端粒与端粒酶研究在肺癌中的临床应用前景与挑战

肺癌是世界范围内发病率和死亡率较高的恶性肿瘤之一。端粒和端粒酶与肺癌的发生发展密切相关。虽然端粒酶可能不是导致细胞癌变的直接原因,但在维持端粒长度和肿瘤生长方面起到关键作用。包括肺癌在内的大部分肿瘤端粒长度缩短。端粒长度的变化与肺癌发生风险相关,并可能成为肺癌的治疗靶标和预测指标。针对端粒和端粒酶信号通路的靶向治疗药物正在探索中,以端粒酶抑制剂为代表的小分子药物有希望应用于肺癌的临床治疗中。但是,人们对于端粒和端粒酶的研究还远远不够,端粒长度维持的旁路作用机制可能是下一步需要深入研究的方向。     

反义端粒酶RNA对人胃癌细胞端粒长度及端粒酶活性调控的研究

 目的　探讨反义端粒酶RNA(hTR)对人胃癌细胞 端粒长度(TRF)及端粒酶活性的调控作 用。方法　应用反义hTR真核表达载体经脂质体介导转染胃癌细胞SGC7901 ,通过分子杂交及端粒重复扩增PCR方法检测hTR表达及端粒、端粒酶活性变化。结 果　经HYR筛选,转染细胞形成稳定克隆,反义hTR表达增强、正义hTR表达下调,平 均TRF缩短、端粒酶活性受抑。结论　反义hTR对胃癌细胞TRF及端粒酶活性 的调控可能是通过其对hTR模板的“封闭”而发挥作用的,反义hTR可以作为胃癌基因治疗的 一种新靶点。     

人喉鳞癌细胞端粒长度与放射敏感性的关系探讨

 目的 探讨人喉鳞癌细胞端粒长度与放射敏感性的关系,以寻求能够预测肿瘤细胞内在放射敏感性的分子标志物. 方法 体外长期传代的人喉鳞癌细胞系Hep-2经0、2、4、8、12Gy剂量照射3次后的存活后代体外培养20代,以克隆形成实验测定其放射敏感性参数SF2,用Southern-blotting法测定其端粒长度(TRF). 结果 体外长期传代的Hep-2细胞系随着受照剂量的增加, 其放射存活后代的SF2逐渐升高(P<0.05),其TRF逐渐缩短(P<0.01);而且,SF2与TRF呈现明显的正相关关系(r=0.921, P<0.01). 结论 通过不同放射剂量处理体外长期传代的人喉鳞癌细胞系可获得不同放射敏感性的细胞存活后代,且放射存活后代的放射敏感性与其细胞端粒长度具有较好的负相关关系,提示端粒长度检测有望成为预测肿瘤细胞内在放射敏感性的分子标志物.     

乳腺浸润性导管癌中PS2和GSTл的表达及临床意义

目的了解乳腺浸润性导管癌中雌激素调节蛋白(PS2)和谷胱甘肽S-转移酶π(GSTπ)的表达及其对预后和治疗的指导作用。方法用标记的链亲和素生物素(LSAB)免疫组化法对210例乳腺浸润性导管癌患者的石蜡标本进行PS2和GSTπ的检测。结果PS2的表达阳性率为49.5%,GSTπ几的表达阳性率为48.1%。术后5年和10年生存率从高到低依次为PS2表达阳性/GSTπ表达阴性组、PS2表达阳性/GSTπ表达阳性组、PS2表达阴性/GSTπ几表达阴性组和PS2表达阴性/GSTπ表达阳性组。结论PS2表达阳性/GSTπ表达阴性组患者的预后最好,PS2表达阳性/GSTπ表达阳性组和PS2表达阴性/GSTπ表达阳性组患者的预后次之,PS2表达阴性/GSTπ表达阳性组的预后最差。因此,在临床中应根据患者的情况合理应用内分泌治疗和化疗。     

Gene Expression for Suppressors of Telomerase Activity (Telomeric-repeat Binding Factors) in Breast Cancer

Mechanisms regulating telomerase activity and telomere length remain incompletely understood in human breast cancer. We therefore studied gene expression for telomeric-repeat binding factors (TRFs) in relation to telomerase activity, telomere length, and clinicopathologic factors in human breast cancer. Telomerase activity was detected in 65.8% of 38 breast cancers, but none of 16 non-cancerous samples. Terminal restriction fragments were longer in noncancerous than in cancerous tissues, but not significantly. Among 8 patients with both cancer and paired noncancerous tissue available for terminal restriction fragments length assay, terminal restriction fragments were shorter in cancers than in paired noncancerous samples in all but one. Significantly more mRNA encoding TRF1 and 2 was detected in noncancerous than in cancer tissues. Additionally, expression of TRF1 and 2 mRNA was significantly higher in cancers without detectable telomerase activity than in cancers showing activity. Expression of these genes tended to show a negative correlation with terminal restriction fragments length, but this was not statistically significant. No correlation was seen between TRF1 or 2 mRNA expression, and clinicopathologic factors except for TRF1 with respect to tumor size and progesterone receptor status. In addition to reactivation of telomerase activity, escape from negative regulation of this activity is needed to maintain telomere length during cell proliferation in breast cancer. Genes encoding telomerase inhibitors might be of value in gene therapy against human breast cancer.     

乳腺浸润性导管癌伴神经内分泌分化预后因素的分析

目的通过分析C—erbB-2、ER、PR在乳腺浸润性导管癌伴神经内分泌分化（NED）中的表达,探讨乳腺浸润性导管癌伴NED患者的预后。方法选取根据CgA和Syn免疫组织化学染色结果确诊的乳腺浸润性导管癌伴NED的病例35例（NED阳性组）和乳腺浸润性导管癌病例100例（NED阴性组）,分析比较2组C—erbB-2、ER、PR的表达及淋巴结转移情况。结果c—erbB-2、ER、PR的阳性表达率：NED阳性组分别为62．86％（22／35）、88．57％（31／35）、82．86％（29／35）;NED阴性组分别为92．00％（92／100）、71．00％（71／100）、65．00％（65／100）,2组C—erbB-2、ER、PR的阳性表达率比较差异均有统计学意义（P均〈0．05）。淋巴结转移：NED阳性组和NED阴性组分别为16例（45．71％）和40例（40．00％）,差异无统计学意义（P〉0．05）。结论乳腺浸润性导管癌伴NED与乳腺浸润性导管癌不伴NED相比,恶性程度低,预后较好。     

E-Cadherin Expression Correlates With Histologic Type But Not Tumour Grade in Invasive Breast Cancer

The traditional classification of infiltrating breast carcinomas into ductal and lobular can be diagnosticallychallenging in a small proportion of cases with equivocal histological features and in in-situ lesions withoverlapping features. Distinguishing between the infiltrating ductal (IDC) and lobular (ILC) carcinomas isclinically important because of the different pattern of systemic metastases and prognostic evaluation. E-cadherinis a potentially useful immunohistochemical marker which may serve to differentiate between the two tumourtypes. We therefore studied E-cadherin expression in 32 cases of breast carcinomas comprising 16 IDCs and 16ILCs. The correlation between E-cadherin expression and the histological grade of IDCs was also analysed. Ourresults showed complete loss of E-cadherin expression in all ILCs, while the IDCs consistently showed variableE-cadherin positivity. No significant correlation was found between E-cadherin expression and the histologicalgrade of IDCs. We conclude from this study that E-cadherin is a useful marker to differentiate between IDCand ILC of the breast. A larger study of IDCs is now needed to further evaluate the correlation between Ecadherinand tumour grade to estimate its prognostic potential.     

Significant SNPs Related to Telomere Length and Hepatocellular Carcinoma Risk in Chronic Hepatitis B Carriers

Chronic hepatitis B virus (HBV) infection increases the risk of developing cirrhosis and hepatocellular carcinoma(HCC) with suspected interactions between virus replication and host immune responses. A number of reports havesuggested that telomerase function may be involved in chronic hepatitis B (CHB) pathogenesis, but positive or negativeassociations with HCC risk remain for discussion. Mean telomere length is an indicator of biological aging and it hasbeen reported that reduction in NBV carriers compared to normal individuals. In somatic cells, telomeres containsimple, tandemly repeated G-rich sequences that frequently are reduced by 50 to 200 base pairs at each cell division.Several genome-wide association studies (GWAS) in diverse ethnic populations have revealed eleven single nucleotidepolymorphisms (SNPs) linked to telomere length. Two of these, rs398652 and rs621559, have prognostic value and couldbe used as genetic markers. This review describes current knowledge concerning telomerase activity and telomere lengthas well as significant polymorphisms in HBV-related HCC patients. In particular, to cast light on genotype-phenotypeinteractions, we used SNPnexus to evaluate effects of the two SNPs on risk of disease and complex disorders.     

Patterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer

Background

Homeostasis of telomere in breast cancer might be altered as a result of cumulative effects of various factors causing genomic instability and affecting prognosis. This study aimed to compare the relative telomere length (RTL) and hTERT mRNA expression in the tissue of patients with breast cancer along with the clinicopathologic parameters.

Telomeres and Telomerase in Lung Cancer

Protected telomeres ensure normal chromosomal segregation during mitosis but at the same time can endow genetically abnormal cancer cells with immortality. Telomerase has a pivotal role in telomere protection, both in normal and cancer cells. Understanding the functional interplay between telomere shortening and telomerase expression in cancer cells is of critical importance to elucidating the precise mechanisms by which these cells are able to bypass telomere crisis and become immortal.     

Breast Cancer Arising Adjacent to an Involuting Fibroadenoma: Serial Changes in Radiologic Features

Fibroadenoma is a common benign breast lesion and its malignant transformation is rare. There have been several case reports and studies that retrospectively reviewed breast cancers that arose within fibroadenomas; however, none of these studies reported serial changes in radiologic features of the cancer, including findings from mammography and ultrasound (US). We report a case of breast cancer arising adjacent to an involuting fibro adenoma in a 39-year-old woman who was undergoing serial follow-up after her fibroadenoma was diagnosed. Seven years after her diagnosis, the lesion showed evidence of coarse calcifications, a typical sign of involution. Four years later, US revealed a newly developed hypoechoic lesion with irregular margins and peripherally located calcifications adjacent to the fibroadenoma. A core biopsy was performed, and histopathological examination resulted in a diagnosis of invasive ductal carcinoma. When new suspicious features are observed in a fibroadenoma, radiologists should raise the concern for breast cancer and proceed with diagnosis and treatment accordingly.     

Telomerase Activity and Metastasis: Expansion of Cells Having Higher Telomerase Activity within Culture Lines and Tumor Tissues

Tumor cells with metastatie potential may have a high telomerase activity that augments telomeric DNA repeats, allowing the cells to escape from the inhibition of cell proliferation due to shortened telomeres. We examined the expression level of telomerase activity using the telomeric repeat amplification protocol among a series of cell lines obtained by repeated transplantation of a mouse fibrosarcoma. The lines could be grouped into three; one has no metastatic potential, and the other two show metastatic abilities after intravenous or subcutaneous injection. Comparison of their telomerase activity indicated that more malignant lines had higher activity. A similar relation was seen in metastatic nodules formed through clonal expansion from the heterogeneous population of inoculated cells; clonality was monitored in terms of variable patterns of subtelomeric repeats. The results suggest that a high level of telomerase activity may not be requisite for metastasis, but may confer a propensity to dominate in a tumor tissue.     

Expression of CD44 Isoforms in Infiltrating Lobular Carcinoma of the Breast

Expression of CD44 has been shown to correlate with the progression and prognosis of some malignant tumors. The aim of this study was to evaluate the expression of CD44 isoforms in infiltrating lobular carcinomas and analyse their potential as prognostic indicators. A panel of 39 tumors were examined for their expression of membranous and cytoplasmic CD44s, v3, v5, v6, v7 and v3-10 in the infiltrating cells, by immunohistochemical staining. The protein positive tumors showed membranous and/or cytoplasmic staining with all antibodies used except for CD44v7, which only displayed cytoplasmic staining. Cytoplasmic expression of CD44v3 (P=0.014) and membranous expression of v6 (P=0.039) were significantly associated with alveolar, classical/alveolar carcinomas and mucinous/alveolar carcinomas. Furthermore, in alveolar, classical/alveolar and mucinous/alveolar carcinomas, cytoplasmic staining of CD44v5 was correlated with lymph node negative patients (P=0.048), whereas membranous v5 was correlated with lymph positive patients (P=0.048). In classical, classical/trabecular and trabecular carcinomas expression of membranous CD44s was significantly correlated with lymph node status (P=0.042).     

肿瘤浸润性淋巴细胞在乳腺癌预后评估及免疫治疗中的应用进展

2020年女性乳腺癌已超越肺癌成为全球最常见的癌症,大量研究证实肿瘤浸润性淋巴细胞（TILs）对肿瘤具有杀伤力,并在识别肿瘤抗原中发挥重要作用,因此TILs在临床免疫治疗及乳腺癌预后评估中的应用受到广泛关注。本文综述了近期TILs在不同分子分型乳腺癌中的基础研究进展和临床应用现状,评估了TILs对乳腺癌预后评估及临床免疫治疗的价值。     

A Clinicopathologic Study of Breast Lumps in Bhairahwa,Nepal

Background: Various types of lesion from inflammation to carcinoma can affect the breast. Some lesions are common in young females while others are more common in elderly age group. Early presentation and prompt diagnosis is essential to relieve anxiety of non-neoplastic conditions, and in casse of carcinoma, it can save the patient from metastases. Many cases related to breast lesions from the region are reported in the surgery clinics of this institute and various breast diseases are being managed in the clinical departments. Analysis of pattern and prevalence should provide a valuable guideline for clinicians in Nepal for comparison with other countries. Methods: In the retrospective clinical study during a 9 year period, cases of breast lesions and lumps underwent fine needle aspiration cytology and Pap staining was done in alcohol fixed smears. A total of 65 doubtful cases were diagnosed through histopathological examinations by conventional methods. All those with undetermined and inconclusive material were excluded from the study. Results: In the study of total 243 cases, inflammatory conditions 22.6%, fibrocystic change 41.2%, fibroadenoma 21.8%, other benign breast disease 4.5%, gynaecomastia 2.5% and carcinoma 7.4% were detected. Conclusion: Fibrocystic change was the commonest lesion in this study with 33 years as the average age of presentation. However, malignancy was detected above 40 years of age.     

浸润性导管癌原发灶CD3和CD20的表达与临床病理及预后指标的相关性分析

目的研究CD3^+和CD20^+淋巴细胞在浸润性导管癌原发灶中的表达及其与预后的关系。方法入组100例乳腺癌患者石蜡包埋病理标本,采用免疫组化法检测浸润性导管癌原发灶中CD3^+淋巴细胞、CD20^+淋巴细胞与临床病理及预后的关系。结果 100例乳腺癌患者原发灶中,CD3^+96例(96.0%),CD20^+54例(54.0%),原发灶CD3^+淋巴细胞的百分率与临床分期、组织学分级及淋巴结转移状态有关(P<0.05)。结论乳腺癌原发灶有淋巴细胞浸润,CD3^+与病变的严重程度密切相关。     

乳腺癌患者外周血中端粒酶活性表达及其临床意义

目的：探讨端粒酶活性在乳腺癌患外周血癌细胞中的表达及其与浸润转移的关系。方法：通过用TRAP-PCR-ELISA法检测65例乳腺癌患外周血端粒酶的活性，按照肿瘤大小、分级程度、浸润情况、淋巴结有无转移来分析端粒酶与乳腺癌患生物学行为的相关性。结果：外周血中检测端粒酶活性阳性率为40．00％，低于相应的乳腺癌组织阳性率(61．54％)，乳腺癌患外周血中肿瘤细胞端粒酶相对活性的升高与患的淋巴结转移和浸润呈正相关。结论：检测患外周血中端粒酶活性可能优于检测肿瘤组织的端粒酶活性，可以对肿瘤患的病情进行实时监控，指导临床化疗。     

Shortened Telomere Length in Hepatocellular Carcinomas and Corresponding Background Liver Tissues of Patients Infected with Hepatitis Virus

The telomere length in 20 surgically resected human hepatocellular carcinomas (HCCs) and adjacent non-cancerous, livers with hepatitis virus infection were investigated. All the HCC samples examined demonstrated shorter telomere length than the corresponding non-cancerous liver tissues, the respective average values being 5.4 kbp and 8.8 kbp ( P < 0.001). The shortening of telomere length was most prominent in HCCs larger than 30 mm in diameter, and in both tumors and non-cancerous livers it was more marked with hepatitis B virus as compared with hepatitis C virus infection. These results indicate that telomere shortening is associated with not only progression, but also development of HCC, and there is a possible difference in the nature of the association in patients with hepatitis viruses of B and C types.