HDAC抑制剂抗肿瘤效应靶基因的研究
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摘要
目的
通过建立一种全新的、基于基因功能的筛选手段——SMART(Suppression ofMortality by Antisense Rescue Technique)技术，寻找抵抗HDAC抑制剂诱导肿瘤细胞凋亡的效应基因并初步探讨其作用机制。
方法
250 nmol／LTSA诱导乳腺癌细胞MCF-7凋亡，并收集处于凋亡不同时段的细胞提取mRNA，构建反义cDNA文库。文库DNA随机转入HeLa细胞中，筛选出阳性转染细胞克隆，存活克隆经扩增后提取Hirt DNA，转化感受态细菌并测序。经生物信息学分析后选择感兴趣的基因进行功能验证，并进一步探讨其作用机制。
结果
成功构建反义cDNA文库，片段插入率大于90％，平均长度约为1．5kb，库容约为2×10~5；运用NCBI blast比对获得76个EST片段；再次重复筛选验证，选定LIV-1基因进行进一步研究。实验显示，HDAC抑制剂可以选择性诱导肿瘤细胞中LIV-1基因的表达，平板克隆形成实验、MTT实验和FACS检测凋亡实验显示下调LIV-1表达可以抵抗HDAC抑制剂诱导的细胞凋亡，这一效应可能与封闭LIV-1后肿瘤细胞内锌离子稳态被破坏有关。
结论
SMART技术作为一种基于基因功能的筛选手段，可以高通量、特异性的获得在HDAC抑制剂诱发细胞凋亡过程中的效应基因；基因LIV-1可能是HDAC抑制剂抗肿瘤效应的靶基因，下调LIV-1表达可抵抗HDAC抑制剂诱导肿瘤细胞凋亡，这一效应可能与封闭LIV-1后肿瘤细胞内锌离子稳态被破坏有关。
背景和目的
研究表明，在HDAC抑制剂的作用下，细胞中占总数17％的基因转录水平会发生变化。如此广泛的作用靶点使得HDAC抑制剂在启动某些治疗性反应的同时也启动了某些意想不到的保护性程序，后者严重影响到HDAC抑制剂的最佳临床疗效。目前临床上由于HDAC抑制剂单药用药治疗效能较低，仅被作为辅助用药，与一些传统的一线化疗药联用，达到增强疗效的目的。因此，揭示其低效能背后暗藏的分子机制对推动该类治疗性药物的临床应用具有重要意义。方法和结果
通过cDNA芯片分析，我们发现HDAC抑制剂作用后细胞内大量粘附分子表达上调，其中以粘附分子CDl46的上调最为显著。以CD146为代表，通过Realtime PCR、Western blot和免疫组化等方法证实了，在HDAC抑制剂的作用下，多种肿瘤细胞系、原代肿瘤细胞和动物体内CD146被明显上调。将CDl46的单克隆抗体与HDAC抑制剂联用显著增强了HDAC抑制剂的促进凋亡和抑制血管生成的作用，从而抑制肿瘤恶性生长与转移。其作用机制可能与下调PI3K/AKT／mTOR通路的活性有关。结论
HDAC抑制剂单药用药治疗效能较低的原因可能是由肿瘤细胞中粘附分子表达增高引起，将粘附分子的单抗与HDAC抑制剂联用可以增强HDAC抑制剂抗肿瘤的生物学效应。这些临床前期研究提示抗粘附剂的使用将对提高HDAC抑制剂效能有很大帮助，为今后的临床治疗提供了一种新的思路和策略。
Objective
To construct a noval functional-screening-based method--- SMART (Suppression ofMortality by Antisense Rescue Technique) for the screening of target genes responsible forHDAC inhibitor induced apoptosis and explore the mechanism underlying the action of thegenes.
Methods
To confirm the time course of apoptosis in MCF-7 induced by different concentrationsof Trichostatin A.To induce apoptosis in MCF-7 by treated with 250 nM Trichostatin A.mRNA were extracted from cells collected at multiple time-points after Trichostatin Atreatment.cDNA were synthesized and inserted reversely into plasmid pCEP4 to constrctan anti-sense cDNA library.Library DNA was transfected randomly into Hela,positivetransfected cell clones were screened by Trichostatin A and Hygromycin B.Screening wasstoped when all control cells were died.Surviving cell clones then were amplified andplasmids DNA in cells were acquired by the method of Hirt DNA Extraction.Insertedsequences were then sequenced and EST fragments were obtained.The data were analyzedby the method ofbioinformatics and functional identification.
Results
Apoptosis of MCF-7 induced by Trichostatin A started at 36 hours later after drugtreatment and climaxed at about 72 hours.Antisense cDNA library was constructed formcells treated with Trichostatin A within 48 hours at multiple time-points.Insert efficiencywas about 90%,average inserted fragment was about 15 kb and the volum of library wasabout 4×10~5.Library plasmid DNA were transfected into Hela,after two rounds ofscreening,several cell clones that showed an anti-apoptosis activity were formed.Theseclones were amplified and Hirt DNA was extracted.76 EST fragments were obtained bysequencing.After bioinformatics analysis and functional identification,we acquiredLIV-lgene.Further study showed that these genes knockdown in tumor cell lines couldresist HDACI induced apoptosis,which is caused,at least in part,by disruption ofintracellular zinc homeostasis.
Conclusions
SMART cDNA library with high quantity and quality based on HDAC inhibitorinducing apoptosis was successfully constructed;LIV1 gene may be one of the essentialgenes with anti-tumor effects on apoptosis induced by HDAC inhibitors;down-regulationof LIV1 is capable of conferring a significant resistance to HDACi-induced cell death intumor cells,which is caused,at least in part,by disruption of intracellular zinc homeostasis.
Evidence for a protective role of CD146 in SAHA-inducederadication of tumor
Introduction
Histone deacetylase inhibitors (HDACi) show promise as a novel class of anticanceragents with potent activity to inhibit proliferation,induce apoptosis and differentiation in awide spectrum of tumors.At least 14 HDACi are being tested in over 100 clinical trials anddisplay encouraging therapeutic response with surprisingly good safety profiles~(1,2).Theclinical potential of HDACi has been well exemplified by the successful development ofVorinostat (suberoylanilide hydroxamic acid,SAHA),which has recently been approved bythe US Food and Drug Administration for treating cutaneous T-cell lymphoma~3.However,despite the rapid clinical progress achieved,the mechanisms of action of HDACi are not yetwell understood.Early studies using gene profiling techniques have revealed that up to 17%of all known genes are affected by HDACi at the transcriptional level~4.A large number ofpro- or anti-apoptotic genes and cell cycle regulatory genes have been independentlyidentified by different groups as the downstream targets to HDACi.In addition to HDACs,many non-histone proteins are also regulated by HDACi including transcription factors,nuclear import proteins,signal transduction molecules,cytoskeletal proteins and DNArepair enzymes~4.One of the central problems with respect to the action of HDACi is thatmodulation of such extensive substrates by these agents might result in the initiation of boththerapeutic responses and unanticipated protective procedures,which significantly limitsthe optimal application of this class of drugs.Identification of the potential protectivesubstrates in HDACi-induced eradication of tumors would set critical biomarkers andfacilitates development of novel HDACi.
Recently,a set of clinical data show that there is limited efficacy for HDACi as asingle agent.For example,patients with MDS and AML have had biologic responsesfollowing HDACi therapy;however,true PRs or CRs are infrequent~2.The majority of thenew trials are combination studies looking at HDACi in combination with other agents~(5,6)Two PhaseⅠstudies demonstrated that the combination of SAHA with conventionalchemotherapeutic agents such as carboplatin/paclitaxel and FOLFOX regimen (fluorouracil, leucovorin and oxaliplatin) displayed synergistic effect in the treatment of advanced solidmalignancies~(7,8).Three PhaseⅠ/Ⅱtrials combining HDACi (PB or VPA) with thedemethylating agents of 5-azacytidine or decitabine in patients with AML and MDSshowed both tolerability and promising efficacy~(9-11).Similarly,synergism has also beenobserved between HDACi and other agents such as all-trans-retinoic acid,proteasomeinhibitor,HSP90 antagonists,tyrosine kinase inhibitors and so on~(12-15).All of thesecombination trials seek to increase the tumoricidal impact.However,although thesecombination strategies follow a rational molecular approach in some cases;in most cases,they are relatively empirical.Furthermore,unfortunately,synergism in efficacy might beaccompanied by adverse effects that are rarely or never seen with HDACi alone such asmyelosuppression~6.And high-dose HDACi with substantially longer half-lives show ahigher toxicity that precludes daily treatment~(16).Therefore,revealing the molecularmechanisms underlying the low potency of HDACi is pivotal to develop potentially lesstoxic and more effective treatments and promote the optimal application of this class oftherapeutic drugs.
In this study we analyzed the HDACi-induced expression pattern using cDNAmicroarrays and confirmed that many of adhesion molecules could be significantlyup-regulated.Interestingly,among these inducible adhesion molecules,CD146 expressionlevel was the highest.To further elucidate whether the increased expression levels ofadhesion molecules influenced HDACi activity we took CD146 for example investigatingthe therapeutic effects of combined treatment with CD146 mAb and HDACi onangiogenesis,tumor growth and metastasis.
通过建立一种全新的、基于基因功能的筛选手段——SMART(Suppression ofMortality by Antisense Rescue Technique)技术，寻找抵抗HDAC抑制剂诱导肿瘤细胞凋亡的效应基因并初步探讨其作用机制。
方法
250 nmol／LTSA诱导乳腺癌细胞MCF-7凋亡，并收集处于凋亡不同时段的细胞提取mRNA，构建反义cDNA文库。文库DNA随机转入HeLa细胞中，筛选出阳性转染细胞克隆，存活克隆经扩增后提取Hirt DNA，转化感受态细菌并测序。经生物信息学分析后选择感兴趣的基因进行功能验证，并进一步探讨其作用机制。
结果
成功构建反义cDNA文库，片段插入率大于90％，平均长度约为1．5kb，库容约为2×10~5；运用NCBI blast比对获得76个EST片段；再次重复筛选验证，选定LIV-1基因进行进一步研究。实验显示，HDAC抑制剂可以选择性诱导肿瘤细胞中LIV-1基因的表达，平板克隆形成实验、MTT实验和FACS检测凋亡实验显示下调LIV-1表达可以抵抗HDAC抑制剂诱导的细胞凋亡，这一效应可能与封闭LIV-1后肿瘤细胞内锌离子稳态被破坏有关。
结论
SMART技术作为一种基于基因功能的筛选手段，可以高通量、特异性的获得在HDAC抑制剂诱发细胞凋亡过程中的效应基因；基因LIV-1可能是HDAC抑制剂抗肿瘤效应的靶基因，下调LIV-1表达可抵抗HDAC抑制剂诱导肿瘤细胞凋亡，这一效应可能与封闭LIV-1后肿瘤细胞内锌离子稳态被破坏有关。
背景和目的
研究表明，在HDAC抑制剂的作用下，细胞中占总数17％的基因转录水平会发生变化。如此广泛的作用靶点使得HDAC抑制剂在启动某些治疗性反应的同时也启动了某些意想不到的保护性程序，后者严重影响到HDAC抑制剂的最佳临床疗效。目前临床上由于HDAC抑制剂单药用药治疗效能较低，仅被作为辅助用药，与一些传统的一线化疗药联用，达到增强疗效的目的。因此，揭示其低效能背后暗藏的分子机制对推动该类治疗性药物的临床应用具有重要意义。方法和结果
通过cDNA芯片分析，我们发现HDAC抑制剂作用后细胞内大量粘附分子表达上调，其中以粘附分子CDl46的上调最为显著。以CD146为代表，通过Realtime PCR、Western blot和免疫组化等方法证实了，在HDAC抑制剂的作用下，多种肿瘤细胞系、原代肿瘤细胞和动物体内CD146被明显上调。将CDl46的单克隆抗体与HDAC抑制剂联用显著增强了HDAC抑制剂的促进凋亡和抑制血管生成的作用，从而抑制肿瘤恶性生长与转移。其作用机制可能与下调PI3K/AKT／mTOR通路的活性有关。结论
HDAC抑制剂单药用药治疗效能较低的原因可能是由肿瘤细胞中粘附分子表达增高引起，将粘附分子的单抗与HDAC抑制剂联用可以增强HDAC抑制剂抗肿瘤的生物学效应。这些临床前期研究提示抗粘附剂的使用将对提高HDAC抑制剂效能有很大帮助，为今后的临床治疗提供了一种新的思路和策略。
Objective
To construct a noval functional-screening-based method--- SMART (Suppression ofMortality by Antisense Rescue Technique) for the screening of target genes responsible forHDAC inhibitor induced apoptosis and explore the mechanism underlying the action of thegenes.
Methods
To confirm the time course of apoptosis in MCF-7 induced by different concentrationsof Trichostatin A.To induce apoptosis in MCF-7 by treated with 250 nM Trichostatin A.mRNA were extracted from cells collected at multiple time-points after Trichostatin Atreatment.cDNA were synthesized and inserted reversely into plasmid pCEP4 to constrctan anti-sense cDNA library.Library DNA was transfected randomly into Hela,positivetransfected cell clones were screened by Trichostatin A and Hygromycin B.Screening wasstoped when all control cells were died.Surviving cell clones then were amplified andplasmids DNA in cells were acquired by the method of Hirt DNA Extraction.Insertedsequences were then sequenced and EST fragments were obtained.The data were analyzedby the method ofbioinformatics and functional identification.
Results
Apoptosis of MCF-7 induced by Trichostatin A started at 36 hours later after drugtreatment and climaxed at about 72 hours.Antisense cDNA library was constructed formcells treated with Trichostatin A within 48 hours at multiple time-points.Insert efficiencywas about 90%,average inserted fragment was about 15 kb and the volum of library wasabout 4×10~5.Library plasmid DNA were transfected into Hela,after two rounds ofscreening,several cell clones that showed an anti-apoptosis activity were formed.Theseclones were amplified and Hirt DNA was extracted.76 EST fragments were obtained bysequencing.After bioinformatics analysis and functional identification,we acquiredLIV-lgene.Further study showed that these genes knockdown in tumor cell lines couldresist HDACI induced apoptosis,which is caused,at least in part,by disruption ofintracellular zinc homeostasis.
Conclusions
SMART cDNA library with high quantity and quality based on HDAC inhibitorinducing apoptosis was successfully constructed;LIV1 gene may be one of the essentialgenes with anti-tumor effects on apoptosis induced by HDAC inhibitors;down-regulationof LIV1 is capable of conferring a significant resistance to HDACi-induced cell death intumor cells,which is caused,at least in part,by disruption of intracellular zinc homeostasis.
Evidence for a protective role of CD146 in SAHA-inducederadication of tumor
Introduction
Histone deacetylase inhibitors (HDACi) show promise as a novel class of anticanceragents with potent activity to inhibit proliferation,induce apoptosis and differentiation in awide spectrum of tumors.At least 14 HDACi are being tested in over 100 clinical trials anddisplay encouraging therapeutic response with surprisingly good safety profiles~(1,2).Theclinical potential of HDACi has been well exemplified by the successful development ofVorinostat (suberoylanilide hydroxamic acid,SAHA),which has recently been approved bythe US Food and Drug Administration for treating cutaneous T-cell lymphoma~3.However,despite the rapid clinical progress achieved,the mechanisms of action of HDACi are not yetwell understood.Early studies using gene profiling techniques have revealed that up to 17%of all known genes are affected by HDACi at the transcriptional level~4.A large number ofpro- or anti-apoptotic genes and cell cycle regulatory genes have been independentlyidentified by different groups as the downstream targets to HDACi.In addition to HDACs,many non-histone proteins are also regulated by HDACi including transcription factors,nuclear import proteins,signal transduction molecules,cytoskeletal proteins and DNArepair enzymes~4.One of the central problems with respect to the action of HDACi is thatmodulation of such extensive substrates by these agents might result in the initiation of boththerapeutic responses and unanticipated protective procedures,which significantly limitsthe optimal application of this class of drugs.Identification of the potential protectivesubstrates in HDACi-induced eradication of tumors would set critical biomarkers andfacilitates development of novel HDACi.
Recently,a set of clinical data show that there is limited efficacy for HDACi as asingle agent.For example,patients with MDS and AML have had biologic responsesfollowing HDACi therapy;however,true PRs or CRs are infrequent~2.The majority of thenew trials are combination studies looking at HDACi in combination with other agents~(5,6)Two PhaseⅠstudies demonstrated that the combination of SAHA with conventionalchemotherapeutic agents such as carboplatin/paclitaxel and FOLFOX regimen (fluorouracil, leucovorin and oxaliplatin) displayed synergistic effect in the treatment of advanced solidmalignancies~(7,8).Three PhaseⅠ/Ⅱtrials combining HDACi (PB or VPA) with thedemethylating agents of 5-azacytidine or decitabine in patients with AML and MDSshowed both tolerability and promising efficacy~(9-11).Similarly,synergism has also beenobserved between HDACi and other agents such as all-trans-retinoic acid,proteasomeinhibitor,HSP90 antagonists,tyrosine kinase inhibitors and so on~(12-15).All of thesecombination trials seek to increase the tumoricidal impact.However,although thesecombination strategies follow a rational molecular approach in some cases;in most cases,they are relatively empirical.Furthermore,unfortunately,synergism in efficacy might beaccompanied by adverse effects that are rarely or never seen with HDACi alone such asmyelosuppression~6.And high-dose HDACi with substantially longer half-lives show ahigher toxicity that precludes daily treatment~(16).Therefore,revealing the molecularmechanisms underlying the low potency of HDACi is pivotal to develop potentially lesstoxic and more effective treatments and promote the optimal application of this class oftherapeutic drugs.
In this study we analyzed the HDACi-induced expression pattern using cDNAmicroarrays and confirmed that many of adhesion molecules could be significantlyup-regulated.Interestingly,among these inducible adhesion molecules,CD146 expressionlevel was the highest.To further elucidate whether the increased expression levels ofadhesion molecules influenced HDACi activity we took CD146 for example investigatingthe therapeutic effects of combined treatment with CD146 mAb and HDACi onangiogenesis,tumor growth and metastasis.
引文
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1. Bolden JE PM, Johnstone RW. Anticancer activities of histone deacetylase inhibitors.Nature Reviews Drug Discovery. 2006;5:769-784.
2. Marchion D MP. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7:583-598.
3. Marks PA BR. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnology. 2007;25:84-90.
4. Lindemann RK GB, Johnstone RW. Histone-Deacetylase Inhibitors for the treatment of cancer. Cell Cycle. 2004;3:779-788.
5. Saverio Minucci PGP. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer Nature Reviews Cancer. 2006;6:38-51.
6. Walid K Rasheed RWJ, H Miles Prince. Histone deacetylase inhibitors in cancer therapy. Expert Opin Investig Drugs. 2007; 16:659-678.
7. Ramalingam S PR, Egorin MJ, et al. Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin (Cb) and paclitaxel (P) for patients with advanced solid malignancies (NCI 6922). J Clin Oncol. 2006;24:2077.
8. Fakih MG PL, Toth K, et al. A Phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC). J Clin Oncol. 2006;24:3592.
9. Gore SD BS, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361-6369.
10. Maslak P CS, Camacho, LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia. 2006;20:212-217.
11. Garciamanero G KH, Sanchezgozalez B, et al. Phase Ⅰ/Ⅱ study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. 108.2006;10:3271-3279.
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13. Catley L WE, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and a-tubulin hyeracetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006; 108:3441-3449.
14. Rahmani M YC, Dai Y, et al. Coadministration of the heat shock protein 90 antagonist 17-allylamino-17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res.2003;63:8420-8427.
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16. Ryan QCea. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912-3922.
1. Bolden JE PM, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nature Reviews Drug Discovery. 2006;5:769-784.
2. Marchion D MP. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7:583-598.
3. Marks PA BR. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnology. 2007;25:84-90.
4. Saverio Minucci PGP. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews Cancer. 2006;6:38-51.
5. Walid K Rasheed RWJ, H Miles Prince. Histone deacetylase inhibitors in cancer therapy. Expert Opin Investig Drugs. 2007; 16:659-678.
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17. Jianfeng Zhou QG, Gang Chen, Xiaoyuan Huang, Yunping Lu, Kanyan Li, Daxing Xie,Liang Zhuang, Jingniu Deng, and DingMa. Novel Oncolytic Adenovirus Selectively Targets Tumor-Associated Polo-Like Kinase land Tumor Cell Viability. Clin Cancer Res. 2005; 11:8431-8440.
18. R MVA. Angiogenesis in the mouse cornea. Science. 1979;205:1416-1418.
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20. Taylor KMN, R. I. The LZT proteins; the LIV-1 subfamily of zinc transporters.Biochim Biophys Acta Biomembr. 2003;1611:16-30.
21. RQCe. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor,in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912-3922.
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1. Bolden JE PM, Johnstone RW. Anticancer activities of histone deacetylase inhibitors.Nature Reviews Drug Discovery. 2006;5:769-784.
2. Marchion D MP. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7:583-598.
3. Marks PA BR. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnology. 2007;25:84-90.
4. Lindemann RK GB, Johnstone RW. Histone-Deacetylase Inhibitors for the treatment of cancer. Cell Cycle. 2004;3:779-788.
5. Saverio Minucci PGP. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer Nature Reviews Cancer. 2006;6:38-51.
6. Walid K Rasheed RWJ, H Miles Prince. Histone deacetylase inhibitors in cancer therapy. Expert Opin Investig Drugs. 2007; 16:659-678.
7. Ramalingam S PR, Egorin MJ, et al. Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin (Cb) and paclitaxel (P) for patients with advanced solid malignancies (NCI 6922). J Clin Oncol. 2006;24:2077.
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16. Ryan QCea. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912-3922.
1. Bolden JE PM, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nature Reviews Drug Discovery. 2006;5:769-784.
2. Marchion D MP. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7:583-598.
3. Marks PA BR. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnology. 2007;25:84-90.
4. Saverio Minucci PGP. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews Cancer. 2006;6:38-51.
5. Walid K Rasheed RWJ, H Miles Prince. Histone deacetylase inhibitors in cancer therapy. Expert Opin Investig Drugs. 2007; 16:659-678.
6. Ryan QCea. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912-3922.
7. Robert M Lafrenie CAB, Mary A Bewick. Cell adhesion and cancer: is there a potential for therapeutic intervention? Expert Opin Ther Targets. 2007;11:727-731.
8. Cavallaro U CG. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer.Nat Rev Cancer. 2004;4:118-132.
9. Aplin AE HA, Juliano RL. Cell adhesion molecules, signal transduction and cell growth. Curr Opin Cell Biol.1999;11:737-744.
10. Kobayashi H BK, Lin PC. Endothelial cell adhesion molecules and cancer progression.Curr Med Chem. 2007;14:377-386.
11. Nissen LJ CR, Hedlund EM, Wang Z, Zhao X, Wetterskog D, Funa K, Brakenhielm E,Cao Y. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest. 2007; 117:2762-2765.
12. Hood JD CD. Role of integrins in cell invasion and migration. Nat Rev Cancer.2002;2:91-100.
13. Rabascio C ME, Mancuso P. Assessing Tumor Angiogenesis: Increased Circulating VE-Cadherin RNA in Patients with Cancer Indicates Viability of Circulating Endothelial Cells. Cancer Res. 2004;64:4373-4377.
14. Xiyun Yan YL, Dongling Yang, Yi Shen, Mei Yuan, Zhiqiang Zhang, Peiyu Li,Hongtian Xia, Li Li, Dandan Luo, Qin Liu, Karlheinz Mann, and Bernhard L. Bader. A novel anti-CD 146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood. 2003; 102:184-191.
15. National Center for Biotechnology Information. GenBank database.http://www.ncbi.nlm.nih.gov/ entrez. Accessed January 12.
16. Tabe Y KM, Contractor R, Munsell M,Schober WD,Jin L,Tsutsumi Ishii Y,Nagaoka I,Igari J,Andreeff M. Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells.. Blood. 2006; 107:1546-1554.
17. Jianfeng Zhou QG, Gang Chen, Xiaoyuan Huang, Yunping Lu, Kanyan Li, Daxing Xie,Liang Zhuang, Jingniu Deng, and DingMa. Novel Oncolytic Adenovirus Selectively Targets Tumor-Associated Polo-Like Kinase land Tumor Cell Viability. Clin Cancer Res. 2005; 11:8431-8440.
18. R MVA. Angiogenesis in the mouse cornea. Science. 1979;205:1416-1418.
19. Taylor KM MH, Johnson A, Hadley LJ and Nicholson RI. Structure-function analysis of LIV-1,the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J. 2003;375:51-59.
20. Taylor KMN, R. I. The LZT proteins; the LIV-1 subfamily of zinc transporters.Biochim Biophys Acta Biomembr. 2003;1611:16-30.
21. RQCe. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor,in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912-3922.
22. Xie S LM, Huang S, Gutman M, Reich R, Johnson JP, Bar-Eli M. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res. 1997;57:2295-2303.
23. Ostmeier H FB, Otto F, Mawick R, Lippold A, Krieg V, Suter L. Prognostic immunohistochemical markers of primary human melanomas. Br J Dermatol.2001;145:203-209.
24. MC LKSVJMCRM. Expression and distribution of MUC18 in human uveal melanoma.Virchows Arch. 2007;45:967-976.
25. Wu GJ VV, Wu MW, Wang SW, Qu P, Yang H, Petros JA, Lim SD, Amin MB.Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues. Prostate. 2001 ;48:305-315.
26. Wu GJ WM, Wang SW, Liu Z, Qu P, Peng Q, Yang H, Varma VA, Sun QC, Petros JA,Lim SD, Amin MB. Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression. Gene. 2001 ;279:17-31.
27. D LJNJJCLJHRKMOKYKvCVWGMCTBS. Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer. Prostate. 2008; 68:418-426.
28. Daniela A FD, Claudio D, Dolores DV, Enzo G, Sonia B, Bruna Z, Claudia G, Cristina P, Marina Z, Manuela G, Emanuela B, Delia M, Silvana C and Mattia B. M-cam expression as marker of poor prognosis in epithelial ovarian cancer. Int J Cancer.2006;119:1920-1926.
29. Kristiansen G YY, Schluns K, Sers C, Dietel M, Petersen I. Expression of the cell adhesion molecule CD146/MCAM in non-small cell lung cancer. Anal Cell Pathol. 2003;25:77-81.
30. C GSDJCJECMSAMLJJACLMACBPC. Poor prognosis in breast carcinomas correlates with increased expression of targetable CD 146 and c-Met and with proteomic basal-like phenotype. Hum Pathol. 2007;38:830-841.
31. EH D. Integrins:regulators of tissue function and cancer progression. Curr Pharm Des.2005;11:881-891.
32. Oian X KT,Sheppard AM, Mcnally J, Lowy DR. E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J.2004;23:1739-1784.
33. Wang S CE, Pop LM, Brooks KJ, Vitetta ES, Niederkorn JY. Effect of an anti-CD54 (ICAM1) monoclonal antibody (UV3) on the growth of human uveal melanoma cells transplanted hetertopically and orthotopically in SCID mice. Int J Cancer.2006; 118:932-941.
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