Biological and clinical significance of cathepsin D in breast cancer

Cathepsin D is an acidic lysosomal protease present in all cells. In breast cancer cells, pro-cathepsin D expression and secretion are markedly increased and its processing is altered. This protease is induced by estrogens and growth factors. In vitro, pro-cathepsin D is an autocrine mitogen on breast cancer cells and can be auto-activated to degrade extracellular matrix and proteoglycans in acidic microenvironment. In patients, there is a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and development of metastasis. This marker is independent of other prognostic factors and appears to be particularly useful in lymph node-negative tumors. These results suggest that derouting and overexpression of cathepsin D plays an important role in invasion and metastasis of breast cancer cells.     

IGFR-1在乳腺癌组织中的表达及意义

目的:探讨胰岛素样生长因子受体1(IGFR-1)在乳腺癌及正常乳腺组织中的表达及与ER、PR、cerbB-2的关系。方法:采用免疫组织化学法检测IGFR-1在40例乳腺癌和正常乳腺组织中的表达率。结果:IGFR-1在乳腺癌组织中的表达率为77.5%,在正常乳腺组织中的表达率为35%,两者之间有明显统计学差异(P<0.05);IGFR-1在乳腺癌组织中的表达与雌激素受体(ER)、孕激素受体(PR)呈正相关(r=0.41,P<0.05;r=0.36,P<0.05);与cerbB-2状态及临床分期无关(r=0.28,P>0.05;r=0.17,P>0.05)。结论:IGFR-1在乳腺癌组织中的高表达可作为乳腺癌的诊断的标志物,IGFR-1在乳腺癌的发生中有重要作用,IGFR-1可作为乳腺癌治疗的新靶点。     

血管内皮生长因子及色素上皮衍生因子在乳腺癌中的表达及临床意义

目的：探讨血管内皮生长因子（VEGF）、色素上皮衍生因子（PEDF）在乳腺癌组织中的表达水平及其与乳腺癌病理特征的关系。方法采用Envision免疫组织化学方法对20例乳腺良性病变组织（纤维腺瘤）、85例乳腺浸润性导管癌组织中的VEGF、PEDF和CD34表达情况进行检测。 CD34表达反映微血管密度（ MVD ）。计数资料采用χ2检验, Spearman 等级相关分析方法进行相关性分析。结果 VEGF 在乳腺癌组织中的阳性表达率为71.7％（61/85）,高于在乳腺良性组织中的阳性表达率40％（8/20）,差异有统计学意义（χ2＝9.959, P＝0.002）;PEDF在乳腺癌组织中的阳性表达率为41.2％（35/85）,低于在乳腺良性组织中的阳性表达率90％（18/20）,差异有统计学意义（χ2＝19.683, P＝0.000）。在乳腺癌组织中VEGF与PEDF表达呈负相关（ r＝-0.365, P＝0.019）。乳腺癌组织中VEGF表达与肿瘤直径（χ2＝26.31,P＝0.000）、TNM分期（χ2＝5.428,P＝0.020）、淋巴结转移有关（χ2＝5.368, P＝0.021）;PEDF表达与TNM分期（χ2＝8.584, P＝0.003）、肿瘤直径（χ2＝11.079,P＝0.001）、绝经状态（χ2＝4.507,P＝0.034）、ER状态有关（χ2＝3.974,P＝0.046）。 MVD值在PEDF阴性组高于阳性组（38.67±6.52比22.56±5.16,Z＝-0.984,P＝0.000）,在VEGF阳性组则高于阴性组（38.78±6.28比25.36±5.12,Z＝-0.972,P＝0.000）。结论乳腺癌组织中存在PEDF、VEGF的表达相关性,且与MVD相关,对认识乳腺癌的生物学特性以及指导乳腺癌的诊疗具有重要意义。     

Biological and clinical significance of cathepsin D in breast cancer.

Cathepsin D, an aspartyl protease of lysosomes, is overproduced and hypersecreted by breast cancer cells. The prognostic value of its immunoassay in breast cancer cytosol is reviewed from the first retrospective clinical studies available, which show a strong correlation between high concentrations of cathepsin D in the cytosol of primary tumor and further occurrence of metastasis. This new prognostic factor is induced by estrogen in hormone dependent breast cancer but expressed at a high level in hormone independent breast cancer and appears to be independent of other more classical factors. Its value in node negative patients varies according to the studies. In nude mice, transfection of cathepsin D cDNA into tumor cells increases their metastatic potential, suggesting that overexpression of this protease may be one of the factors responsible for metastasis in human breast cancer. The mechanism by which this protease might facilitate metastasis in vivo is still unknown, even though cathepsin D has the potential to initiate a proteolytic cascade, to degrade extracellular matrix and to liberate FGFs like growth factors from the matrix. These studies should stimulate the search for new therapeutical agents in order to inhibit cathepsin D action.     

Serum levels of hepatocyte growth factor in patients with breast cancer.

OBJECTIVE: Hepatocyte growth factor (HGF) has been reported the cause of many biological events, including cell proliferation, movement, invasiveness, morphogenesis, and angiogenesis. Elevated hepatocyte growth factor content in tumor tissue was reported to predict a more aggressive biology in non-small cell lung cancer patients. However, there is still limited knowledge about the role of HGF in breast cancer. This study was designed with the aim to elucidate the possible relationship between the preoperative circulating soluble HGF and breast cancer. MATERIALS AND METHODS: One hundred twenty-four consecutive patients with invasive breast cancer undergoing surgery were prospectively included and evaluated. Venous blood samples were collected before the surgery. Sera were obtained by centrifugation and stored at -70 degrees C until assayed. The control group consisted of 35 patients with benign breast tumor (20 with fibrocystic disease and 15 with fibroadenoma). Serum concentrations of soluble HGF were measured by the quantitative sandwich enzyme immunoassay technique. The data on primary tumor staging, age, estrogen receptor status, lymph node status, distant metastases status, histologic grading, and tumor-node-metastasis (TNM) staging were reviewed and recorded. RESULTS: The mean value of serum soluble HGF in patients with invasive breast cancer was 529.05 +/- 123.33 pg/mL and that of control group was 343.00+/- 31.03 pg/mL and the difference was significant (P < 0.001). Furthermore, there were significantly higher serum levels of soluble HGF in patients with negative estrogen receptor (P = 0.035), in patients with poorer differentiated tumor (P < 0.001), in patients with more advanced primary tumor staging (P < 0.001), in patients with more advanced lymph node status (P < 0.001), in patients with distant metastases (P < 0.001), and in patients with more advanced TNM staging (P < 0.001). In multivariate analysis by the multiple linear regression method, TNM staging (P < 0.001) seemed an independent factor regarding the significant higher serum levels of soluble HGF. CONCLUSION: Patients with more advanced TNM staging were shown to have higher serum soluble HGF. Thus, preoperative serum soluble HGF levels might reflect the severity of invasive breast cancer and deserve further evaluation.     

Biological and clinical significance of PARP1 protein expression in breast cancer

Breast Cancer Research and Treatment - Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the...     

Racial differences in breast cancer outcomes by hepatocyte growth factor pathway expression

Breast Cancer Research and Treatment - Black women have a 40% increased risk of breast cancer-related mortality. These outcome disparities may reflect differences in tumor pathways and a lack of...     

肝细胞生长因子及其受体c-met在卵巢上皮性肿瘤组织中的表达及意义

目的:研究肝细胞生长因子(hepatocytegrowthfactor,HGF)和cmet蛋白在卵巢上皮性肿瘤组织中的表达以及与临床病理特征的关系。方法:应用免疫组织化学SP法对45例卵巢上皮性恶性肿瘤及10例卵巢上皮性良性肿瘤组织中HGF和cmet蛋白的表达进行定位分析;应用蛋白印迹法检测HGF、cmet蛋白在卵巢上皮性肿瘤中的表达。结果:在卵巢癌组织中,HGF在上皮细胞的表达强于间质细胞,cmet在上皮细胞强表达,间质细胞无表达。HGF和cmet蛋白在卵巢癌组织中阳性率分别为60.0%(27/45)和73.0%(33/45),较良性肿瘤组织的阳性率20.0%(2/10)和50.0%(5/10)显著升高,P值分别为0.000和0.000。手术病理分期Ⅲ～Ⅳ期者HGF和cmet蛋白表达的阳性率为70.4%(19/27)和88.9%(24/27),较Ⅰ～Ⅱ期者的38.9%(7/18)和50.0%(9/18)显著升高,P值分别为0.048和0.000。淋巴结转移者阳性率分别为78.6%(11/14)和92.8%(13/14),较无淋巴结转移者阳性率51.6%(16/31)和64.5%(21/31)升高显著,P值分别为0.025和0.000。HGF和cmet蛋白表达阳性率与年龄和病理分级无关,P值分别为0.436、0.549、0.465和0.124。HGF和cmet蛋白相对表达强度在卵巢癌组织中为1.29±1.25和1.57±1.25,在良性肿瘤组织中为0.17±0.34和0.44±0.46,两组比较差异有统计学意义,P值分别为0.000和0.007。在卵巢癌组织中HGF和cmet蛋白的表达呈正相关性,P=0.009。结论:卵巢上皮性肿瘤组织中存在HGF和cmet蛋白的表达,HGF和cmet与卵巢癌的发生、侵袭和转移密切相关。     

血管内皮生长因子C蛋白在乳腺癌组织中的表达及其意义

目的:研究血管内皮生长因子C(VEGF-C)蛋白在乳腺癌组织中的表达及意义。方法:采用免疫组化法对60例乳腺癌、12例良性乳腺病变组织中VEGF-C的表达进行检测,探讨其与微血管密度(MVD)、微淋巴管密度(MLD)、增殖细胞核抗原(PCNA)蛋白及临床病理因素之间的相关性。结果:乳腺癌组织中VEGF-C表达水平高于良性乳腺病变组织(u=137.5,P=0.001)。乳腺癌组织中VEGF-C表达与MVD无相关性(P=0.951),而与MLD(r=0.286,P=0.027)及PCNA(r=0.315,P=0.014)有相关性;VEGF-C(r=0.389,P=0.002)、MLD(r=0.335,P=0.009)与患者淋巴结转移状况相关,与其他临床病理因素无相关性。单因素Logistic回归分析显示,高VEGF-C、MLD组发生淋巴结转移的风险分别是低VEGF-C、MLD组的4.059倍(95%CI为1.234～13.349,P=0.021)和3.519倍(95%CI为1.209～10.240,P=0.021)。多因素Logistic回归分析显示,VEGF-C对淋巴结转移的影响独立于MLD。结论:乳腺癌组织中VEGF-C蛋白表达水平升高,VEGF-C在乳腺癌淋巴管生成及淋巴结转移中起重要作用,且它对淋巴结转移的影响独立于MLD。另外,VEGF-C高表达的患者肿瘤细胞的增殖性较强。     

乳腺癌易感基因(BRCA)的生物学功能与临床意义

乳腺癌是女性比较常见的恶性肿瘤。乳腺癌易感基因(BRCA)是与乳腺癌相关的重要抑癌基因,包括BRCA1、BRCA2和BRCA3,其生物学功能广泛,对细胞周期、基因转录表达、DNA损伤修复等均有影响,BRCA基因的突变、启动子甲基化、基因杂合性缺失与乳腺癌的发生密切相关,研究BRCA对于乳腺癌的临床特点分析、筛查、监测以及治疗都具有指导性意义。     

Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer

Overall survival (OS) and relapse free survival (RFS) were studied in 297 patients according to the presence of insulin-like growth factor 1 receptors (IGF1-R). All the patients were surgically treated for locoregional disease in the same institution from January 1986. The median duration of follow-up was 40 months. RFS was better in patients with IGF1-R in their tumors as assessed by actuarial survival (P = 0.014) as well as Cox analysis (P = 0.016). OS was better in IGF1-R positive tumors studied by actuarial (P = 0.007) as well as Cox analysis (P = 0.010). By Cox analysis the other prognostic factors on RFS were estrogen receptor (P = 0.002), progesterone receptor (P = 0.002), axillary node metastases (P = 0.032), histoprognostic grading (GHP) according to the standard of Scarff and Bloom (P = 0.004), and tumor diameter (P = 0.019). The other prognostic factors on OS (Cox analysis) were estrogen receptor (P = 0.001), axillary node metastases (P = 0.010), GHP (P = 0.009), progesterone receptor (P = 0.012), and tumor diameter (P = 0.007). When combining IGF1-R, GHP, and axillary node metastases, it appeared that IGF1-R, GHP, and axillary node metastases had independent prognostic significance. In this prospective study IGF1-R had a prognostic significance on RFS as well as on OS studied by actuarial as well as Cox analysis.     

Epidermal growth factor receptors in intracranial and breast tumours: their clinical significance

A method to determine the binding of epidermal growth factor (EGF) to the particulate fraction of the cell has been established and evaluated using rat liver, human placenta, and tumours of human breast and brain. Little EGF receptor (EGFR) activity was detected in normal or benign tumour tissues except for meningioma (positive in 95% samples), but EGFR were present in 43% of 131 breast tumours and 75% of 55 primary cerebral tumours. Despite the strong inverse correlation between EGFR activity and oestrogen receptors in breast tumours and a tendency for high levels of EGFR activity to be associated with glioblastoma multiforme, analysis showed that EGFR was of little prognostic significance in patients with tumours of either breast or brain.     

Serum levels of hepatocyte growth factor/scatter factor in patients with liver metastases from breast cancer.

OBJECTIVE: Recent studies have shown that the pleiotropic cytokine hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-Met play major roles in the malignant progression of numerous tumors. For patients with breast cancer liver metastases, increased serum levels of HGF/SF have been reported. We studied the relationship between the clinical course of the disease and the serum levels of HGF/SF in such patients. METHODS: We examined 51 patients treated for breast cancer liver metastases. Serum concentrations of HGF/SF were measured before each therapy cycle and compared to the corresponding tumor marker levels. RESULTS: Mean serum levels of HGF/SF in patients with liver metastases were increased above the reported reference levels of primary breast cancer patients. Serum levels of HGF/SF were correlated with tumor marker levels in a logarithmic relation (r = 0.47, p < 0.001). In some cases serum concentrations of HGF/SF changed similarly to the course of the corresponding tumor markers. CONCLUSIONS: Serum levels of HGF/SF are associated with the clinical course of metastatic breast cancer patients with liver metastases. Further studies are required to clarify the potential value of the HGF/SF serum concentration as a tumor marker. HGF/SF and its receptor c-Met should be further evaluated as therapeutic targets.     

VEGF及EGFR在非小细胞肺癌组织中的表达及临床意义

背景与目的：研究显示,血管内皮生长因子（vascular endothelial growth factor,VEGF）和表皮生长因子受体（epidermal growth factor receptor,EGFR）在非小细胞肺癌（non-small cell lung cancer,NSCLC）组织中过度表达,是NSCLC重要的治疗靶点。本研究旨在探讨VEGF和EGFR在NSCLC肿瘤组织中的表达及其临床意义。方法：采用免疫组织化学法检测186例NSCLC患者在不同临床病理特征下VEGF和EGFR的表达情况,并分析两者表达的相关性。结果：NSCLC组织中,VEGF阳性表达率在有淋巴结转移的患者中明显高于无淋巴结转移者,两者比较,差异有统计学意义（P〈0.05）。EGFR阳性表达率在男性、吸烟和鳞癌患者中明显低于女性、非吸烟和腺癌患者（P〈0.05）,N1～N3、Ⅲ～Ⅳ期患者明显高于N0、Ⅰ～Ⅱ期患者（P〈0.05）。VEGF和EGFR低表达患者的3年和5年生存期明显优于高表达患者（P〈0.05）。NSCLC组织中VEGF和EGFR的表达具有相关性（rs=0.161,P〈0.05）。结论：VEGF与NSCLC淋巴结转移具有相关性。EGFR在非吸烟、女性和腺型NSCLC组织中高表达,与淋巴结转移及分期密切相关。NSCLC组织中VEGF和EGFR的表达具有相关性,可作为判断NSCLC患者病情及预后的参考指标。     

转录因子 Sp1和 VEGF 在乳腺癌中的表达和意义

目的：检测转录因子 Sp1和 VEGF 在乳腺癌中的表达,探讨两者表达的相关性及临床意义。方法：采用免疫组织化学方法检测68例乳腺癌患者肿瘤组织及18例癌旁组织中 Sp1和 VEGF 的表达。结果：Sp1和 VEGF 在68例乳腺癌中表达的阳性率分别为72．05％（49／68）和64．71％（44／68）,与在18例正常乳腺组织中表达阳性率（分别为33．3％和16．67％）的差异有统计学意义（P 均＜0．01）。Sp1的过表达与乳腺癌的TNM分期、脉管浸润及淋巴结转移相关（P ＜0．05）,而与患者的年龄、肿瘤大小、组织学分级无明显相关性;在乳腺癌组织中 Sp1和 VEGF 的表达之间呈明显正相关（P ＜0．01）。结论：Sp1和 VEGF 的表达与乳腺癌的生物学行为密切相关,且 Sp1高表达与乳腺癌的血管生成及患者的预后相关。     

神经生长因子在原发性肝癌组织中的表达及其临床意义

目的探讨神经生长因子(NGF)在原发性肝癌组织中的表达及其临床意义。方法选取2017年4月至2019年4月间上海复旦大学附属中山医院青浦分院收治的50例原发性肝癌患者作为研究组,以及同期门诊体检的50名健康人员作为对照组,两组患者均进行NGF检测,比较两组患者NGF检测水平、检测阳性率,并分析原发性肝癌病理特征与血清NGF相关性。结果研究组NGF水平为(34. 26±3. 62) ng/L,显著高于对照组的(11. 05±0. 21) ng/L,差异有统计学意义(P <0. 05)。研究组NGF检测阳性率为96. 0%,显著高于对照组的8. 0%,差异有统计学意义(P <0. 05)。不同性别和不同年龄原发性肝癌患者的血清NGF水平比较,差异无统计学意义(P> 0. 05)。肿瘤直径≥5cm患者NGF水平显著高于肿瘤直径<5cm者,高侵袭患者NGF水平显著高于低侵袭者,低分化患者NGF水平显著高于高分化者,Ⅲ～Ⅳ期患者NGF水平显著高于Ⅰ～Ⅱ期患者,差异均有统计学意义(均P <0. 05)。结论血清NGF检测可为诊断原发性肝癌患者病情提供一定的科学依据,根据血清NGF检测,可协助临床诊断肿瘤侵袭性、病理分级、临床分期以及肿瘤直径等,值得借鉴。