In JoVE (1)
Other Publications (9)
- Neoplasia (New York, N.Y.)
- The American Journal of Pathology
- Molecular Cancer Research : MCR
- Neoplasia (New York, N.Y.)
- American Journal of Physiology. Heart and Circulatory Physiology
- British Journal of Pharmacology
- Basic & Clinical Pharmacology & Toxicology
- Microcirculation (New York, N.Y. : 1994)
- Arteriosclerosis, Thrombosis, and Vascular Biology
Articles by Matthew J. Socha in JoVE
Other articles by Matthew J. Socha on PubMed
SPARC Inhibits LPA-mediated Mesothelial-ovarian Cancer Cell Crosstalk Neoplasia (New York, N.Y.). Jan, 2007 | Pubmed ID: 17325741 The interplay between peritoneal mesothelial cells and ovarian cancer cells is critical for the initiation and peritoneal dissemination of, and ascites formation in, ovarian cancer. The production of lysophosphatidic acid (LPA) by both peritoneal mesothelial cells and ovarian cancer cells has been shown to promote metastatic phenotype in ovarian cancer. Herein, we report that exogenous addition or ectopic overexpression of the matricellular protein SPARC (secreted protein acidic and rich in cysteine) significantly attenuated LPA-induced proliferation, chemotaxis, and invasion in both highly metastatic SKOV3 and less metastatic OVCAR3 ovarian cancer cell lines. SPARC appears to modulate these functions, at least in part, through the regulation of LPA receptor levels and the attenuation of extracellular signal-regulated kinase (ERK) 1/2 and protein kinase B/AKT signaling. Moreover, our results show that SPARC not only significantly inhibited both basal and LPA-induced interleukin (IL) 6 production in both cell lines but also attenuated IL-6-induced mitogenic, chemotactic, and proinvasive effects, in part, through significant suppression of ERK1/2 and, to a lesser extent, of signal transducers and activators of transcription 3 signaling pathways. Our results strongly suggest that SPARC exerts a dual inhibitory effect on LPA-induced mesothelial-ovarian cancer cell crosstalk through the regulation of both LPA-induced IL-6 production and function. Taken together, our findings underscore the use of SPARC as a potential therapeutic candidate in peritoneal ovarian carcinomatosis.
Secreted Protein Acidic and Rich in Cysteine Deficiency Ameliorates Renal Inflammation and Fibrosis in Angiotensin Hypertension The American Journal of Pathology. Oct, 2007 | Pubmed ID: 17717147 The matricellular protein secreted protein acidic and rich in cysteine (SPARC) modulates cell adhesion, proliferation, matrix deposition, and tissue remodeling. SPARC has been shown to regulate the expression of collagen type I and transforming growth factor-beta1 in mesangial cells and to be highly expressed during tubulointerstitial fibrosis in rat angiotensin (ANG) II infusion models. We hypothesized that SPARC is a downstream effector of ANG II and that loss of host SPARC function provides a protective effect on renal damage and fibrosis associated with ANG II hypertension. Our results revealed that cultured primary mesangial cells displayed a concentration-dependent increase in SPARC expression in response to ANG II. After a 14-day chronic infusion of ANG II, hypertensive SPARC-null mice exhibited significantly attenuated levels of urinary and renal indicators of oxidative stress and inflammation and decreased renal perivascular and tubulointerstitial fibrosis relative to wild-type hypertensive controls. Moreover, the observed renal protective changes in SPARC-null mice were found to be independent of blood pressure. These results identify SPARC as an effector of ANG II signaling and suggest an important role for SPARC in mediating ANG II-induced oxidative stress, inflammation, and fibrosis.
Normalization of the Ovarian Cancer Microenvironment by SPARC Molecular Cancer Research : MCR. Oct, 2007 | Pubmed ID: 17951402 Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP(-/-) mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid-enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of alpha(v) and beta(1) integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP(+/+), SP(-/-) ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP(-/-) ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F(2)alpha) that were positively correlated with extensive infiltration of SP(-/-) ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation.
Aberrant Promoter Methylation of SPARC in Ovarian Cancer Neoplasia (New York, N.Y.). Feb, 2009 | Pubmed ID: 19177197 Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in several cancers. We hypothesized that SPARC is downregulated in ovarian cancer through aberrant promoter hypermethylation. To that end, we analyzed SPARC expression in ovarian cancer cell lines and investigated the methylation status of the Sparc promoter using methylation-specific polymerase chain reaction. Our results show that SPARC mRNA expression is decreased in three (33%) and absent in four (44%) of the nine ovarian cancer cell lines studied, which correlated with hypermethylation of the Sparc promoter. Treatment with the demethylating agent 5-aza-2'-deoxycytidine rescued SPARC mRNA and protein expression. Addition of exogenous SPARC, as well as ectopic expression by an adenoviral vector, resulted in decreased proliferation of ovarian cancer cell lines. Investigation of primary tumors revealed that the Sparc promoter is methylated in 68% of primary ovarian tumors and that the levels of SPARC protein decrease as the disease progresses from low to high grade. Lastly, de novo methylation of Sparc promoter was shown to be mediated by DNA methyltransferase 3a. These results implicate Sparc promoter methylation as an important factor in the genesis and survival of ovarian carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and/or treatment modality for this disease.
对形态完整和 Ca²⁺ 信号在新鲜分离小鼠饲料动脉内皮细胞管温度影响。 American Journal of Physiology. Heart and Circulatory Physiology. Sep, 2011 | Pubmed ID: 21705671 研究经中的小鼠的饲料动脉内皮细胞信号转导我们确定的内皮细胞的体外稳定性 (EC) 管新鲜分离饲料 (5-9 mo，25-35 g) 的男性和女性 C57BL/6 小鼠动脉的腹部肌肉。我们测试假设该细胞经浓度 ([Ca(2+)](i)) 毒蕈碱受体激活响应将随温度增加。完好的统管 (长度： 1-2 毫米、 宽度： 65-80 μ m） 被隔离使用温和的酶消化与研制删除平滑肌细胞。新鲜孤立的统管是担保在会议厅和 superfused (室温) 24、 32、 或 37 ° c。使用 fura 2 染料 [Ca(2+)](i) 是被监视 （比率在 340-380 nm 波长的荧光） 在休息和响应丸剂量的 ACh (到 200 μ m o 20 nmol)。统管的形态完整保存在 24 和 32 ° C基于我们为 fura 2 确定的经 K(d) 值 (174 在 24 ° C 和 146 nM nM 在 32 ° C)、 休息 [Ca(2+)](i) 保持稳定为 180 分钟，24 和 32 ° C (27 ± 4 和 34 ± 2 nM，分别)，与 ACh 峰值响应 (20 μ m o) 增加从 ∼220 nM 在 24 ° C 到 32 ° c ∼500 nM (P < 0.05)。没有任何差别 ACh 统管从男性与女性的小鼠之间的答复中。时统管被保持在 37 ° C （典型的体内温度），休息 [Ca(2+)](i) 增加了 ∼30%在 15 分钟内和个别 ECs 之间他们收回并形成挤压染料，进一步排除研究的空白。我们得出的结论统管使经要计算在新鲜孤立的小鼠饲料动脉内皮细胞信号转导。虽然由于大约 32 与 24 ° C 在两个方面得到加强，经反应，统管在 37 ° C 的不稳定性排除典型体温在其研究。
沿血管内皮细胞管从鼠标的电传导饲料动脉： 混杂的甘草次酸衍生物的行动。 British Journal of Pharmacology. Dec, 2011 | Pubmed ID: 22168386 背景和目的： 阻力血管内皮细胞沿导电尚未确定独立于平滑肌，周围组织或血液的影响。两个相互关联的假设进行了检验： (1) 细胞间传导的电信号是清单中血管内皮细胞 (EC) 管 ；(2) 抑制剂的差距交界处频道 (GJCs) 有一些混淆 EC 电气和经信号操作。实验方法： 完好统管被隔离来自饲料的 C57BL/6 小鼠动脉的腹部肌肉。间接 (乙酰胆碱) 和 (NS309) 直接刺激的中间体和小-电导经发起了极化-激活 K(+) 渠道 (IK(Ca) /SK(Ca))。胞内电流注入远程膜潜在 （V(m)） 响应定义电传导的长度常数 (λ)。染料耦合了评价后细胞内的注射碘化丙锭。胞经动力学是使用 Fura 2 光度法确定的。珀 (CBX) 或 β-甘草次酸 (βGA) 被用来调查 GJCs.主要结果的作用： 稳态 ECs V(m) 是 ∼ 25 mV。乙酰胆碱和 NS309 超分别由 ∼ 40 mV 和 ∼ 60 mV，极化 ECs。腐烂的电传导 monoexponentially 与距离 （λ∼1.4 毫米）。碘化丙锭注入一教统会蔓延到周围 ECs。CBX 或 βGA 可逆抑制染料转移、 导电和 EC 极化。这两个代理高架休息经虽然 βGA 抑制乙酰胆碱的回应。结论和所涉问题： 单个单元格是 well-coupled 彼此统管内。与甘草次酸衍生物抑制 GJCs 与 IK(Ca) /SK(Ca) 不论经信号、 避免使用这些制剂在解决沿内皮细胞的电传导的关键决定因素介导超极化失去吻合。
钙和电气信号沿抗血管内皮细胞。 Basic & Clinical Pharmacology & Toxicology. Jan, 2012 | Pubmed ID: 21917120 这一进展被侧重于沿有助于协调血流量控制血管阻力网络中的内皮细胞间信号的性质。发起的承包骨骼肌血管舒张功能登的小动脉内的组织，包括抗动脉上游，从而增加血流量期间行使。在阻力血管，乙酰胆碱 microiontophoresis 或胞内电流注入启动进行渠道差距交界处 (GJCs) 沿进行血管舒张功能 (CVD) 造成血管壁的极化。升序血管舒张和 CVD 被消除干扰内皮细胞 (EC)，指向常见信号事件和 EC 完整性的相互依赖。所示电耦合和染料转移在胞内录制过程中，其纵向方向和鲁棒的 GJCs 的表达使 ECs 在 CVD 中发挥着主导作用。传导开始后，主要的兴趣集中在 CVD 是纯粹的被动还是涉及到额外的活跃信号事件。在这里，我们讨论组件经和电气信号与重点放在通过 GJCs 血管内皮细胞间耦合。我们强调了解细胞经动态、 EC 极化和 CVD 之间关系的重要性，同时从孤立 ECs 结果融入体内的更复杂的相互作用。血管内皮功能障碍伴心血管疾病和 cellular 间信号的组件都已日益明确界定，而鲜为人知的病国家如何改变经信号和沿微血管内皮细胞的电传导。因此，更好地了解这些关系如何受和交互是继续的努力研究的主要目标。
Coordination of Intercellular Ca(2+) Signaling in Endothelial Cell Tubes of Mouse Resistance Arteries Microcirculation (New York, N.Y. : 1994). Nov, 2012 | Pubmed ID: 22860994 To test the hypothesis that Ca(2+) responses to GPCR activation are coordinated between neighboring ECs of resistance arteries.
Aging Impairs Electrical Conduction Along Endothelium of Resistance Arteries Through Enhanced Ca2+-activated K+ Channel Activation Arteriosclerosis, Thrombosis, and Vascular Biology. Aug, 2013 | Pubmed ID: 23723370 Intercellular conduction of electrical signals underlies spreading vasodilation of resistance arteries. Small- and intermediate-conductance Ca(2+)-activated K(+) channels of endothelial cells serve a dual function by initiating hyperpolarization and modulating electrical conduction. We tested the hypothesis that regulation of electrical signaling by small- and intermediate-conductance Ca(2+)-activated K(+) channels is altered with advancing age.