SPARC蛋白在胃癌中的表达及与胃癌预后的关系

目的 探讨富含半胱氨酸(Cys)的酸性分泌蛋白(SPARC蛋白)在胃腺癌组织中的表达及与胃腺癌患者预后的关系。方法 免疫组化法检测104例胃腺癌组织和30例癌旁组织中SPARC蛋白的表达差异,并应用统计学的方法分析SPARC蛋白与胃腺癌患者预后的关系。结果 SPARC蛋白在30例癌旁胃黏膜组织中阳性率为20%(6/30),且均为弱表达或无表达,在104例胃腺癌组织中阳性率为76.1%(79/104),二者差异有统计学意义(P＜0.01)。胃腺癌组织中,SPARC蛋白表达高低与淋巴结转移及组织分化程度呈正相关(P＜0.05);SPARC蛋白高表达的胃腺癌患者平均生存时间为27.4个月,明显低于低表达者的40.9个月(P＜0.05)。结论 SPARC蛋白在胃腺癌组织中高表达,且主要表达于胃腺癌细胞周围的间质中;其与淋巴结转移及组织分化程度显著相关;SPARC蛋白高表达的胃腺癌患者生存期短,预后差,但SPARC蛋白不是其独立的预后因素。     

胃癌化疗的现状

胃癌是人类第二位常见恶性肿瘤,同时胃癌是消化道肿瘤中对化疗较为敏感的一种,因此化疗已成为胃癌综合治疗中必不可少的重要组成部分。作者通过阅读相关文献,现就胃癌化疗的现状加以综述。     

胃癌的生物化疗

胃癌（Gastric carcinoma）具有明显的地域性，尤其是东亚三国（日本、韩国和中国）为高发区，约占全球总数的2／3，近年来发病率略呈下降趋势。可是在我国，胃癌仍高居各种恶性肿瘤之首。     

SPARC在胃癌发生机制中作用的研究进展北大核心CSCD

富含半胱氨酸的酸性分泌蛋白(secreted protein,acidic and rich in cysteine,SPARC)作为一种细胞外基质糖蛋白,能够调节细胞和基质之间的相互作用,与多种恶性肿瘤的发生发展相关,且具有组织特异性。SPARC在胃癌组织中的表达,高于正常胃黏膜组织且主要定位于胃癌间质细胞;而在大多数胃癌细胞系中,内源性SPARC呈现表达抑制或缺失状态。SPARC对胃癌的侵袭、转移、血管新生等存在负性调节的作用,而对于增殖的影响目前尚无一致性结论。此外,SPARC启动子Cp G岛甲基化在胃癌中较普遍。本文对SPARC在胃癌多种生物学行为方面的作用机制进行综述,旨在总结SPARC在胃癌发生发展中的作用,为胃癌早期诊断和靶向治疗提供新思路。     

血清标志物对晚期胃癌化疗疗效的预测价值

目的　探索晚期胃癌患者血清中可以预测化疗疗效的标志物。方法　共选取４２例初治晚期胃腺癌患者,采用ＤＣＦ方案（多西他赛＋顺铂＋氟尿嘧啶）一线化疗。于治疗开始前以及每２周期结束后抽取外周静脉血,直至出现进展或不可耐受的副反应。ＥＬＩＳＡ法检测患者血清中人富含半胱氨酸的酸性分泌蛋白（ＳＰＡＲＣ）、Ｄｉｃｋｋｏｐｆ１（ＤＫＫ- １）以及人血管内皮生长因子（ＶＥＧＦ）的蛋白表达水平。结果　血清中ＳＰＡＲＣ蛋白的差异表达出现在敏感组和原发耐药组患者间,ＶＥＧＦ蛋白的差异表达出现在敏感组患者化疗前后以及原发耐药患者化疗前后。各组间未观察到ＤＫＫ-１水平的显著差异。结论　胃癌患者血清中ＳＰＡＲＣ水平可以作为ＤＣＦ方案化疗疗效的预测指标,ＶＥＧＦ水平的变化与化疗疗效有关。     

胃癌的辅助化疗

胃癌病变局限在粘膜层或粘膜下层者术后 5年生存率为 95 %～ 98% ;病变侵及肌层者 ,术后 5年生存率为 40 %～ 5 0 % ,而病变侵及浆膜或以外者 ,术后 5年生存则仅 0 %～ 1 0 % ,所以胃癌的辅助化疗占有重要的位置。1　术后辅助化疗胃癌切除术后 ,根据病变侵犯深度及有否淋巴结转移 ,或术中所见肿瘤情况 ,决定术后是否进行辅助化疗。病变局限于粘膜或粘膜下层 ,淋巴结无转移者 ,术后定期观察 ,不作化疗 ;病变侵及肌层或肌层以外 ,术后常规辅助化疗 ;无论病变侵犯深度如何 ,凡淋巴结有转移的 ,术后应常规行辅助化疗 ;尽管已行根治术 ,但有潜在…     

区域化疗对中晚期胃癌的疗效

目的　探讨区域化疗对中晚期胃癌的疗效。方法　 5 2例中晚期胃癌 :2 7例手术配合术中及术后早期区域化疗 ,术后全身静脉化疗 ;2 5例手术后配合全身静脉化疗。结果　区域化疗组 5年复发转移率 5 1 9% ,5年生存率 44 4% ;对照组分别为 92 0 %、16 0 % ,有统计学意义。结论　区域化疗能明显降低中晚期胃癌的复发转移率 ,提高生存率 ,是治疗中晚期胃癌的有利措施     

喉鳞癌组织中SPARC基因的差异表达

 目的 探讨富含半胱氨酸的酸性蛋白（SPARC）在喉鳞癌的增殖、侵润和转移中的作用及指导意义。方法 用半定量逆转录-聚合酶链反应（RT-PCR）分析SPARC在不同的喉鳞癌组织和其相邻的正常粘膜组织的差异表达量。利用免疫组化技术研究SPARC在喉鳞癌组织和其相邻的正常粘膜组织的表达差异,同时对蛋白表达进行定位。结果 RT-PCR分析SPARC在20对配对标本中的表达,在其中16对喉鳞癌组织中的表达明显高于其相应的正常粘膜组织,在4对中差异表达不明显,R=80.0%（有差异的例数/总例数）。免疫组化技术分析了30对配对喉鳞癌手术标本的石蜡切片（肿瘤组织和正常粘膜组织）,其中25对SPARC蛋白在癌巢细胞中的表达高于相邻的正常粘膜组织,5例在癌巢细胞中和相邻的正常粘膜组织内表达不明显,R=83.3%。同时对SPARC蛋白在不同分化程度的喉癌组织中的表达进行分析,发现SPARC在中低分化喉癌中的表达与高分化喉癌无显著差异（P〉0.05）。而在有淋巴结转移的喉癌的表达比无淋巴结转移的高（P=0.036）。细胞核和细胞浆均有表达。结论 通过mRNA和蛋白水平分析得出,SPARC和喉鳞癌的发生密切相关,喉鳞癌淋巴结转移时SPARC表达升高。     

腹腔内温热灌注化疗对胃癌根治术后胃癌干细胞的影响

目的探讨腹腔内温热灌注化疗对胃癌根治术后胃癌干细胞的影响。方法选择胃癌患者80例,分为2组,各40例。对照组完成胃癌根治术,术毕常规实施DC方案化疗;观察组术后使用腹腔内温热灌注治疗。比较2组患者治疗前及治疗后3年CD44+情况,统计2组3年生存率,并分析2组治疗后相关并发症。结果治疗前2组CD44+比率差异无统计学意义(P>0.05),治疗后观察组CD44+比率显著低于对照组(P<0.05);观察组1年、2年及3年的生存率均显著高于对照组(P<0.05)。2组治疗期间腹腔脓肿、肠道损伤、吻合口瘘和粘连肠梗阻的发生率差异无统计学意义(P>0.05)。结论腹腔内温热化疗对于杀灭或抑制胃癌干细胞具有积极意义,其在不增加术后并发症的同时,能有效延长患者生存时间,值得临床推广。     

区域化疗对中晚期胃癌的疗效

目的 探讨区域化疗对中晚期胃癌的疗效。方法 52例中晚期胃癌；27例手术配合术中及术后早期区域化疗，术后全身静脉化疗；25例手术后配合全身静脉化疗。结果 区域化疗组5年复发转移率51.9%。5年生存率44.4%；对照组分别为92.0%,16.0%，有统计学意义。结论 区域化疗能明显降低中晚期胃癌的复发转移率，提高生存率，是治疗中晚期胃癌的有利措施。     

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

Background:

Secreted protein acidic and rich in cysteine (SPARC), a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix and is capable of altering the growth of various cancers. We therefore sought to determine the effect of SPARC expression on medulloblastoma tumour growth and angiogenesis.

Methods:

To this extent, we selected three SPARC full-length cDNA overexpressed clones (Daoy-SP). Consequences of SPARC overexpression were studied in terms of cell growth, angiogenesis using co-culture assay in vitro, dorsal skin-fold chamber assay in vivo, PCR Array for human angiogenic genes, as well as western blotting for angiogenic molecules and tumour growth, in an orthotopic tumour model.

Results:

The SPARC protein and mRNA levels were increased by approximately three-fold in Daoy-SP cells compared with parental (Daoy-P) and vector (Daoy-EV) controls. Daoy-SP clones reduced tumour cell-induced angiogenesis in vitro and in vivo, and formed small tumours with fewer blood vessels when compared with controls. Matrix metalloprotease-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression were decreased in Daoy-SP clones. Further, inhibition of MMP-9 expression caused SPARC-mediated inhibition of angiogenesis and tumour growth as MMP-9 rescued SPARC-mediated anti-angiogenic effect in vitro and tumour growth inhibition in vivo.

Conclusion:

Overexpression of SPARC decreases angiogenesis, which leads to decreased tumour growth. Further, the role of MMP-9 could be attributed to the anti-angiogenic effect of SPARC.     

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma

Background:

We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM).

Methods:

Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts.

Results:

Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC.

Conclusions:

Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.     

Expression of secreted protein acidic and rich in cysteine (SPARC) in breast cancer and response to neoadjuvant chemotherapy

BackgroundSecreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types.Patients and methodsWe evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS).ResultsAn increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036).ConclusionsSPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel.Clinical trial numberNCT00544765.     

富含半胱氨酸的酸性分泌蛋白与肿瘤相关性研究进展

目的:总结富含半胱氨酸的酸性分泌蛋白(SPARC)在肿瘤发生发展中的作用和对肿瘤信号传导通路的调节功能.方法:应用NCBI的PubMed全文数据库检索系统和CNKI检索系统,以“SPARC、侵袭、凋亡、血管形成和信号传导”为关键词,检索1995-01-2011-12相关文献352篇.纳入标准:1)SPARC;2)肿瘤;3)信号传导通路,包括MAPK、ILK和FAK信号通路;4)血管生成与侵袭.根据纳入标准分析32篇文献.结果:SPARC是一种在机体内广泛分布的小分子酸性糖蛋白,在肿瘤组织中肿瘤细胞和宿主细胞都有表达和分泌.SPARC功能非常复杂且具有组织特异性,肿瘤组织中的SPARC能够调节基质细胞和肿瘤细胞的功能,能够通过对肿瘤细胞表面的整合素的影响而激活ILK、FAK、AKT和MAPK等下游通路,从而最终调控肿瘤的生长和侵袭.结论:SPARC对不同肿瘤的生长、侵袭、血管形成和信号通路以不同的方式发挥重要影响,对SPARC的深入研究,将为不同肿瘤治疗提供新的策略和方法.     

Knockdown of secreted protein acidic and rich in cysteine (SPARC) expression diminishes radiosensitivity of glioma cells

Secreted protein acidic and rich in cysteine (SPARC) has been shown to play an important role in the promotion of glioma. In this study, we investigated the effects of downregulated SPARC expression on the radiosensitivity of human glioma U-87MG cells and its possible mechanism. With a small-interfering RNA (siRNA) expression plasmid vector targeting SPARC, we obtained the stably transfected cells in which the expression of SPARC was successfully downregulated. Then, the cells were irradiated with 60Co-γ-rays and analyzed by several methods, such as clonogenic assay, flow cytometry, comet assay, and western blotting. Clonogenic assay showed that downregulation of SPARC expression enhanced cell survival after radiation. Flow cytometry analysis indicated that SPARCsiRNA decreased cell apoptosis responding to irradiation. Analysis of signaling molecules with western blotting showed that the level of Akt phosphorylation was increased in irradiated U-87MG/SPARCsiRNA cells. Further, cell-cycle analysis by flow cytometry showed enhanced G2 accumulation in U-87MG/SPARCsiRNA cells after irradiation. Comet assay revealed that SPARCsiRNA promoted the repair of radiation-induced DNA damage. Our results suggest that inhibition of SPARC expression may diminish the radiosensitivity of human glioma U-87MG cells. One of the mechanisms for this effect may be associated with the reduced cell apoptosis responding to radiation, which may be contributed by the phosphoinositide 3-kinase/AKT pathway activation. Moreover, enhanced G2 accumulation and increased DNA repair may also account for the decreased radiosensitivity.     

Silencing of secreted protein acidic and rich in cysteine inhibits the growth of human melanoma cells with G1 arrest induction

The overexpression of secreted protein acidic and rich in cysteine (SPARC) is associated with increased aggressiveness and poor prognosis in malignant melanoma. Its roles and underlying mechanisms on melanoma cell growth, however, are not fully clarified. To validate the potential of SPARC as a therapeutic target, we examined the effect of the knockdown of SPARC with SPARC‐specific siRNA on the growth of human melanoma cell lines. SPARC siRNAs exerted a potent knockdown effect. Silencing of SPARC resulted in growth inhibition with G₁ arrest accompanied by accumulation of p21, a G₁ cyclin‐dependent kinase inhibitor, in MeWo and CRL1579 cells. Moreover, the induction of p53 was observed in MeWo cells, but not in CRL1579 cells. Conditioned media containing SPARC from MeWo cells could not restore the growth of SPARC‐silenced MeWo cells. This result suggests that intracellular SPARC, but not secreted SPARC, is involved in cell proliferation. In addition, silencing of SPARC induced apoptosis in MeWo and CRL1579 cells. Furthermore, when MeWo cells in which SPARC expression was transiently knocked down by SPARC siRNA were implanted in nude mice, the tumor growth was suppressed. Our findings suggest that SPARC contributes to cell growth and could be a potential target molecule for melanoma therapy. (Cancer Sci 2010; 101: 913–919)     

胃癌的辅助治疗与新辅助治疗

胃癌是全世界范围内的常见肿瘤.约40%的胃癌患者可行根治术,但术后复发或远处转移率高.为提高胃癌根治术的机会,改善患者生存,以手术为主的多学科综合治疗一直是研究热点,但东西方国家在治疗模式、化疗方案选择和治疗结果等方面存在差异.