P13K／AKT／mTOR信号通路在乳腺癌Her-2治疗耐药中的作用研究进展

Her-2靶向治疗是Her-2过表达乳腺癌治疗的重要组成部分,但Her-2靶向治疗的耐药严重影响了乳腺癌的治疗。研究证实乳腺癌Her-2靶向治疗出现耐药的过程中有P13K／AKT／mTOR信号通路的激活,因此对P13K／AKT／mTOR信号通路及以P13K／AKT／mTOR信号通路为靶点的药物研究对乳腺癌治疗具有重要意义。     

Her-2与胃癌的分子靶向治疗

人表皮生长因子受体-2 (Her-2)是一种具有酪氨酸激酶活性的185 000的跨膜糖蛋白,在细胞分裂增殖信号跨膜转导中发挥重要功能,最终从多个途径影响肿瘤细胞的生物活动,如肿瘤细胞增殖、黏附、转移和分化等相关基因的调控.研究表明Her-2在胃癌患者中过表达率约12％～ 35％,是胃癌的预后不良因素,而Her-2单克隆...     

乳腺癌Her-2基因扩增及其蛋白表达与ER、PR的关系及临床意义

目的:探讨乳腺癌中Her-2基因及其蛋白表达状况,并研究其与ER、PR的关系及临床意义。方法:采用荧光标记原位杂交(FISH)和免疫组化法(IHC)检测45例乳腺癌组织中Her-2基因及其蛋白表达并检测ER、PR表达。实验数据采用SPSS统计软件处理。结果:在45例乳腺癌中有17例出现Her-2基因扩增,阳性率为37.7%。Her-2蛋白总阳性率为66.7%。Her-2基因阳性率在ER阳性组为32.3%,在ER阴性组为50.0%,Her-2基因阳性率在PR阳性组为27.5%,在PR阴性组为56.2%。FISH法检测Her-2基因扩增与Her-2蛋白过表达之间相关(P<0.05),而与淋巴结转移、组织学分级及ER、PR的表达无关(P>0.05)。结论:FISH检测Her-2基因扩增和免疫组化检测Her-2蛋白一致性较好,ER、PR和Her-2三者在乳腺癌的发生发展中起重要作用。     

人表皮生长因子受体2表达对腋淋巴结阳性和阴性乳腺癌患者预后的不同影响

目的 探讨人表皮生长因子受体2(Her-2)表达在腋淋巴结阳性和阴性乳腺癌患者预后中的意义.方法 采用抗Her-2单克隆抗体CB11进行免疫组化,检测981例原发性乳腺癌肿瘤组织Her-2蛋白的表达,分析其与乳腺癌预后的关系.结果 981例原发性乳腺癌Her-2蛋白的阳性表达率为19.7%(193/981),Her-2表达水平与乳腺癌患者的发病年龄、雌激素受体(ER)和孕激素受体(PR)表达状态明显相关(P<0.05).单因素分析显示,在腋淋巴结阳性的乳腺癌患者中,Her-2表达与预后显著相关,Her-2阳性者的5年无病生存(DFS)率和5年总生存(OS)率分别为48.8%和55.2%,Her-2阴性者分别为66.9%和76.4%,差异均有统计学意义(P<0.01).而在腋淋巴结阴性的患者中,Her-2表达与患者的5年DFS率和5年OS率均无显著相关性(P>0.05).多因素分析显示,在腋淋巴结阳性的乳腺癌患者中,Her-2表达水平是影响乳腺癌OS的独立因素,但不是影响乳腺癌DF5的独立因素.结论 在腋淋巴结阳性乳腺癌患者中,Her-2表达水平是重要的预后因素.     

免疫组织化学方法和荧光原位杂交技术检测胃癌组织中Her-2表达的比较

 目的　探讨不同方法检测胃癌中Her-2蛋白表达和基因表达的相关性,寻求胃癌中Her-2检测的有效手段。方法　应用免疫组织化学方法（IHC）对68例胃癌进行Her-2蛋白标记,同时采用荧光原位杂交技术（FISH）检测Her-2基因扩增的情况。 结果　68例胃癌患者中,IHC检测Her-2蛋白阳性12例（17.65 ％）,分别+++ 3例,++ 9例、+ 7例和- 49例;FISH检测Her-2基因扩增11例（16.17 %）,与IHC阳性强度相对应的FISH检测结果分别为3例（100 %）、8例（88.89 %）、0例、0例。Her-2基因扩增与Her-2蛋白表达存在相关性（P＜0.05）。结论　胃癌中存在Her-2蛋白的表达和基因扩增,Her-2蛋白在胃癌中的表达呈现明显的异质性。IHC与FISH检测胃癌Her-2的表达差异主要在IHC++组,IHC++有意愿进行Her-2基因靶向治疗的患者建议进行Her-2基因检测。     

关爱乳腺癌患者，关注Her-2指标检测--尽早检测及时治疗提高获益

乳腺癌如今已成为威胁女性健康的主要恶性肿瘤，全世界每年有100多万女性罹患乳腺癌，40多万女性死于乳腺癌。分子靶向药物治疗是乳腺癌个体化治疗的又一新的突破，目前的研究进展主要集中在针对Her-2基因（人类表皮生长因子-2），它是由原癌基因编码的Her-2受体，Her-2在调控正常细胞的生长发育和分化中起重要作用。在欧美国家，所有乳腺癌患者确诊后都会常规行Her-2指标的检测，在我国，只有2／3的患者进行了该指标的检测。     

胃癌组织Her-2/neu与TopoⅡα的表达及临床意义

目的：探讨Her-2／neu、TopoⅡα在胃癌组织中的表达及临床意义。方法：应用免疫组织化学PV-9000方法检测90例胃癌及30例正常胃组织中Her-2／neu、TopoⅡα的表达情况，分析二者的表达与临床病理特征之间的关系。结果：90例胃癌组织和30例正常胃组织中Her-2／neu阳性表达率分别为20．0％和3．3％（P〈0．05），TopoⅡα阳性表达率分别为65．6％、86．7％（P〈0．05）。胃癌组织Her-2／neu的过表达与胃癌的Lauren分型、分化程度、淋巴转移显著相关。胃癌组织中TopoⅡα阳性表达仅与肿瘤的分化程度相关。在18例Her-2／neu高表达的胃癌中有72．2％（13／18）伴有TopoⅡα的表达，在77例TopoⅡα阳性表达的组织中有16．9％（13／77）伴有Her-2／neu的过表达。结论：Her-2／neu、TopoⅡα在胃癌组织表达增高与胃癌的发生发展密切相关，联合检测Her-2／neu、TopoⅡα对于胃癌的治疗具有指导意义，也是判断预后的重要指标。     

Her-2/neu基因与放射敏感性

Her-2受体己成为一些恶性肿瘤的重要生物靶标,在恶性肿瘤的生物行为中发挥重要作用.其过度表达可能与肿瘤的放射抗拒密切相关,因此抗Her-2受体抗体可能具有放射增敏作用.抗Her-2受体抗体结合放射治疗可能为肿瘤治疗开辟新的道路.     

EGFR、Her-2和细胞周期素A在食管鳞癌中的表达

目的：探讨食管鳞癌中EGFR信号传导通路相关分子（EGFR、Her-2）及细胞周期素A的表达情况及三者之间的相互关系。方法：随机选取食管鳞癌根治术后的切除标本76例和21例癌旁正常鳞状上皮组织,应用免疫组化法检测EGFR、Her-2和细胞周期素A的表达。结果：EGFR、细胞周期素A在食管鳞癌的表达明显高于癌旁正常鳞状上皮（63.2%vs 33.3%、61.8%vs 23.8%,P〈0.05）,Her-2在食管鳞癌低表达（3.9%）,正常鳞状上皮不表达;EGFR、Her-2和细胞周期素A均与脉管累犯、淋巴结转移正相关,此外,Her-2和细胞周期素A还与肿瘤浸润深度正相关;EGFR与细胞周期素A的表达成正相关（P〈0.01）,而Her-2与EGFR及细胞周期素A表达未发现相关关系。结论：EGFR和细胞周期素A在食管鳞癌中高表达可能与食管鳞癌的发生发展有关,并有可能成为靶向治疗的靶点,而Her-2在食管鳞癌由于表达很低,有可能不是该肿瘤分子治疗的靶点。     

乳腺癌组织中Her-2和p27的表达及意义

目的探讨乳腺癌中Her-2及p27的表达及两者之间的关系。方法用免疫组化法检测232例乳腺癌标本中Her-2及p27的表达情况，并根据乳腺癌患者的临床病理学特征进行分析。结果Her-2基因阳性与病理学类型，淋巴结转移，ER阴性明显相关。p27的低表达与乳腺癌分期晚，淋巴结转移，ER阴性明显相关。Her-2阳性与p27高表达呈负相关。结论Her-2、p27及两者之间的关系在乳癌的发生发展中起重要作用。     

Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2

Recent findings indicate that tumor-associated macrophages are important drivers of tumor angiogenesis. Here, we review the essential role played by Tie2-expressing monocytes (TEM) in this phenomenon. TEMs are present in human blood and tumors and their elimination in various tumor models suppresses tumor angiogenesis. A ligand for Tie2, angiopoietin-2 (Ang-2), is produced by angiogenic tumor vessels and is a chemoattractant for TEMs. Hypoxia up-regulates Tie2 expression on TEMs and, together with Ang-2, down-regulates their antitumor functions. Learning more about the regulation of TEMs by the tumor microenvironment may yield new strategies to ablate the tumor vasculature.     

Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth

Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to protect tumor endothelial cells, the effect on tumor vasculature of high levels of exogenous Ang-2 with different levels of VEGF has not been studied in detail. Here, we report that systemic overexpression of Ang-2 leads to unexpected massive tumor vessel regression within 24 h, even without concomitant inhibition of VEGF. By impairing pericyte coverage of the tumor vasculature, Ang-2 destabilizes the tumor vascular bed while improving perfusion in surviving tumor vessels. Ang-2 overexpression transiently exacerbates tumor hypoxia without affecting ATP levels. Although sustained systemic Ang-2 overexpression does not affect tumor hypoxia and proliferation, it significantly inhibits tumor angiogenesis, promotes tumor apoptosis, and suppresses tumor growth. The similar antitumoral, antiangiogenic efficacy of systemic overexpression of Ang-2, soluble VEGF receptor-1, and the combination of both suggests that concomitant VEGF inhibition is not required for Ang-2-induced tumor vessel regression and growth delay. This study shows the important roles of Ang-2-induced pericyte dropout during tumor vessel regression. It also reveals that elevated Ang-2 levels have profound pleiotropic effects on tumor vessel structure, perfusion, oxygenation, and apoptosis.     

Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism

Understanding tumor-specific metabolism under hypoxia is important to find novel targets for antitumor drug design. Here we found that tumor cells expressed higher levels of cytosolic acetyl-CoA synthetase (ACSS2) under hypoxia than normoxia. Knockdown of ACSS2 by RNA interference (RNAi) in tumor cells enhanced tumor cell death under long-term hypoxia in vitro . Our data also demonstrated that the ACSS2 suppression slowed tumor growth in vivo . These findings showed that ACSS2 plays a significant role in tumor cell survival under hypoxia and that ACSS2 would be a potential target for tumor treatment. Furthermore, we found that tumor cells excreted acetate and the quantity increased under hypoxia: the pattern of acetate excretion followed the expression pattern of ACSS2. Additionally, the ACSS2 knockdown led to a corresponding reduction in the acetate excretion in tumor cells. These results mean that ACSS2 can conduct the reverse reaction from acetyl-CoA to acetate in tumor cells, which indicates that ACSS2 is a bi-directional enzyme in tumor cells and that ACSS2 might play a buffering role in tumor acetyl-CoA/acetate metabolism. ( Cancer Sci 2009; 100: 821–827)     

Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium

It is well known that tumor-derived proangiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of "angiocrine" signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function, has been proposed, yet remains underinvestigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor data sets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal.     

Bcl-2 determines susceptibility to induction of lung cancer by oncogenic CRaf

The efficiency of tumor induction by oncogenes is influenced by modifier genes that determine individual susceptibility. We have used a transgenic mouse model to examine the role of a candidate susceptibility gene, bcl-2, for development of Raf oncogene-induced lung adenomas. Loss of bcl-2 greatly retarded tumor development without affecting tumor phenotype. Tumor tissues from bcl-2 positive and negative mice were compared for the fraction of S phase cells by staining for proliferating cell nuclear antigen and for the fraction of apoptotic cells by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. The data indicate that the increased tumor latency in the absence of bcl-2 results primarily from an increased apoptotic rate but also involves a decrease in tumor cell proliferation. Both effects can be rescued by breeding with H2K-bcl-2 transgenic mice demonstrating that loss of bcl-2 was the major genetic factor determining tumor resistance. These findings suggest that bcl-2 is a major susceptibility gene for development of lung cancer in mice and perhaps in humans.     

Absence of PPP2R1A mutations in Wilms tumor

Evidence from genetic linkage analysis indicates that a gene located at 19q13.4, FWT2, is responsible for predisposition to Wilms tumor in many Wilms tumor families. This region has also been implicated in the etiology of sporadic Wilms tumor through loss of heterozygosity analyses. The PPP2R1A gene, encoding the alpha isoform of the heterotrimeric serine/threonine protein phosphatase 2A (PP2A), is located within the FWT2 candidate region and is altered in breast and lung carcinomas. PPP2R1B, encoding the beta isoform, is mutated in lung, colon, and breast cancers. These findings suggested that both PPP2R1A and PPP2R1B may be tumor suppressor genes. Additionally, PP2A is important in fetal kidney growth and differentiation and has an expression pattern similar to that of the Wilms tumor suppressor gene WT1. Since PPP2R1A was therefore a compelling candidate for the FWT2 gene, we analysed the coding region of PPP2R1A in DNA and RNA samples from affected members of four Wilms tumor families and 30 sporadic tumors and identified no mutations in PPP2R1A in any of these 34 samples. We conclude that PPP2R1A is not the 19q familial Wilms tumor gene and that mutation of PPP2R1A is not a common event in the etiology of sporadic Wilms tumor.     

Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis

Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.     

HIF prolyl hydroxylase-2 inhibition diminishes tumor growth through matrix metalloproteinase-induced TGFβ activation

A right amount of oxygen and nutrients is essential for a tumor to develop. The role of oxygen dependent pathways and their regulators is therefore of utmost importance although little is known about the detailed impact they can have. Recently we have shown that inhibition of the oxygen sensor PHD2 in tumor cells blocks tumor growth due to the anti-proliferative activity of TGFβ. In this study, we refined these results by comparing different shPHD2 sequences in depth in the early phase of tumor growth. Our findings also reveal an intriguing role for MMP2 and MT1MMP in these settings, as these activated proteases display an anti-proliferative characteristic through the activation of downstream TGFβ targets. In conclusion, PHD2 inhibition is essential for the regulation of the anti-tumoral activity in mouse tumor cells and might bring some new insight in our understanding of tumor growth inhibition.     

LZTS2抑癌基因与肿瘤相关性的研究进展

亮氨酸拉链肿瘤抑制因子2（leucine zipper tumor suppressor 2,LZTS2）是一种新的肿瘤抑制基因,近年受到越来越多的关注。目前许多研究表明,LZTS2与多种肿瘤的发生和细胞异常增殖等多个环节密切相关,是重要的候选肿瘤抑制基因,可为肿瘤的治疗提供新的思路。