细胞凋亡,增殖状态及bcl—2,Bax基因表达与大肠癌的预后

探讨大肠组织原位凋亡及其抑制或促进基因ｂｃｌ－２及Ｂａｘ有砂水平与肿瘤生物学行为及预后的关系。方法用脱氧核酸末端转移酶介导的ＴＵＮＥＬ法缺口末端标记技术和组化方法，检测７７例大肠癌组织细胞的原位凋亡，原位增殖及ｂｃｌ－２、Ｂａｘ基因蛋白表达。结果大肠癌组织中ＡＩ与ＫＩ相关，有随肿瘤的进展趋势；ｂｃｌ－２在高分化癌和早期癌中高表达：Ｃｏｘ模型多因素分析结果表明，ＫＩ指数及ｂｘｌ－２可作为临床和早期癌     

Apoptosis in prostate cancer: Bax correlation with stage

BACKGROUND: Dysregulation of apoptosis may contribute to the process of prostate tumorigenesis by reducing the rate of cell death. Bcl-2 and bax are important molecules involved in the regulation of apoptosis. The aim of the present study is to examine apoptosis and related regulatory molecular markers in a group of Iranian patients with prostate cancer. METHODS: Paraffin-embedded tissues from 50 patients of prostate carcinoma were examined for the expression of bcl-2 antiapoptotic and bax proapoptotic markers and also proliferation marker, Ki-67, by immunohistochemistry. Detection of apoptotic cells was performed using TUNEL method. Correlation between apoptotic index, proliferation index and bcl-2 and bax expression with stage, pathological grade and Gleason score was determined. RESULTS: Apoptosis was detected in 12% of prostate cancers. No correlation was observed between apoptosis and differentiation status of carcinoma. Bcl-2 expression was detected in 21 of samples. A significant correlation between bcl-2 expression and Ki-67 staining index (r = 0.349, P = 0.012) was observed. High bax protein expression was shown in our study. We found a significant correlation between bax expression and stage of carcinoma (r = 0.388, P = 0.031), but not with the apoptosis index, suggesting the presence of a non-functional bax protein or the role of other proapoptotic molecules. CONCLUSION: The patients in the present study showed a different pattern of apoptosis positivity compared to other reports. Bax expression may be a useful marker for prognosis of prostate cancer.     

Bax基因表达在胰腺癌组织细胞凋亡中的作用

目的:探讨胰腺癌组织中细胞凋亡与bax基因表达的相互关系及其在肿瘤发生发展中作用。方法：采用原位末端标记法（ISEL）和免疫组织化学技术检测40例胰腺癌组织及14例慢性胰腺炎组织的细胞凋亡（AI），凋亡相关基因bax蛋白的表达。结果：胰腺癌组织中的AI均值明显高于慢性胰腺炎组织（P＜0．01），随肿瘤进展AI逐渐减少。在癌组织中bax 基因阳性表达率为72．50％（29／40），且bax基因高表达组的AI均值明显高于低表达组（P＜0．01）。结论：细胞凋亡相对减少，在胰腺癌发生发展中起重要作用。bax蛋白是调节胰腺癌组织中细胞凋亡的重要因素。     

肾细胞癌中bcl-2、p53、增殖细胞核抗原表达与细胞增殖和凋亡

目的 探讨肾细胞癌(RCC)中bcl—2、p53、增殖细胞核抗原(PCNA)表达与细胞增殖、凋亡及病理参数之间的关系。方法 应用链霉亲和素辣根过氧化物酶(SABC)法分析34例RCC标本中bcl—2、p53和PCNA蛋白的表达，应用末端脱氧核苷酸转移酶介导的脱氧三磷酸尿苷苦(dUTP)缺口末端标记(TUNEL)法检测细胞凋亡。结果 34例RCC标本中，15(44．1％)例bcl-2阳性表达，表达阳性率与增殖指数(PI)、凋亡指数(AI）及RCC病理学参数无关；仅有3例p53表达阳性；PI为6．0％--24．0％(平均为12．3％)，AI为2．0％--8．0％(平均为5．4％)；PI与肿瘤分级、分期密切关系，AI与肿瘤分级有明显关系。结论 明显增高的PI和AI与肿瘤恶性表型有关，提示在RCC中肿瘤细胞过度增殖伴有频繁的凋亡发生。     

生长抑素抑制人结肠癌细胞增殖的实验研究

目的：研究外源性生长激素（GH）和生长抑素（SS）对人结肠癌细胞株HT-29的影响，并探讨其作用机制。方法：人结肠癌细胞株HT-29分成正常对照组、生长抑素组（SS组）、生长激素组（GH组）和生长抑素＋生长激素组（GH＋SS组）。MTT法测定细胞抑制率，流式细胞仪测定细胞周期分布、增殖指数、凋亡率，RT—PCR方法测定bcl．2及baxmRNA水平。结果：生长抑素能够明显抑制人结肠癌细胞株HT-29增殖（P〈0．01）、降低S期和G2／M期细胞比例（P〈0．05）、降低增殖指数（PI）（P〈0．05）、促进细胞凋亡（P〈0．01）、降低bcl-2mRNA表达（P〈0．05）、提高baxmRNA表达（P〈0．01），生长激素则无明显作用。GH＋SS组表现与SS组相似。结论：生长抑素可能通过抑制GdG．期细胞进入S期和G2／M期以及促进细胞凋亡两种途径抑制体外培养的人结肠癌细胞株HT-29增殖。生长抑素可能是通过改变bax基因和bcl-2基因的表达影响肿瘤细胞的凋亡。生长激素对体外培养的人结肠癌细胞株HT-29无显著影响。     

Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients?

BACKGROUND: Although the status of the axillary lymph nodes is widely accepted to be associated with prognosis in breast cancer patients, there is a need for biomarkers to be analyzed as indicators of responsiveness to treatment. The objective of this study was to test the hypothesis that the expression of apoptosis genes, bcl-2 and bax, predicts survival and responsiveness to chemotherapy in node-negative breast cancer patients. METHODS: One hundred thirty premenopausal women with primary breast carcinoma were studied for the expression of bcl-2 and bax genes. The relationship between the expression of bcl-2 and bax proteins and a series of markers of known prognostic value [such as tumor size, nuclear grade, receptors of the steroid hormones estrogen (ER) and progesterone (PgR)].The association of these proteins with survival and responsiveness to chemotherapy was also examined. RESULTS: Sixty (46%) and sixty-four (49%) breast cancer cases were found positive for bcl-2 and bax, respectively, as indicated by immunohistochemistry. A statistically significant association was found between expression of bcl-2 and tumor size (P = 0.001), low grade (grade I) (P = 0.002), positivity of ER (P = 0.001), positivity of PR (P = 0.03), and superior disease-free survival (DFS) (P = 0.04), and superior overall survival (OS) (P = 0.03). In contrast, no similar associations were observed for the bax gene. Overall, there was a trend toward an association between adjuvant chemotherapy and DFS (P = 0.08) and OS (P = 0.07). This trend became statistically significant when the patients were analyzed by individual gene expression. In bax-positive patients, chemotherapy improves 6-year DFS (P = 0.01) and OS (P = 0.03) while similar effects were not observed in the other subgroups of patients. CONCLUSION: Our results indicated that bcl-2 expression is associated with a number of favorable prognostic factors and better clinical outcome, while bax expression seems to have positive predictive value for responsiveness to chemotherapy in lymph node-negative breast cancer patients.     

Cell proliferation, apoptosis, angiogenesis and growth rate of incidentally found renal cell carcinoma

BACKGROUND: Our previous study showed that the growth rate of incidentally found renal cell carcinoma (RCC) varied, and that the initial clinical and pathological features did not predict subsequent growth of the carcinoma. The objective of this study was to determine the relationships between cell proliferation, apoptosis, angiogenesis and the growth rates of these RCC. METHODS: We examined cell proliferation, apoptosis, and angiogenesis in 16 incidentally found cases of RCC. Cell proliferation was assessed by immunohistochemical staining with a Ki-67 antibody. Apoptosis was assessed by the terminal deoxynucleotidyl transferase (TdT) mediated deoxy-UTP biotin nick end labeling (TUNEL) technique. The Ki-67 labeling index (KI) and the apoptotic index (AI) were determined as the ratio of immunohistochemically positive cells per 1000 cancer cells. The KI/AI ratio was also determined. Angiogenesis was evaluated by CD34 immunostaining. Finally, we investigated the correlation between these parameters and the growth rate of primary lesions of incidentally found RCC. RESULTS: The KI ranged from 7 to 73 (median, 20), AI ranged from 6 to 171 (median, 26), and microvessel density (MVD) ranged from 21 to 673 (median, 265) for incidentally found RCC. Ki-67 labeling index, AI and MVD were not closely correlated to each other. Furthermore, these parameters were not associated with growth rates of incidentally found RCC. Only the KI/AI ratio was strongly correlated to the growth rate of incidentally found RCC (r = 0.709; P = 0.0083). CONCLUSION: Our results suggest that the balance between cell proliferation and apoptosis partly determines the growth rate of primary lesions of incidentally found RCC.     

凋亡相关基因 bcl-2、bax、bad与乳腺癌

目的探讨乳腺癌发生、发展过程中bcl-2、bax及bad基因表达水平变化及与乳腺癌其他生物因素的相关性。方法复习国内、外相关文献并进行综述。结果在从正常乳腺组织到乳腺癌逐渐演化的过程中凋亡抑制基因bcl-2的表达水平变化尚有待进一步研究,而凋亡促进基因bax、bad的表达水平呈递减趋势。bcl-2基因表达水平与乳腺癌中一些公认的正性因子如雌激素受体(ER)、孕激素受体(PR)呈正相关,与其他一些负性因子如p53、表皮生长因子受体、c-erbB-2、腋窝淋巴结转移情况等呈负相关。bax基因的表达水平与乳腺癌ER、PR水平以及p53表达水平等无关。对于bad基因与乳腺癌其他生物因素的相关性尚未见报道。结论乳腺癌中bcl-2基因表达水平的变化对乳腺癌预后以及治疗的作用尚存在争议,bad基因与乳腺癌预后的关系亦不清楚,而bax基因表达水平与乳腺癌的预后呈正相关。对于它们的研究将为我们评价乳腺癌的预后提供新的指标,为乳腺癌的治疗开辟新的思路。     

The potential role of bcl-2, bax, and Ki67 expression in thymus of patients with myasthenia gravis, and their correlation with clinicopathologic parameters.

OBJECTIVE: The aim of this study was to evaluate bcl-2, bax (apoptotic-oncoproteins), and Ki67 (cell proliferation-marker) expression in thymus of patients with myasthenia gravis (MG) and to determine the potential correlation with clinicopathologic parameters. METHODS: The study was done on 38 patients (16 males, 22 females; mean age 38+/-10 years) with MG who underwent modified maximal thymectomy (MMT). Clinical staging (Osserman classification) included stage I in three, IIA in 19, IIB in 13 and III in three. Microscopic examination of thymus showed thymic hyperplasia in 19, atrophy in eight, thymoma in nine and thymic carcinoma in two. On paraffin sections, the streptavidin-biotin technique, using antibodies to bcl-2, bax, and Ki67, was employed, and in situ hybridization with digoxigenin-labeled probes to bcl-2 and bax was performed. In addition, the apoptotic body index (ABI) was assessed via the TUNEL method. Staining results were correlated with clinicopathologic parameters. RESULTS: Bcl-2 expression was higher in hyperplasia and thymoma cases, compared to thymic carcinomas (P<0.001). Higher expression in carcinomas, compared to hyperplasia and thymomas, was observed for bax (P<0.001), Ki67 (P<0.001) and ABI (P<0.001). Statistical analysis demonstrated: (A) positive correlation of bax+ cells with MG stage (P<0.001), ABI and %Ki67+ cells with MG stage (P<0.001, respectively), %Ki67+ and %bax+ cells with ABI (P<0.05); and (B) reverse correlation between %bcl-2+ cells and MG stage (P<0.05). CONCLUSIONS: In patients with MG who underwent MMT, bcl-2, bax, and Ki67 expression correlates positively or reversibly with the microscopic findings of thymus. Increased apoptosis and proliferation accompany advanced disease stage and possible worse prognosis.     

Racial differences in prostate cancer growth: apoptosis and cell proliferation in Caucasian and African-American patients

BACKGROUND: Epidemiologic evidence reveals striking racial differences in incidence and clinical behavior of prostate cancer among American men. In this study, we assessed the incidence of apoptosis and cell proliferation in prostate cancer specimens from African-American and Caucasian patients in an attempt to identify potential differences in tumor growth determinants between the two ethnic groups. METHODS: Apoptosis and cell proliferation were analyzed in archival paraffin-embedded prostatic tumors from 44 African-American and 35 Caucasian age-matched men who underwent radical prostatectomy for localized prostate cancer. Both groups had comparable preoperative prostate-specific antigen (PSA) levels, clinical stage, and Gleason scores, and neither group of patients received neoadjuvant therapy prior to surgery. Apoptotic status in prostate tumors was evaluated in situ, using the transferase deoxyuridine end labeling (TUNEL) assay, and the expression profile of two apoptotic proteins, bcl-2 and bax. The proliferative index was determined on the basis of Ki-67 antigen immunoreactivity. RESULTS: Apoptosis in malignant prostate cells was significantly higher in African American than Caucasian men (11.6% vs. 4.2%, P < 0. 001). Interestingly, the rate of cell proliferation of prostate tumor cells was similar in the two ethnic groups (4.5% and 4.2%). The antiapoptotic protein bcl-2 was detected at significantly higher levels in tumors from Caucasian than African-American patients (40. 8% vs. 31.6%, P < 0.05). Expression of bax, the apoptosis promoter, was consistently high among tumor epithelial cells in specimens from both racial groups (68%). CONCLUSIONS: These findings provide a novel insight into the molecular determinants of tumor growth that may underlie the ethnic differences in prostate cancer incidence and clinical behavior. Downregulation of bcl-2 expression may be potentially responsible for the loss of apoptotic control in prostate tumors from African-American men. This study may have significant clinical implications in the development of novel diagnostic approaches for biologically aggressive prostate cancer from diverse racial origin.     

5-氟尿嘧啶诱导直肠癌HR8348细胞凋亡作用的研究

目的　探讨 5 氟尿嘧啶 (5 fluorouracil ,5 FU )体外诱导直肠癌HR83 48细胞凋亡的作用及细胞凋亡与bcl 2、bcl xl、bax及 p5 3表达的关系。 方法　经 5 FU处理HR83 48细胞 2 4h后 ,用甲基绿 派若宁染色法和TUNEL法检测细胞凋亡情况 ,并用SP免疫组织化学法检测HR83 48细胞中bcl 2、bcl xl、bax和 p5 3的表达。 结果　HR83 48细胞经 5 FU作用 2 4h后 ,细胞凋亡指数 (AI)明显高于对照组 ,差异有显著性意义 (P<0 .0 1)。 5 FU作用不同时相bcl 2的表达评分结果与对照组比较差异均无显著性意义 ;不同时相bcl xl的表达评分结果与对照组比较稍降低 ;而bax的表达评分结果随时间延长明显增加 ,2 4h、3 6h的表达评分结果明显高于对照组 (P<0 .0 1) ,而 p5 3在 5 FU组和对照组各时相均未见表达。结论　 5 FU具有诱导HR83 48细胞凋亡的作用 ;5 FU可能通过上调bax的表达并改变bax/bcl xl的比值而诱导HR83 48细胞凋亡。     

结直肠癌组织中胃泌素的表达与Fas／FasL和天冬半胱氨酸蛋白酶的关系

目的了解胃泌素（GAS）mRNA及其蛋白在结直肠癌组织中的表达情况，并探讨其与结直肠癌细胞凋亡指数（AT）和凋亡调控基因Fas／FasL、天冬半胱氨酸蛋白酶（easpases）的关系。方法采用巢式RT-PCR方法检测79例结直肠癌组织中GAS的mRNA表达．用TUNEL法检测细胞凋亡情况，结直肠癌组织中GAS、Fas／FasL、caspase-3、caspase-8的蛋白表达采用免疫组织化学SP法。结果结直肠癌组织中GASmRNA与其蛋白表达呈正相关（rGAS=0．99，P〈0．01）．高、中分化结直肠癌组织中GASmRNA及其蛋白的表达明显低于低分化者（χ^2，（高与低）=10．47、10．23，均P〈0．01；χ^2（中与低）=6．68、4．95，均P〈0．05）；GASmRNA及其蛋白在乳头状腺癌、管状腺癌的阳性表达率明显低于黏液印戒细胞癌及未分化癌（χ^2（乳与黏印）=4．80、6．22，χ^2（乳与未）=5．44、8．43，χ^2（管与黏印）=4．40、4．38．χ^2（管与未）=4．92、6．43，均P〈0．05）；DukesA、B期的GASmRNA及其蛋白阳性表达率明显低于C、D期（χ^2=4．84、4．45，均P〈0．05）。GAS高、中表达组的细胞AI明显低于低表达组，差异有统计学意义（q（高与低）=6．71，q（中与低）=4．60，均P〈0．01）；FasL阳性表达率在GAS低、中、高表达3组间相比。差异具统计学意义（χ^2=9．35，P〈0．011，其中FasL在GAS高、中表达组的阳性表达率明显高于低表达组（χ^2（高与低）=6．24．χ^2（中与低）=4．74，均P〈0．05）：结论GAS对结直肠癌细胞凋亡的调控可能与Fas／FasL的表达失衡及其功能和信号系统的紊乱有关。GAS的检测可作为临床结直肠癌生物学行为的评估指标之一．     

Expression of vascular endothelial growth factor and receptor flk-1 in colon cancer liver metastases

Background/Purpose This study investigated vascular endothelial growth factor (VEGF) and flk-1 expression in hepatic metastases from colon carcinoma, and their associations with tumor angiogenesis, proliferation, and apoptosis.Methods Immunohistochemical studies were performed for VEGF/flk-1, Ki-67, p53, and bcl-2 expression, and microvessel density (MVD) in surgical specimens from 35 patients who underwent hepatectomy for colon cancer liver metastases between 1986 and 2001.Results VEGF and flk-1 were expressed mainly in the cytoplasm of tumor cells. High VEGF expression was associated with high flk-1 expression (P = 0.043). MVDs of less than 15 and 15 or more were found in 5 (14.3%) and 30 (85.7%) of 35 hepatic metastases, respectively. A Ki-67 index (KI) of 50% or more was detected in 33/35 (94.3%) of tumors, and 23 of these (65.7%) showed a KI of 85% or more. A KI of less than 50% was present in 2/35 (5.7%) of tumors. The expression of VEGF/flk-1 was related to elevated MVD (P 0.026). VEGF was also associated with an increased KI (P = 0.025). Mutant p53 and bcl-2 expressions were detected in 26/35 (74.3%) and 17/35 (48.6%) of liver metastases, respectively. Mutant p53 was not related to VEGF/flk-1 expression, but bcl-2 was highly associated with flk-1 (P = 0.007). The incidences of high flk-1 expression and a KI of 85% or more were significantly higher in tumors which were both p53- and bcl-2-positive (93.3% and 73.3%) than in tumors which were negative for both (42.9% and 14.3%; P 0.021).Conclusions The VEGF-flk-1 system takes part in tumor angiogenesis, proliferation, and apoptosis in colon liver metastases. The bcl-2 pathway may upregulate VEGF activity via the flk-1 receptor. These findings are preliminary, requiring a larger sampling in order to elucidate the role of VEGF/flk-1 in metastatic colon cancer.Presented at the 89th Annual Clinical Congress of the American College of Surgeons, Chicago, IL, USA, October 19–23, 2003.     

胃泌素调节胆管癌细胞凋亡的初步研究

目的探讨胃泌素 (gastrin)对胆管癌细胞凋亡的调节及机理。方法用TUNEL技术和定量RT PCR分别检测胃泌素 17(G 17)对QBC939人胆管癌细胞系白僵菌素诱发性凋亡指数 (AI)和bcl 2 /baxmRNA表达的影响 ,用反义寡核苷酸技术研究bcl 2基因在胃泌素调节细胞凋亡中的作用。结果与对照组比较 ,G 17组AI降低、bcl 2mRNA表达增强 (P <0 0 1) ,baxmRNA无变化 ;胃泌素受体拮抗剂L36 5 ,2 6 0 (L6 0 )可拮抗G 17对AI和bcl 2mRNA表达的影响 (P <0 0 1) ;反义bcl 2寡核苷酸转染可逆转G 17对AI的抑制 (P <0 0 1) ,正义和随机片段无作用。结论胃泌素能提高凋亡阈值、抑制胆管癌细胞凋亡 ,其机理与上调bcl 2表达有关     

术前介入动脉化疗对胰腺癌细胞凋亡和细胞增殖的影响

目的检测术前选择性介入动脉化疗对胰腺癌细胞凋亡和细胞增殖的作用,探讨区域性化疗抑制胰腺癌生长的分子机制.方法采用原位末端标记法(ISEL)对32例术前行介入化疗和未化疗的胰腺癌患者的病理切片进行细胞凋亡指数和增殖指数的检测,同时测定细胞凋亡调控基因bcl-2和bax的表达水平.结果(1)术前介入化疗组胰腺癌细胞凋亡率比未介入化疗组明显增高,两组的细胞凋亡率分别为(46.89±26.46)和(5.67±2.43)(P＜0.01);而细胞增殖指数(PCNA)在术前介入化疗组与非化疗组之间无显著差异(P＞0.05).(2)肿瘤细胞凋亡率与组织类型有关,高分化腺癌中的细胞凋亡率比低分化腺癌高(P＜0.05).(3)术前介入化疗组bcl-2表达率低于未介入化疗组,bax表达率高于未介入化疗组(P＜0.05).结论术前选择性的动脉介入化疗能够诱导胰腺细胞凋亡,诱导细胞凋亡是抑制胰腺癌细胞的生长重要途径.     

米非司酮诱导雄激素非依赖性前列腺癌细胞凋亡的实验研究

目的探讨米非司酮在体外诱导雄激素非依赖性前列腺癌DU-145、PC-3细胞凋亡的作用。方法采用四甲基偶氮唑蓝法检测1,10,50和100μmol／L米非司酮作用于前列腺癌DU-145、PC-3细胞24～120h的吸光度（A）值,用流式细胞仪检测10μmol／L米非司酮作用24和48h后DU．145、PC-3细胞凋亡率的变化;采用免疫组化法检测米非司酮作用DU-145、PC．3细胞后bax、bcl-2、血管内皮生长因子（VEGF）蛋白表达的变化。结果1μmol／L米非司酮组的A值与对照组相比,差异无统计学意义（P〉0．05）;10,50和100μmol／L米非司酮组的A值与对照组比较,差异有统计学意义（P〈0．01）;米非司酮对前列腺癌DU-145、PC-3细胞的抑制作用呈时间-剂量依赖性。10μmol／L米非司酮作用前列腺癌DU-145细胞24和48h的凋亡率分别为15．3％和30．4％,PC-3细胞的凋亡率分别为22．2％和32．0％。经10μmol／L米非司酮作用后,DU-145、PC-3细胞中VEGF和bcl-2蛋白的表达明显减少,而bax的表达显著增加（P〈0．05）。结论米非司酮以时间．剂量依赖性方式抑制激素非依赖性前列腺癌DU-145和Pc-3细胞的增殖,其作用可能是通过降低VEGF蛋白的表达。从而下调bcl-2、激活bax蛋白的表达来实现。     

Differential expression of bcl-2 family proteins in bladder carcinomas. Relationship with apoptotic rate and survival

OBJECTIVE: To elucidate the role of various bcl-2 family molecules in the regulation of apoptosis and the progression of urothelial cancer, in relation to standard prognosticators. METHODS: Paraffin-embedded archival tissue from 103 N0M0 consecutive patients with invasive bladder cancer (28 T1, 57 T2, 13 T3 and 5 T4) was immunostained for bcl-2, bax, bcl-XL, bcl-Xs, p53, Ki-67 and with an anti-single stranded DNA monoclonal antibody recognizing the apoptotic cells. Survival analysis was restricted to T2-T4 tumours. Patients were followed-up until death (n = 27) or for a mean (+/- S.D.) follow-up of 37.6 (+/- 17.4) months. Within this period, 39 patients relapsed after a mean (+/- S.D.) period of 13.6 (+/- 12.3) months. RESULTS: Most tumours were immunoreactive for bax (73.1%) and bcl-XL (80.9%) whereas bcl-2 and bcl-XS expression was comparatively less common (44.4 and 28.9%, respectively). The bcl-XL and bcl-XS positivity was related to high grade (P = 0.007) and advanced stage (P = 0.010), respectively. On the contrary, bax and bcl-2 positivity was unrelated to stage or grade. Apoptotic rate was independently influenced only by p53, bcl-2 and proliferation rate. In multivariate analysis of T2-T4 urothelial carcinomas (UC)s, only bax along with T-category and age were the significant predictors of disease-free survival. Increased apoptosis and T-category were also independently related to the overall survival in T2-T4 UCs. CONCLUSIONS: The expression of bcl-2 family members appears to be differentially regulated in association with UC evolution. Most importantly, bax immunostaining offers additional information to that provided by traditional prognosticators, with regard to disease-free survival of T2-T4 UCs.     

Bisphosphonate induces apoptosis and inhibits pro-osteoclastic gene expression in prostate cancer cells

AIM: Bisphosphonates are well established for the management of cancer-induced skeletal complications. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors. METHODS: PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed. RESULTS: The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells. CONCLUSIONS: Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.     

Molecular markers in breast cancer: can we use c-erbB-2, p53, bcl-2 and bax gene expression as prognostic factors?

We examined the prognostic value of c-erbB-2, p53, bcl-2 and bax overexpression in breast cancer. Immunostaining for c-erbB-2, p53, bcl-2 and bax gene expression was performed on 121 paraffin-embedded specimens of Stage I, II and III breast cancer patients diagnosed and treated in Hippokration Hospital, Athens Medical School, between 1986 and 1992. The primary tumor from 27 (24.1%), 69 (59%), 18 (15%) and 63 (53.4%) patients stained positively for c-erbB-2, p53, bcl-2 and bax gene expression, respectively. Significant correlations were found between bax overexpression and age (P=0.04), tumor size (P=0.02) and disease stage (P=0.001), while no other significant associations were found between other molecular markers and clinical or histological parameters. None of the individual molecular markers examined proved to be independent prognostic factor for patients with breast carcinoma. C-erbB-2, p53, bcl-2 and bax genes have limited prognostic value. An approach that combines several molecular markers with established clinicopathological criteria may help physicians make more accurate predictions of prognosis in patients with breast cancer.     

应用半巢式PCR检测大肠癌组织及患者粪便中bcl-2基因的重排

目的研究大肠癌中bcl－2基因重排的规律，探讨通过粪便途径的基因诊断筛查大肠癌的可行性。方法应用半巢式PCR技术检测28例大肠癌患者癌组织及粪便中bcl－2基因重排。结果28例大肠癌组织标本中24例（85．7％）检出bcl－2重排，粪便中检出17例bcl－2重排，其癌组织标本中bcl－2均有重排。癌组织中bcl－2基因重排在大肠癌早期即已出现，随着病程演变，这种异常表现增多趋势。结论bcl-2基因参与大肠癌发生发展的调节，并在大肠癌细胞的增殖、进展及转移中起一定作用。存在基因异常的癌细胞的绝大多数能够通过粪便标本得以检出。bcl－2半巢式PCR灵敏、特异，具有实际应用价值。