Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment

1. Download : Download high-res image (125KB)
2. Download : Download full-size image

     

左右半结肠癌多组学分子特征差异的研究进展

结肠癌(colon cancer,CC)是一种常见的恶性肿瘤,其发病率和死亡率均占癌症前列.根据解剖学位置,CC可分为左半结肠癌(left-sided colon cancer,LCC)和右半结肠癌(right-sided colon cancer,RCC),两者在临床特征上表现出较大的差异.近些年来,随着生物学技术和...     

Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness

DLK1 is a maternally imprinted, paternally expressed gene coding for the transmembrane protein Delta-like homologue 1 (DLK1), a non-canonical NOTCH ligand with well-described roles during development, and tumor-supportive functions in several aggressive cancer forms. Here, we review the many functions of DLK1 as a regulator of stem cell pools and tissue differentiation in tissues such as brain, muscle, and liver. Furthermore, we review recent evidence supporting roles for DLK1 in the maintenance of aggressive stem cell characteristics of tumor cells, specifically focusing on central nervous system tumors, neuroblastoma, and hepatocellular carcinoma. We discuss NOTCH -dependent as well as NOTCH-independent functions of DLK1, and focus particularly on the complex pattern of DLK1 expression and cleavage that is finely regulated from a spatial and temporal perspective. Progress in recent years suggest differential functions of extracellular, soluble DLK1 as a paracrine stem cell niche-secreted factor, and has revealed a role for the intracellular domain of DLK1 in cell signaling and tumor stemness. A better understanding of DLK1 regulation and signaling may enable therapeutic targeting of cancer stemness by interfering with DLK1 release and/or intracellular signaling.     

Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome

Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of activated fibroblasts that constitute a dominant cellular component of the tumor microenvironment (TME) performing distinct functions. Here, the role of tumor‐derived exosomes (Exos) in activating quiescent fibroblasts into distinct functional subtypes is investigated. Proteomic profiling and functional dissection reveal that early‐ (SW480) and late‐stage (SW620) colorectal cancer (CRC) cell‐derived Exos both activated normal quiescent fibroblasts (α‐SMA^?, CAV⁺, FAP⁺, VIM⁺) into CAF‐like fibroblasts (α‐SMA⁺, CAV^?, FAP⁺, VIM⁺). Fibroblasts activated by early‐stage cancer‐exosomes (SW480‐Exos) are highly pro‐proliferative and pro‐angiogenic and display elevated expression of pro‐angiogenic (IL8, RAB10, NDRG1) and pro‐proliferative (SA1008, FFPS) proteins. In contrast, fibroblasts activated by late‐stage cancer‐exosomes (SW620‐Exos) display a striking ability to invade through extracellular matrix through upregulation of pro‐invasive regulators of membrane protrusion (PDLIM1, MYO1B) and matrix‐remodeling proteins (MMP11, EMMPRIN, ADAM10). Conserved features of Exos‐mediated fibroblast activation include enhanced ECM secretion (COL1A1, Tenascin‐C/X), oncogenic transformation, and metabolic reprogramming (downregulation of CAV‐1, upregulation of glycogen metabolism (GAA), amino acid biosynthesis (SHMT2, IDH2) and membrane transporters of glucose (GLUT1), lactate (MCT4), and amino acids (SLC1A5/3A5)). This study highlights the role of primary and metastatic CRC tumor‐derived Exos in generating phenotypically and functionally distinct subsets of CAFs that may facilitate tumor progression.     

Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies

1. Download : Download high-res image (223KB)
2. Download : Download full-size image

     

Immune Cell Types and Secreted Factors Contributing to Inflammation-to-Cancer Transition and Immune Therapy Response

1. Download high-res image (177KB)
2. Download full-size image

     

单吸入器三联疗法联合肺早期康复运动训练治疗中重度慢性阻塞性肺疾病患者的临床研究

摘要 目的：探讨单吸入器三联疗法联合肺早期康复运动训练治疗中重度慢性阻塞性肺疾病（COPD）患者的临床研究。方法：根据随机数字表法,将汕头大学医学院第二附属医院2022年7月-2023年1月间收治的84例中重度COPD患者分为对照组（42例,单吸入器三联疗法治疗）和实验组（42例,对照组的基础上接受肺早期康复运动训练治疗）。观察并对比两组的肺功能指标[用力肺活量（FVC）、第一秒用力呼气容积（FEV₁）、FEV₁/FVC]、血气分析指标[血氧饱和度（SaO₂）、动脉血氧分压（PaO₂）、动脉血二氧化碳分压（PaCO₂）]、6分钟步行距离（6MWD）、COPD评估测试（CAT）评分、治疗期间急性加重频率、血清炎症因子[肿瘤坏死因子-α（TNF-α）、白介素-6（IL-6）、C反应蛋白（CRP）]。结果：治疗后,实验组FEV₁、FVC、FEV₁/FVC高于对照组（P<0.05）。治疗后,实验组PaCO₂低于对照组,PaO₂、SaO₂高于对照组（P<0.05）。治疗后,实验组6MWD高于对照组,CAT评分、治疗期间急性加重频率低于对照组（P<0.05）。治疗后,实验组血清TNF-α、IL-6、CRP水平低于对照组（P<0.05）。结论：单吸入器三联疗法联合肺早期康复运动训练治疗中重度COPD患者,可增强运动耐力,提高生活活动能力,减少治疗期间疾病急性加重频率,同时还可改善血气分析和肺功能指标,降低血清炎症因子水平。     

Body composition adaptations to lower-body plyometric training: a systematic review and meta-analysis

The aim of this meta-analysis was to explore the effects of plyometric jump training (PJT) on body composition parameters among males. Relevant articles were searched in the electronic databases PubMed, MEDLINE, WOS, and SCOPUS, using the key words “ballistic”, “complex”, “explosive”, “force-velocity”, “plyometric”, “stretch-shortening cycle”, “jump”, “training”, and “body composition”. We included randomized controlled trials (RCTs) that investigating the effects of PJT in healthy male’s body composition (e.g., muscle mass; body fat), irrespective of age. From database searching 21 RCTs were included (separate experimental groups = 28; pooled number of participants = 594). Compared to control, PJT produced significant increases in total leg muscle volume (small ES = 0.55, p = 0.009), thigh muscle volume (small ES = 0.38, p = 0.043), thigh girth (large ES = 1.78, p = 0.011), calf girth (large ES = 1.89, p = 0.022), and muscle pennation angle (small ES = 0.53, p = 0.040). However, we did not find significant difference between PJT and control for muscle cross-sectional area, body fat, and skinfold thickness. Heterogeneity remained low-to-moderate for most analyses, and using the Egger’s test publication bias was not found in any of the analyses (p = 0.300–0.900). No injuries were reported among the included studies. PJT seems to be an effective and safe mode of exercise for increasing leg muscle volume, thigh muscle volume, thigh and calf girth, and muscle pennation angle. Therefore, PJT may be effective to improve muscle size and architecture, with potential implications in several clinical and sport-related contexts.     

术前呼吸功能训练联合术后快速康复操对胸腔镜肺叶切除术肺癌患者呼吸功能、生活质量和康复效果的影响

摘要 目的：观察术前呼吸功能训练联合术后快速康复操对胸腔镜肺叶切除术肺癌患者呼吸功能、生活质量和康复效果的影响。方法：97例研究病例选取自2019年4月~2021年5月期间我院收治的行胸腔镜肺叶切除术肺癌患者。将97例患者根据信封抽签法分为对照组（48例）和观察组（49例）,对照组患者予以术前呼吸功能训练和手术常规康复训练,观察组患者在对照组基础上联合术后快速康复操。对比两组术前、术后1周的呼吸功能、生活质量和康复效果,对比两组术后并发症发生率。结果：观察组术后1周用力肺活量（FVC）、第1秒用力呼气容积（FEV₁）、动脉血氧分压（PaO₂）高于对照组（P<0.05）。观察组术后1周动脉二氧化碳分压（PaCO₂）低于对照组（P<0.05）。观察组术后1周症状领域评分低于对照组（P<0.05）。观察组术后1周功能领域、总体健康状况评分高于对照组（P<0.05）。观察组患者的术后肛门排气时间、保留尿管时间、保留胸管时间、住院时间短于对照组（P<0.05）。观察组的术后并发症发生率低于对照组（P<0.05）。结论：术前呼吸功能训练联合术后快速康复操应用于胸腔镜肺叶切除术肺癌患者,可促进术后康复,改善其呼吸功能,提高生活质量,减少并发症发生风险。     

Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth

Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N⁸-acetylspermidine (N⁸-AcSpd). Although intracellular concentrations of N⁸-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N⁸-AcSpd in this context is unknown. We hypothesized that HDAC10, by converting N⁸- AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting anticancer therapies. Inhibitors of polyamine biosynthesis, including α-difluoromethylornithine (DFMO), inhibit tumor growth, but compensatory uptake of extracellular polyamines has limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. Here, we use CRISPR/Cas9-mediated HDAC10-knockout cell lines and HDAC10-specific inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. We demonstrate inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by exogenous N⁸-AcSpd (at physiological concentrations), which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Furthermore, we show loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have value in improving the response to polyamine-blocking therapies. Additionally, the cell-based assay developed in this study provides an inexpensive, high-throughput method of screening potentially selective HDAC10 inhibitors.     

eEF2K Activity Determines Synergy to Cotreatment of Cancer Cells With PI3K and MEK Inhibitors

PI3K-mammalian target of rapamycin and MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK) are the most frequently dysregulated signaling pathways in cancer. A problem that limits the success of therapies that target individual PI3K-MAPK members is that these pathways converge to regulate downstream functions and often compensate each other, leading to drug resistance and transient responses to therapy. In order to overcome resistance, therapies based on cotreatments with PI3K/AKT and MEK/MAPK inhibitors are now being investigated in clinical trials, but the mechanisms of sensitivity to cotreatment are not fully understood. Using LC-MS/MS-based phosphoproteomics, we found that eukaryotic elongation factor 2 kinase (eEF2K), a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to cotreatment with trametinib plus pictilisib (which target MEK1/2 and PI3Kα/δ, respectively). Inhibition of eEF2K by siRNA or with a small molecule inhibitor reversed the antiproliferative effects of the cotreatment with PI3K plus MEK inhibitors in a cell model–specific manner. Systematic analysis in 12 acute myeloid leukemia cell lines revealed that eEF2K activity was increased in cells for which PI3K plus MEKi cotreatment is synergistic, while PKC potentially mediated resistance to such cotreatment. Together, our study uncovers eEF2K activity as a key mediator of responses to PI3Ki plus MEKi and as a potential biomarker to predict synergy to cotreatment in cancer cells.