 in RA synovium tissues. Our results showed that both MMP-2 and MMP-9 immunostaining could be found in synoviocytes and vascular endothelial cells. Moreover, our con-focal scanning also showed that MMP-2 could be found in infiltrating CD14⁺ monocytes and CD68⁺ macrophages, and MMP-9 could be found in infiltrating CD68⁺ macrophages in RA synovium tissues, while weak or negative staining of these two MMPs could be found in infiltrating CD20⁺B cells and CD3⁺T cells in RA synovium. Thus, our finding suggests that both MMP-2 and MMP-9 expressed by synoviocytes as well as certain infiltrating immune cells role importantly in the angiogenesis in RA progression.     

妊高征肾病患者血清MMP-2、MMP-9检测的临床意义

目的：探讨了妊高征肾病患者血清MMP2、MMP9水平的变化及临床意义。方法：应用酶联法测定了32例妊高征肾病和50例无肾病组及35名正常孕妇血清MMP2、MMP9水平的变化。结果：妊高征肾病组和无肾病组血清MMP2水平非常显著高于正常孕妇组（P〈0.01）,而MMP9水平则非常显著地低于正常孕妇组（P〈0.01）,妊高征肾病组与无肾病组亦有显著性差异（P〈0.05）。结论：检测妊高征患者血清MMP2、MMP9水平的变化对其病情和预后判断均具有重要的临床价值。     

Combination of Strong MMP-2 and Weak TIMP-2 Immunostainings Is a Significant Prognostic Factor in Endometrial Carcinoma

Objective. The aim of this study was to evaluate the combined effects of MMP-2 and TIMP-2 protein immunoreactivities on the prognosis in endometrial carcinoma. Methods. Paraffin-embedded tissue samples from 225 primary endometrioid adenocarcinomas and 13 histologies other than endometrioid adenocarcinoma were immunohistochemically stained for MMP-2 and TIMP-2. Results. In Kaplan-Meier analysis, the 5-year cancer-specific survival rate of the endometrioid adenocarcinoma patients with negative MMP-2 and positive TIMP-2 staining was 100%, whereas only 78% of patients presenting with positive MMP-2 and negative TIMP-2 staining results were alive at that time. In Cox regression analysis, patients with positive MMP-2 and negative TIMP-2 immunostaining had a 4.7-fold relative risk of death from endometrial carcinoma compared to the group of patients with negative MMP-2 and positive or negative TIMP-2 immunoreaction. Conclusions. MMP-2 seems to be the main metalloproteinase determining the prognosis in endometrial carcinoma. Combination of strong MMP-2 and weak TIMP-2 immunostainings was the most potent prognostic marker for poor survival.     

慢性肾炎患者输注红细胞前后血清Ferritin、MMP-2和MMP-9检测的临床意义

目的：探讨了慢性肾炎患者在输注红细胞前后Ferritin、MMP-2和MMP-9水平的变化。方法：应用放射免疫分析和酶联法对32例慢性肾炎患者进行了输注红细胞前后Ferritin、MMP-2和MMP-9检测,并与35名正常人组作比较。结果：慢性肾炎患者在输注红细胞前血清Ferritin和MMP-9水平非常显著地低于正常人组（P〈0.01）,而MMP-2水平则显著地高于正常人组（P〈0.01）。经2周输注红细胞后则与正常人组比较无显著性差异（P〉0.05）。结论：检测慢性肾炎患者输注红细胞治疗前后血清Ferritin、MMP-2和MMP-9水平的变化对其病情的发展和预后的判断均具有重要的临床价值。     

宫颈癌COX-2、MMP-9和CD105表达与肿瘤血管生成及侵袭转移的关系

目的探讨环氧合酶-2(cyclooxygenase,COX-2)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)在宫颈癌局部肿瘤血管生成及肿瘤侵袭转移过程中的作用。方法采用免疫组化SP法检测32例正常宫颈上皮及68例宫颈癌中COX-2、MMP-9的表达。并用CD105标记新生血管内皮细胞,计算肿瘤内微血管密度(microvascular density,MVD)。结果COX-2、MMP-9在宫颈癌组织中的阳性表达率均显著高于正常宫颈上皮中的表达(P<0.01)。COX-2、MMP-9阳性组的MVD均显著高于COX-2、MMP-9阴性组(P<0.01),淋巴结转移组COX-2、MMP-9阳性率均高于无淋巴结转移组(P<0.05)。结论COX-2、MMP-9阳性表达可能在宫颈癌血管生成和侵袭转移中起重要作用,两者在宫颈癌血管生成中可能具有协同作用。检测宫颈癌中COX-2、MMP-9表达对进一步了解宫颈癌局部血管生成情况及判断预后有一定的应用价值。     

脑出血患者血清MMP-3、MMP-9变化及临床意义

目的观察血清基质金属蛋白酶-3(MMP-3)与基质金属蛋白酶-9(MMP-9)在脑出血患者不同时期的动态变化。方法49例脑出血患者作为脑出血组,随机取30例健康体检者为对照组,采用ELISA法分别检测脑出血组发病24、48 h、7 d及对照组血清MMP-3、MMP-9的含量变化。结果脑出血组血清MMP-3和MMP-9水平在发病24、48 h及7 d与对照组比较显著升高(P<0.05);MMP-3、MMP-9含量在不同血肿体积脑出血组中比较具有显著性差异(P<0.05)。在轻、中、重型神经功能缺损程度之间比较具有显著性差异(P<0.05)。结论脑出血患者MMP-3、MMP-9水平与血肿体积、发病时间和神经功能损伤程度都具有密切关系,可作为判定病情和评估预后的参考指标。     

Antisense Oligonucleotide Targeting Matrix Metalloproteinase-7 (MMP-7) Changes the Ultrastructure of Human A549 Lung Adenocarcinoma Cells

Antisense oligonucleotide (ASODN) targeting specific gene can be capable of potently downregulating proliferation and invasion in human cancer cells. However, the underlying mechanisms are less well defined. Here the authors show that matrix metalloproteinase-7 (MMP-7) ASODN changes the ultrastructure of human A549 lung adenocarcinoma cells. Transfection of MMP-7 ASODN significantly lowered the expression of MMP-7 protein in A549 cells. Decreased microvilli, endoplasmic reticulum dilation, swelling of mitochondria, and formation of apoptotic bodies were observed by transmission electron microscope. Collectively, the findings identified the morphological mechanism that MMP-7 ASODN inhibited proliferation and invasion in A549 cells.     

乳腺癌MMP-2表达与间质微血管密度和肿瘤转移的关系

目的 :研究乳腺癌组织中基质金属蛋白酶 2 (MMP 2 )的表达特点 ,探讨其与间质微血管密度及肿瘤转移的关系。方法 :应用免疫组化S P法 ,检测 49例乳腺癌、10例癌旁正常组织MMP 2的表达 ,并在CD34染色切片上检测间质微血管密度(MVD)。结果 :乳腺癌组织MMP 2的表达 (75 5 % )明显高于癌旁正常组织 (30 % ) ,二者之间差异有显著性 (P <0 0 1) ;MMP 2阳性组MVD均值 (5 4 93± 13 86 )高于MMP 2阴性组 (4 1 2 8± 11 6 9) ,MMP 2的表达与MVD呈正相关 (P <0 0 1)。此外 ,乳腺癌MMP 2的表达与组织学分级、淋巴结转移密切相关 (P <0 0 5 ) ,而与患者年龄、肿瘤大小、组织学分型、临床分期无关。结论 :MMP 2促进乳腺癌间质血管生成 ,促进肿瘤的侵袭和转移 ,有可能成为判定乳腺癌生物学行为和预后的重要指标     

乳腺癌细胞基质MMP-9和TIMP-2的表达及其临床意义

目的 :研究乳腺癌组织中细胞外基质金属蛋白酶 9(MMP 9)和组织基质金属蛋白酶抑制剂 2 (TIMP 2 )的表达及其与淋巴转移和预后的相关性。方法 :通过免疫组织化学的方法检测 10 9例乳腺癌组织中MMP 9和TIMP 2表达的情况。结果 :MMP 9和TIMP 2在人乳腺癌中表达的阳性率分别为 6 6 97%和 30 2 7% ;MMP 9的表达与组织学分级、淋巴结转移呈正相关 (P <0 0 1) ,与术后生存率呈负相关 ,而TIMP 2的表达则相反。结论 :MMP 9和TIMP 2的表达与乳腺癌淋巴结转移与预后密切相关 ,可作为判断乳腺癌转移和预后的指标     

Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung

The expression of matrix mdalloproteinase-2 (MMP-2; 72 kDa type IV collagenase/gelatinase A) and MMP-9 (92 kDa type IV collagenase/gelatinase B) was Immunohisto chemically Investigated In 79 T1 adenocarcinomas of the lung using non-commerclal polydonal anti-MMP-2 and -9 antibodies. Thirty-two (41%) and 22 (28%) among the 79 cases were positive in the tumor cells for MMP-2 and -9, respectively. The incidences of MMP-2 and -9 Immunoreactivities were higher (64 and 45%, respectively) in poorly differentiated tumors than in well differentiated tumors (36 and 25%, respectively), and lower in bronchloloalveolar carcinoma (22 and 10%, respectively) compared with other subtypes of adenocarcinoma. The prognosis for patients with MMP-2 andor -9 positive Immunoreactivities was significantly poorer than for those with a MMP-negative tumor (P<0.05). The degree of collagenization was divided into four grades, and tumors with a small to abundant amount of collagen (grade 2 and grade 3 fibrosis) had a higher Incidence of Immunoreactivity to both types of MMP. It is estimated that these expressions might be responsible for tumor Invasion, metastasis, and for grade 2 and grade 3 fibrosis In T1 adenocarcinoma of the lung.     

基质金属蛋白酶-9及其组织抑制物-1在妊娠输卵管黏膜中的表达

目的:检测基质金属蛋白酶-9(MMP-9)及其组织抑制物-1(TIMP-1)在输卵管黏膜中的表达,探讨与输卵管妊娠的关系。方法:采用免疫组织化学显色技术和图像半定量分析法,检测MMP-9和TIMP-1在人妊娠输卵管黏膜、人正常输卵管黏膜及正常宫内早孕子宫蜕膜组织中的表达。结果:MMP-9和TIMP-1在正常宫内早孕组中表达最强,在输卵管妊娠组中的表达较强,在正常输卵管组中表达较弱。两两比较差异均有显著性。结论:MMP-9/TIMP-1参与了输卵管妊娠中胚胎着床过程,且与输卵管妊娠缺乏蜕膜化反应有关。     

宫颈癌中MMP-2及TIMP-2的表达及其临床意义

目的 :通过检测基质金属蛋白酶 - 2 (MMP - 2 )及基质金属蛋白酶组织抑制物 - 2 (TIMP - 2 )在宫颈癌中的表达 ,探讨其与宫颈癌侵袭转移的关系。方法 :采用免疫组化S -P法检测 5 1例宫颈癌和 16例正常宫颈组织中MMP - 2和TIMP - 2的表达情况。结果 :MMP - 2、TIMP - 2在正常宫颈上皮组织中均无表达 ,在宫颈癌组织中的阳性表达率分别为 74 .5 % (38/ 5 1)、4 7.1% (2 4 / 5 1) ,有显著性差异 (P <0 .0 1)。MMP - 2、TIMP - 2的表达与组织学类型无关 ,但与临床分期、细胞分化程度、淋巴结转移有关。结论 :MMP - 2、TIMP - 2的表达与宫颈癌的侵袭转移有关 ,MMP - 2、TIMP - 2可作为预测宫颈癌侵袭转移潜能和临床预后的指标。     

慢性低O2高CO2性肺动脉高压大鼠肺血管基质金属蛋白酶基因表达

目的:研究基质金属蛋白酶在低O₂高CO₂性肺动脉高压中的作用。方法:在慢性低氧高二氧化碳肺动脉高压大鼠模型上,采用图像分析、免疫杂交、免疫组化、组织原位杂交技术等方法测定不同缺氧时间(1周、2周、3周)肺细小动脉基质金属蛋白酶(MMPs)的含量及肺小血管显微结构。结果:①慢性低O₂高CO₂大鼠的肺动脉平均压(mPAP)和右心室(RV)与左心室加室间隔(LV+S)重量比(RV/LV+S)随缺氧时间延长而增高,显著高于正常对照组(P<0.01)。②光镜下正常对照组肺细小动脉内弹力板自然弯曲,平滑肌层未见明显增厚,管壁均匀一致,而低O₂高CO₂组内弹力板扭曲,中膜平滑肌细胞增生,管腔明显狭窄。③免疫杂交、免疫组化、原位杂交法发现肺细小动脉MMP-2、MMP-9及其mRNA平均吸光度值,低O₂高CO₂高于正常对照组(P<0.01),且随着低氧时间的延长而升高。结论:低O₂高CO₂促使基质金属蛋白酶表达升高,提示金属蛋白酶可能参与了肺动脉高压及肺血管重建的形成。     

脊柱浆细胞瘤中MMP-2和MMP-9蛋白的表达及临床意义

目的：探讨脊柱浆细胞瘤中基质金属蛋白酶-2（matrix metallopro teinase-2,MMP-2）和基质金属蛋白酶-9（MMP-9）蛋白的表达及其与脊柱浆细胞骨髓瘤生物学行为的关系。方法：应用免疫组织化学SP法检测41例脊柱浆细胞瘤及14例脊柱良性单纯性骨囊肿中MMP-2和MMP-9蛋白的表达。结果：41例脊柱浆细胞瘤中MMP-2和MMP-9蛋白阳性表达率(分别为63.41%和95.12%)明显高于良性骨囊肿（全阴性,P<0.01);MMP-2和MMP-9的过表达与患者生存期、临床分型、免疫球蛋白分型、轻链分型性别及年龄等比较均无统计学差异(P>0.05);但病理形态学分级与预后有相关性,病理分级为III级者平均生存期较 I 级和 II 级者明显降低。结论：病理形态学分级对浆细胞骨髓瘤的预后判断可能具有一定的临床意义;MMP-2和MMP-9在脊柱浆细胞瘤中的高表达也提示二者可作为新的抗转移治疗靶点。     

糖尿病肾病肾组织中基质金属蛋白酶-9表达的定量分析

目的对糖尿病肾病(DN)大鼠模型的肾组织中的基质金属蛋白酶-9(MMP-9)的表达进行定量研究。方法取成年健康SD大鼠20只,随机分成糖尿病组(DM组)和正常对照组(NC组),DM组大鼠采用一次性腹腔内注射STZ诱导制造糖尿病大鼠模型。分别于造模后第4、8周行HE染色,在光镜下观察肾小球大小和肾小球内细胞数目的变化。通过免疫组织化学方法观察肾脏局部MMP-9的表达,以MMP-9平均光密度做为观察指标。结果HE染色:DM组8周时见肾小球体积增大,肾小球内系膜区增宽.细胞核数目增加。免疫组织化学:DM组大鼠肾脏MMP-9的表达明显低于正常大鼠(P<0.05)。结论糖尿病肾病时MMP-9表达水平降低,可能是引起肾小球细胞外基质积聚和降解减少的重要原因之一。     

Correlation between expression of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma.

Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which degrade extracellular matrix, are believed to play a crucial role in tumor invasion and metastasis. Angiogenesis is also perceived as an important step in tumor growth and metastasis. To investigate the expression of MMPs and the correlation between the expression of MMPs and angiogenesis in colorectal adenocarcinoma, we studied 72 cases of colorectal adenocarcinoma in Inha University Hospital from 1996 to 1997. We evaluated the expression of MMPs by immunohistochemistry and angiogenesis by counting the microvessels. The expression of MMP-2 was increased according to the Astler-Coller stage (p< 0.05). Angiogenesis in the metastatic group was higher than that of the localized one (p<0.05). The expression of MMP-2 positively correlated with angiogenesis (p<0.05), and marked expression of MMP-9 positively correlated with angiogenesis (p<0.05). The present results suggest that the expression of MMP-2 provides clues for tumor progression and angiogenesis provides significant information to predict whether metastasis is present in colorectal adenocarcinoma.     

恶性外周神经鞘膜瘤中MMP-2和TIMP-2的表达

目的 探讨恶性外周神经鞘膜瘤(malignant peripheral nerve sheath tumors,MPNST)中基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)及其相应的组织金属蛋白酶抑制剂-2(tissue inhibitor of metalloproteinase-2,TIMP-2)蛋白表达与病理分级、转移及预后的关系。方法 采用免疫组化S-P法检测MPNST中MMP-2及TIMP-2表达,并行回顾性随访。结果 58例MPNST中MMP-2阳性表达51例,阳性表达率是87．9％,TIMP-2阳性表达36例,阳性表达率是62．1％。MMP-2蛋白表达与病理学分级、远处转移率呈正相关,与术后生存率呈负相关;而TIMP-2则相反。结论 MMP-2、TIMP-2与MPNST病理学分级、远处转移及术后生存期有关,可作为判断肿瘤恶性程度及预后的有用的参考指标。     

A case of pulmonary capillary hemangiomatosis with pulmonary fibrosis associated with MMP-9 related pulmonary remodeling

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension. It is characterized capillary proliferation within the alveolar septa. Here, we report a case of PCH with extensive pulmonary fibrosis. A 52-year-old man with a clinical diagnosis of non-specific interstitial pneumonia died of respiratory failure with severe pulmonary hypertension. Autopsy revealed pronounced right ventricle hypertrophy and pulmonary fibrosis. Consistent with clinical diagnosis, histological examination revealed diffuse pulmonary fibrosis, in addition, it also disclosed marked capillary proliferation within the alveolar septa as well as the fibrotic pulmonary stroma, suggesting the presence of PCH. Hemosiderin-laden macrophages had accumulated in the capillary proliferative area, and bronchiolar-type metaplasia was conspicuous in the fibrotic lesion. Proliferated capillaries were surrounded by fine collagen and α-smooth muscle actin-positive myofibroblasts. Immunohistochemistry revealed that type IV collagen around capillaries in the area of the PCH without inflammation disappeared in the area with inflammation. In addition, the PCH lesion contained significant numbers of macrophages expressing matrix metalloproteinase (MMP) 9 and type II pneumocytes positive for vascular endothelial growth factor. Although pulmonary fibrosis is a distinctive disease entity, different from PCH, MMP-9-driven destruction of the basement membrane may promote unusual pulmonary remodeling, which, in this case, resulted in extensive pulmonary fibrosis.     

Pulmonary adenocarcinoma: review of 106 cases and proposed new classification.

The gross and microscopic appearances of 106 resected pulmonary adenocarcinomas were reviewed and correlated with postoperative survival. Instead of using an established classification based on histological pattern, the tumours were categorised by cellular morphology and site as either parenchymal adenocarcinoma (67%), bronchial adenocarcinoma (13%), or adenocarcinoma of uncertain origin (20%). Despite their pleomorphic appearance parenchymal adenocarcinomas should be regarded as a single entity, derived from multipotential cells of the distal airway; bronchial adenocarcinomas were generally, but not invariably, associated with short postoperative survival; those tumours that could not be reclassified on histological grounds were large adenocarcinomas consisting mainly of mucus cells. Tumours of this type carry a poor prognosis.