Exosomes: Mediators in microenvironment of colorectal cancer

Tumor microenvironment, the soil where tumor thrives, plays a critical role in the development and progression of colorectal cancer (CRC). Various cell signaling molecules in the environment promote tumor angiogenesis, immune tolerance and facilitate immune escape. Exosomes, as messengers between tumor and host cells, are considered key mediators involved in the tumor-accelerating environment. However, the exosome-mediated communication networks in the CRC microenvironment are still largely unclear. In this review, we summarized the relationship between TME and CRC based on recent literature. Then, we revealed the unique impacts and signal molecules of exosomes on account of their regulatory role in the flora, hypoxia, inflammatory and immunological microenvironment of CRC. Finally, we summarized the therapeutically effective of exosomes in CRC microenvironment and discussed their current status and prospects, aiming to provide new molecular targets and a theoretical basis for the CRC treatment.     

Exosomes in cancer development and clinical applications

Exosomes participate in cancer progression and metastasis by transferring bioactive molecules between cancer and various cells in the local and distant microenvironments. Such intercellular cross‐talk results in changes in multiple cellular and biological functions in recipient cells. Several hallmarks of cancer have reportedly been impacted by this exosome‐mediated cell‐to‐cell communication, including modulating immune responses, reprogramming stromal cells, remodeling the architecture of the extracellular matrix, or even endowing cancer cells with characteristics of drug resistance. Selectively, loading specific oncogenic molecules into exosomes highlights exosomes as potential diagnostic biomarkers as well as therapeutic targets. In addition, exosome‐based drug delivery strategies in preclinical and clinical trials have been shown to dramatically decrease cancer development. In the present review, we summarize the significant aspects of exosomes in cancer development that can provide novel strategies for potential clinical applications.     

Exosomes play roles in sequential processes of tumor metastasis

Overwhelming evidence demonstrates that exosomes, a series of biologically functional small vesicles of endocytic origin carrying a variety of active constituents, especially tumor-derived exosomes, contribute to tumor progression and metastasis. This review focuses on the specific multifaceted roles of exosomes in affecting sequenced four crucial processes of metastasis, through which cancer cells spread from primary to secondary organs and finally form macroscopic metastatic lesions. First, exosomes modulate the primary tumor sites to assist cancer growth and dissemination. In this part, five main biological events are reviewed, including the transfer of oncogenic constituents, the recruitment and activation of fibroblasts, the induction of angiogenesis, immunosuppression and epithelial-mesenchymal transition (EMT) promotion. In Step 2, we list two recently disclosed mechanisms during the organ-specific homing process: the exosomal integrin model and exosomal epidermal growth factor receptor (EGFR)/miR-26/hepatocyte growth factor (HGF) model. Subsequently, Step 3 focuses on the interactions between exosomes and pre-metastatic niche, in which we highlight the specific functions of exosomes in angiogenesis, lymphangiogenesis, immune modulation and metabolic, epigenetic and stromal reprogramming of pre-metastatic niche. Finally, we summarize the mechanisms of exosomes in helping the metastatic circulating tumor cells escape from immunologic surveillance, survive in the blood circulation and proliferate in host organs.     

Exosome‐mediated regulation of tumor immunology

Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8⁺ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T‐cell zone of secondary lymphoid organs. Once receiving tumor‐specific antigenic stimulation by dendritic cells (DC), CD8⁺ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer‐associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome‐mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC‐derived and regulatory T (Treg) cell‐derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression.     

放射治疗在胰腺癌治疗中的作用

胰腺癌是难治的肿瘤之一,手术是惟一可能治愈的治疗手段,但是仅有10%～20%患者有施行手术的可能性,术后辅助治疗的价值目前还不十分明确.80%左右的患者就诊时为局部晚期或已有转移,局部晚期胰腺癌同步放化疗可以提高患者的生存质量,但是最优的化疗药物以及放射治疗的范围和剂量还有待于进一步研究.晚期胰腺癌目前无治愈的可能,患者通常伴随疼痛、体重下降、一般状况差等症状,健择对症状的缓解明显优于5-FU或其他化疗药物,中位生存期亦高于5-FU为主的化疗,但健择联合其他新一代化疗药物是否能进一步提高生存期和缓解症状目前正在研究中.     

放疗对机体抗肿瘤免疫效应机制的影响

放疗主要通过对放射野内肿瘤细胞的杀伤使靶区内肿瘤得到控制、可以作用于远处转移灶并能够激活机体抗肿瘤免疫应答。越来越多的研究表明合理的放疗剂量和分割模式能够改善肿瘤微环境,诱导特异性 T 细胞免疫应答,形成原位疫苗并激活机体的抗肿瘤免疫效应。本文重点阐述放疗对机体抗肿瘤免疫效应机制的影响,以及放疗在免疫治疗的辅助下如何发挥抗肿瘤的作用,为恶性肿瘤治疗提供新思路。     

Role of exosomes in cellular communication between tumor cells and the tumor microenvironment

Exosomes are nanovesicles secreted by almost all types of cells. They contain RNAs, microRNAs, proteins and other bioactive substances, and can be used as carriers and for communication between cells. They regulate numerous biological processes, such as tumor development, cell proliferation and resistance to chemotherapy. Exosome-mediated communication between tumor cells and the tumor microenvironment (TME) is crucial in the initiation and progression of tumor development. The present review aims to summarize the role of exosomes in mediating the communication between tumor cells and the TME and to suggest the potential use of exosomes as targets for the development of novel therapeutic strategies against cancer.     

Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer

We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population‐based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 1976–2005 and 750 patients in South Sweden 1977–2005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.27–2.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.40–3.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM‐stage [OR 2.16 (95% CI 1.13–4.11)] and higher histological grade [OR = 2.00 (95% CI 1.08–3.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy.     

脂肪间充质干细胞分泌的Exosome促进结肠癌细胞系上皮间质转化

目的：研究间充质干细胞（mesenchymal stem cell,MSC）来源的Exosome对结肠癌细胞系HCT8上皮间质转化（epithelial mesenchymal transition,EMT）的影响。方法从人脂肪组织中分离出MSC后,对MSC进行培养并传代,并对MSC的分化能力进行鉴定。在人脂肪来源的MSC中提取Exosome后,用透射电子显微镜观察并拍照,并用蛋白质印迹法检测其抗原表达情况。在HCT8培养体系中加入人脂肪来源的MSC分泌的Exosome ,定量PCR和蛋白质印迹法检测上皮和间质转化相关标志物的表达,细胞侵袭和迁移实验检测人脂肪来源的MSC分泌的Exosome对HCT8迁移和侵袭的影响。结果人脂肪来源的MSC具有多系分化能力,人脂肪来源的Exosome直径为40～100 nm ,表达CD63、HSP70和HSP90,下调HCT8上皮相关标志E-cadherin和ZO-1的表达,上调间质相关标志Fibronectin的表达,促进HCT8的迁移和侵袭。结论人脂肪来源的MSC分泌的Exosome可促进结肠癌细胞系HCT8的EMT。     

VEGF-associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy

PURPOSE: In this study, the efficacy of combining ZD6474 (Zactima), a vascular endothelial growth factor (VEGF) receptor 2-associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation, with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model (HT29). METHODS AND MATERIALS: HT29 xenograft-bearing mice were treated with either single-dose (10 Gy) or multifraction (2 Gy/day for 2 weeks) radiotherapy alone or in conjunction with a 2-week course of ZD6474 (25 mg/kg). In the single-dose investigation, ZD6474 treatment followed radiotherapy, whereas in the fractionated dose studies the antiangiogenic therapy was given before, after, or concurrent with the radiation. Tumor response was determined by tumor growth delay. RESULTS: ZD6474 increased the response of HT29 xenografts to both single and fractionated dose radiotherapy. In the fractionation studies sequencing of therapies had little impact on treatment outcomes; the time for the median tumors in each of the treatment groups to grow to five times the starting size was 53, 53.5, and 49 days, respectively. CONCLUSIONS: These studies indicate that ZD6474, when used in conjunction with radiation therapy, has a clear therapeutic advantage, providing a rationale for considering the combination of this agent with radiotherapy in the clinic.     

乳腺癌的术中放疗

乳腺癌是全球女性最高发的恶性肿瘤,不仅威胁患者生命,同时也影响患者的生存质量和生理功能。因此,采用优化的综合治疗策略,延长患者生命,改善患者生存质量,是目前乳腺癌治疗的趋势。放射治疗是乳腺癌综合治疗的重要组成部分,近年来,乳腺癌放射治疗具有照射范围缩小,分割次数减少两大趋势。术中放疗(intraoperative radiotherapy,IORT)由于在手术中直视下给予单次大剂量照射,具有缩短疗程,有效保护正常组织的优势。目前IORT对接受保乳术的乳腺癌患者可作为外照射的局部剂量追加技术方法,或作为替代术后外照射的技术方法。现就IORT技术的优缺点及其临床适应证、疗效和不良反应进行系统回顾,为指导临床开展IORT提供依据。     

血清肿瘤标志物对晚期原发性肺癌老年患者放疗疗效的评估价值

目的：探讨血清肿瘤标志物对晚期原发性肺癌老年患者放疗疗效的评估价值。方法纳入156例晚期原发性肺癌老年患者,放疗结束6周后比较患者的近期疗效并将患者分为完全缓解（complete response, CR）+部分缓解（partial response,PR）组（即CR+PR组）、疾病稳定（stable disease,SD）组（即SD组）及疾病进展（progressive disease,PD）组（即PD组）,比较不同组患者治疗前后血清中癌胚抗原（carcinoembryonic antigen, CEA）、细胞角蛋白21-1片段（human cytokeratin fragment antigen 21-1,CYFRA21-1）、鳞状细胞癌抗原（squa-mous cell carcinoma,SCC）及癌抗原125（carbohydrate antigen 125,CA125）的水平,并计算以血清肿瘤标志物水平评估放疗疗效的方法的灵敏度和特异度。结果156例患者放疗后,CR有2例（1.28%）,PR有83例（53.21%）,SD有22例（14.10%）,以及PD有49例（31.41%）。放疗后CR+PR组患者的CEA、CYFRA21-1、SCC及CA125水平均显著低于治疗前水平（P＜0.05）,SD组患者治疗后各血清肿瘤标志物水平与治疗前无明显差异（P＞0.05）,PD组患者治疗后各血清肿瘤标志物水平均显著高于放疗前水平（P＜0.05）。以血清肿瘤标志物水平评估放疗疗效的方法的灵敏度为72.94%,特异度为76.06%。结论血清肿瘤标志物CEA、CYFRA21-1、SCC及CA125可较准确地评估晚期原发性肺癌老年患者的放疗疗效,并具有较高的灵敏度与准确度。     

三种全乳同步瘤床加量调强放疗计划的比较

背景与目的：目前保乳手术+术后放疗已成为早期乳腺癌标准治疗模式。采用3种不同适形调强放疗技术制定早期乳腺癌保乳术后全乳同步瘤床加量的放疗计划,并对3种放疗计划的肿瘤靶区、危及器官剂量学参数等方面进行比较。方法：随机选取上海交通大学医学院附属第九人民医院黄浦分院放疗科2018年度收治的女性乳腺癌保乳术后患者50例,左、右侧乳腺癌患者各25例。分别采用正向调强、逆向调强、容积调强等3种调强治疗方法制定全乳同步瘤床加量放疗计划。比较3种放疗计划的靶区适形度（conformity index,CI）与均匀度（homogeneity index,HI）;危及器官的剂量学参数,包括同侧肺（V ₅ 、V ₂₀ 、V ₃₀ ）、心脏（D _mean 、左乳癌V ₂₅ 、右乳癌V ₁₅ ）、对侧乳腺（D ₂ 、D _mean ）;单次治疗的总跳数（minute,MU）及出束时间,并进一步分析乳房体积大小对放疗计划的影响。结果：正向调强、逆向调强与容积调强放疗计划的全乳靶区CI分别为0.69±0.09、0.86±0.06和0.79±0.07（两两比较P<0.001）,瘤床靶区CI分别为0.71±0.15、0.79±0.15和0.80±0.12（两两比较P=0.007、P<0.001和P=0.624）,全乳靶区HI分别为0.17±0.03、0.13±0.03和0.18±0.03（两两比较P<0.001）,瘤床靶区HI分别为0.17±0.05、0.07±0.01和0.10±0.02（两两比较P<0.001）。同侧肺V ₅ 为56.08±7.24、46.08±5.48和57.82±6.64（两两比较P<0.001、P=0.079、P<0.001）,V ₂₀ 为27.96±2.57、20.28±2.13和23.44±2.71（两两比较P<0.001、P=0.025、P<0.001）,V ₃₀ 为22.34±2.20、15.40±2.37和16.42±2.82（两两比较P<0.001、P=0.006、P=0.012）。左乳癌心脏D _mean 为775.48±113.23、584.20±223.04和634.24±174.38（两两比较P<0.001、P<0.001、P=0.045）,右乳癌心脏D _mean 为209.32±84.60、125.56±41.65和200.80±49.74（两两比较P<0.001、P=0.524、P<0.001）,左乳癌心脏V ₂₅ 为8.20±1.73、5.02±1.38和6.65±1.56（两两比较P<0.001、P<0.001、P=0.037）,右乳癌心脏V ₁₅ 均为0值不做比较。对侧乳腺的D _mean 为288.05±105.14、108.25±56.47和123.59±73.79（两两比较P<0.001、P<0.001、P=0.023）。单次治疗MU为285.74±17.73、1463.94±227.74和445.50±98.22（两两比较P<0.001）,出束时间为205.12±20.68、343.26±37.59和138.06±13.53（两两比较P<0.001）。50例患者以患侧乳房体积平均值764.89 mL为界分成两组,乳房小体积组3种放疗计划的靶区CI、HI以及单次MU与出束时间优于乳房大体积组,而在正常器官剂量学方面两组间差异无统计学意义。结论：逆向调强与容积调强在靶区剂量学参数及危及器官的保护方面优于正向调强计划。其中逆向调强计划稍优于容积调强,推荐用于耐受较好、有长期生存预期的中、青年患者;而容积调强计划的单次MU更少,出束时间更短,建议老年、乳房体积较大的患者采用。     

乳腺癌术后辅助放疗研究的进展

放射治疗在乳腺癌综合治疗中发挥着重要的作用.随着乳腺癌临床-病理、肿瘤生物学特性研究的深入,化疗/内分必治疗的规范化应用,对传统乳腺癌术后辅助放疗的指征与方式、方法受到质疑,学者应重新认识.鉴于放射治疗在理念、原则、技术等方面都在不断的变化,放疗要有目标性而不是传统的包括区域淋巴结在内的大野照射,旨在提高肿瘤局部控制率和生存率的同时如何减少或避免放射损伤.为规范乳腺癌术后辅助放疗,本文综述近年来相关的临床研究,提出乳腺癌术后各部位辅助放疗的指征、技术方法及剂量.     

Hypofractionated radiotherapy in prostate cancer

In regards to prostate cancer, the classic radiotherapy dose ranges from 70–80 Gy, administered in daily 2-Gy fractions. However, when taking into account the particular radiobiological model of prostate cancer cells, one realizes that there is a potential theoretical advantage to delivering a greater biological effective dose per treatment in a lower number of fractions. Both recent and older publications have attempted to explore this treatment option. This critical review comprehensively examines the current state of knowledge concerning hypofractionated radiotherapy in prostate cancer.     

宫颈癌根治性手术后辅助调强放疗(IMRT)的临床观察

目的 探讨早期宫颈癌术后具有不良预后因素的患者行盆腔调强放射治疗(IMRT/sIMRT)的近期不良反应和复发率.方法 回顾分析2007年1月～2008年6月期间78例早期宫颈癌术后具有不良预后因素行放射治疗的患者资料,其中IMRT组有30例;常规组48例.调强放射治疗方法(IMRT/或sIMRT):CTV上界从腹主动脉...     

MR引导放疗在胰腺癌中的应用

放疗是治疗胰腺癌的重要手段。但受胰腺运动等因素影响,放疗疗效难以充分发挥。更高效的胰腺癌放疗有赖于运动管理方式的改进与高质量的图像引导。新兴的MR引导放疗技术软组织分辨率高、无额外辐射、能进行功能成像,经过大量研究评估与验证,其在靶区与危及器官的精准勾画、辅助运动管理和自适应放疗等方面有着巨大优势,有望更好地发挥放疗在...     

复方斑蝥胶囊联合放疗治疗中晚期恶性肿瘤的临床研究

目的：观察复方斑蝥胶囊与放疗联合应用对中晚期恶性肿瘤的疗效。方法：137例中晚期恶性肿瘤分为治疗组和对照组,两组放疗方法、剂量相同,治疗组联合应用复方斑蝥胶囊。结果：治疗组cR84．8％（56／66）,PR15．2％（10／66）。对照组CR66．2％（47／71）,PR19．7％（14／71）P〈0．05。结论：复方斑蝥胶囊与放疗联合应用治疗中晚期恶性肿瘤能提高放疗患者的免疫功能,增强疗效,减少放疗反应和白细胞下降。