Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity t...Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.展开更多
目的 探讨大剂量维生素C对胰腺癌细胞株PANC-1细胞基质金属蛋白酶2（MMP2）的表达和侵袭能力的影响,为临床维生素C治疗胰腺癌可行性提供理论依据.方法 采用transwell侵袭实验比较不同浓度维生素C组PANC-1细胞的侵袭能力,并运用RT-PCR和W...目的 探讨大剂量维生素C对胰腺癌细胞株PANC-1细胞基质金属蛋白酶2（MMP2）的表达和侵袭能力的影响,为临床维生素C治疗胰腺癌可行性提供理论依据.方法 采用transwell侵袭实验比较不同浓度维生素C组PANC-1细胞的侵袭能力,并运用RT-PCR和Western b1ot检测并比较各组细胞MMP2 mRNA和蛋白水平的表达情况.结果 1.0、5.0和10.0 mM浓度维生素C处理组MMP2 mRNA的相对丰度值较空白对照组显著降低（0.510±0.004 vs 0.792±0.006,0.391±0.007 vs 0.792±0.006,0.282±0.008 vs 0.792±0.006,P＜0.05）.1.0、5.0和10.0 mM浓度维生素C处理组MMP2蛋白的相对丰度值较空白对照组显著降低（0.519±0.004 vs 0.761±0.014,0.310±0.007 vs 0.761±0.014,0.297±0.008 vs 0.761±0.014,P＜0.05）.1.0、5.0和10.0 mM浓度维生素C处理组穿过transwell的细胞数相较空白对照组显著降低（452±22 vs 653±28,340±32 vs 653±28,409±33 vs 653±28,P＜0.05）.结论 大剂量维生素C可以降低PANC-1细胞MMP2的表达,并可减弱其侵袭能力.展开更多
A mesoporous silica/gold （MSN/Au） nanocomposite was designed for photo- controlled drug delivery targeted specifically at tumor cells. The MSN/Au nanocomposite was composed of MSN-based drug carriers and gold nanopa...A mesoporous silica/gold （MSN/Au） nanocomposite was designed for photo- controlled drug delivery targeted specifically at tumor cells. The MSN/Au nanocomposite was composed of MSN-based drug carriers and gold nanoparticle （AuNP）-based indicators. While the MSN-based drug carrier was a mesoporous silica nanoparticle immobilized with photo-switchable azobenzene （Azo） moieties, the AuNP-based indicator was a fluorescence-quenched AuNP modified with a matrix metalloproteinase （MMP） substrate and poly（ethylene glycol）. The two kinds of nanoparticles were connected by an α,β cyclodextrin （α,β CD） dimer ＂bridge.＂ In vitro studies demonstrated that the nanocomposite specifically interacted with tumor sites overexpressing MMP-2, which enabled guidance of the subsequent UV light irradiation for releasing entrapped drugs. Through integration of the AuNP-based indicator and the MSN-based drug carrier, the MSN/Au nanocomposite could precisely localize the released drug to tumor sites, thereby significantly improving therapeutic efficacy.展开更多
基金funding from Guangzhou Pearl River of Science & Technology New Star (Grant No. 2011J2200069)supported in part by grants from the National Institutes of Health (Grant No. P01 CA055164)+2 种基金MD Anderson Cancer Center Support (Grant No. CA016672)the Paul and Mary Haas Chair in Genetics to Michael Andreeffby the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to Bing Z. Carter
文摘Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.
文摘目的 探讨大剂量维生素C对胰腺癌细胞株PANC-1细胞基质金属蛋白酶2（MMP2）的表达和侵袭能力的影响,为临床维生素C治疗胰腺癌可行性提供理论依据.方法 采用transwell侵袭实验比较不同浓度维生素C组PANC-1细胞的侵袭能力,并运用RT-PCR和Western b1ot检测并比较各组细胞MMP2 mRNA和蛋白水平的表达情况.结果 1.0、5.0和10.0 mM浓度维生素C处理组MMP2 mRNA的相对丰度值较空白对照组显著降低（0.510±0.004 vs 0.792±0.006,0.391±0.007 vs 0.792±0.006,0.282±0.008 vs 0.792±0.006,P＜0.05）.1.0、5.0和10.0 mM浓度维生素C处理组MMP2蛋白的相对丰度值较空白对照组显著降低（0.519±0.004 vs 0.761±0.014,0.310±0.007 vs 0.761±0.014,0.297±0.008 vs 0.761±0.014,P＜0.05）.1.0、5.0和10.0 mM浓度维生素C处理组穿过transwell的细胞数相较空白对照组显著降低（452±22 vs 653±28,340±32 vs 653±28,409±33 vs 653±28,P＜0.05）.结论 大剂量维生素C可以降低PANC-1细胞MMP2的表达,并可减弱其侵袭能力.
基金This work was financially supported by the National Natural Science Foundation of China （Nos. 51125014 and 51233003）, National Basic Research Program of China （No. 2011CB606202）, the Ministry of Education of China （No. 20120141130003）, and Fundamental Research Funds for the Central Universities of China （Nos. 2014203020201 and 2014203020204）.
文摘A mesoporous silica/gold （MSN/Au） nanocomposite was designed for photo- controlled drug delivery targeted specifically at tumor cells. The MSN/Au nanocomposite was composed of MSN-based drug carriers and gold nanoparticle （AuNP）-based indicators. While the MSN-based drug carrier was a mesoporous silica nanoparticle immobilized with photo-switchable azobenzene （Azo） moieties, the AuNP-based indicator was a fluorescence-quenched AuNP modified with a matrix metalloproteinase （MMP） substrate and poly（ethylene glycol）. The two kinds of nanoparticles were connected by an α,β cyclodextrin （α,β CD） dimer ＂bridge.＂ In vitro studies demonstrated that the nanocomposite specifically interacted with tumor sites overexpressing MMP-2, which enabled guidance of the subsequent UV light irradiation for releasing entrapped drugs. Through integration of the AuNP-based indicator and the MSN-based drug carrier, the MSN/Au nanocomposite could precisely localize the released drug to tumor sites, thereby significantly improving therapeutic efficacy.
