Lung CSC-derived exosomal miR-210-3p contributes to a pro-metastatic phenotype in lung cancer by targeting FGFRL1

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths can be attributed to metastatic spread. Lung cancer stem cells (CSCs) are a component of the tumour microenvironment that contributes to this process. Exosomes are small membrane vesicles secreted by all types of cells that mediate cell interactions, including cancer metastasis. Here, we show that lung CSC-derived exosomes promote the migration and invasion of lung cancer cells, up-regulate expression levels of N-cadherin, vimentin, MMP-9 and MMP-1, and down-regulate E-cadherin expression. Moreover, we verified that these exosomes contribute to a pro-metastatic phenotype in lung cancer cells via miR-210-3p transfer. The results of bioinformatics analysis and dual-luciferase reporter assays further indicated that miR-210-3p may bind to fibroblast growth factor receptor-like 1 (FGFRL1); silencing FGFRL1 enhanced the metastatic ability of lung cancer cells, whereas overexpressing FGFRL1 suppressed metastasis. Taken together, our results provide new insights into a potential molecular mechanism whereby lung CSC-derived exosomal miR-210-3p targets FGFRL1 to promote lung cancer metastasis. FGFRL1 may be a promising therapeutic target in lung cancer.     

Serum concentrations of interleukin-18 in early and advanced cancer patients: enhanced secretion in metastatic disease

The recent availability of adequate methods for cytokine measurement could contribute to better understanding the immunophysiopathology of neoplastic disease. Unfortunately, very little data is available about cytokine secretion in cancer patients. At present, IL-2, IL-12 and IL-15 represent the major antitumor cytokines in humans. Preliminary clinical studies have shown a progressive decline in IL-2 levels with cancer progression, whereas IL-12 seems to increase in the advanced disease. IL-18 is the latest cytokine discovered by potential anticancer and anti-angiogenetic activity, and it has effects similar to those of IL-12. This preliminary study was carried out to analyze IL-18 secretion in early or advanced cancer patients. The study included 40 cancer patients (lung cancer, 21; gastrointestinal tumors, 19), 17 of whom had metastatic disease, and 50 healthy controls. Serum levels of IL-18 were measured by ELISA. No significant difference in IL-18 mean levels was seen between controls and non-metastatic patients. In contrast, metastatic patients showed significantly higher IL-18 mean values with respect to both healthy controls and non-metastatic patients. This preliminary study seems to suggest that metastatic disease may be characterized by enhanced IL-18 secretion the biological and prognostic significance to be established by successive clinical investigation.     

直肠癌术后肺转移72例的临床分析

目的：探讨直肠癌根治术后肺转移的治疗效果和影响预后的因素。方法：回顾性分析1978～2008年间的直肠癌根治术后发生单纯性肺转移的72例病例资料。结果：自原发灶切除术后全组病例中位生存时间34个月,行转移灶的切除手术23例,中位生存49个月;其余49例行非手术治疗,中位生存33个月;其中转移瘤大于3个组中位生存时间28个月,转移瘤小于等于3个组中位生存时间41个月。手术患者和转移灶个数少的患者的总生存率较大,总生存率可能和是否手术、转移灶的个数有关,但尚未发现年龄、性别、原发灶病理类型、分期、转移灶大小对生存率有明显影响。结论：直肠癌肺转移灶的手术治疗是安全、有效的。手术及转移灶个数可影响患者生存率。     

S100B promotes the proliferation, migration and invasion of specific brain metastatic lung adenocarcinoma cell line

Brain metastasis frequently occurs in cancer patients and is associated with a poor prognosis. We previously reported that S100B was highly expressed in PC14/B, a specific brain metastatic lung adenocarcinoma cell line, which suggests that it is associated with brain metastasis of lung cancer. However, the role of S100B in brain metastasis remains to be elucidated. In this study, using PC14/B cell line, we found that siRNA mediated depletion of S100B in PC14/B cells led to notable differences in cell proliferation, apoptosis, cell cycle progression, colony formation ability, cell migratory and invasive activity compared with the mock-transfected cells. Therefore, our data suggest that S100B promotes the brain metastasis of lung adenocarcinoma by promoting cell proliferation, preventing apoptosis and increasing cell migration and invasion.     

Metastatic small cell lung cancer causing biliary obstruction

We report a case with metastatic small cell lung cancer which first manifested with biliary obstruction due to metastasis. Prognosis of patients presenting with jaundice due to hepatic parenchyma involvement is thought to be poor. However, the patient was successfully treated with percutaneous transhepatic biliary drainage and combination chemotherapy with reduced dosage. We believe this to be the first such case report, despite the frequency of metastasis to the liver from small cell lung cancer.     

Ornithine aminotransferase promoted the proliferation and metastasis of non-small cell lung cancer via upregulation of miR-21

The incidence and mortality of lung cancer ranked the first among all types of cancer in China, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for 85% of all lung cancers. Given that the survival rate of patients with advanced NSCLC is still poor nowadays, identification of novel therapeutic targets and the development of effective therapies are desired for the treatment of NSCLC in clinics. In this study, we reported the upregulation of ornithine aminotransferase (OAT) in NSCLC cells and clinical tumor samples as well as its association with the advanced TNM stage, metastasis, and poor tumor differentiation of lung cancer. Using different NSCLC cell lines, we demonstrated that OAT promoted the proliferation, invasion, and migration, inhibited the apoptosis, and altered cell cycle of NSCLC cells; besides, the involvement of OAT-miR-21-glycogen synthase kinase-3β signaling in the functional role of OAT in NSCLC was also revealed. Importantly, in the absence of OAT, the growth and metastasis of tumor lung cancer xenograft was significantly suppressed in the nude mice. Based on our findings, OAT may be a potential novel biomarker for the diagnosis and therapeutic outcome monitoring of NSCLC. Inhibition of OAT may also represent a new therapeutic strategy of NSCLC.     

TUBB3mRNA表达对紫杉醇化疗晚期非小细胞肺癌患者疗效的影响

目的：探讨TUBB3mRNA表达对紫杉醇化疗晚期非小细胞肺癌患者疗效影响。方法：对我院收治的100例晚期非小细胞肺癌患者根据其TUBB3mRNA表达情况将其分为阳性组55例和阴性组45例,对两组患者均采用紫杉醇联合顺铂进行治疗,分析两组患者的临床资料以及预后。结果：两组患者的临床资料无明显差异性,而阴性组患者在客观缓解率、部分缓解率、疾病进展率、总生存时间以及至肿瘤进展时间均优于对照组（P〈0．05）。阳性组在性别、年龄、淋巴结转移、TNM分期的比较中无差异,而在病理分型中（鳞癌／腺癌）的比较中存在显著性差异。结论：TUBB3mRNA阴性表达的患者其采用紫杉醇联合顺铂进行治疗可明显延长患者生存时间。     

非小细胞肺癌体部寡转移的立体定向放射治疗

非小细胞肺癌(Non-small cell lung cancer, NSCLC)寡转移是NSCLC转移过程中的一种中间状态,是肿瘤生物侵袭过程中较温和的一个阶段,它介于原发灶与远处广泛转移之间,转移瘤数目≦5个,受累器官≦2个,此时肿瘤细胞尚不具备全身播散的倾向。晚期恶性肿瘤患者很大部分处于寡转移状态,而约30%的非小细胞肺癌(NSCLC)患者死于寡转移,目前对于寡转移的治疗以局部治疗为主(包括手术、放疗以及射频消融)。治疗隐匿性转移灶、寡转移灶及全身化学治疗结束后清除残留局部病灶成为治疗寡转移的关键,越来越得到专家共识。在无法手术或者拒绝手术的患者中,局部放放射治疗凸显巨大优势,尤其是体部立体定向放射治疗(Stereotactic Body Radiation Therapy, SBRT),大量临床研究结果显示体部立体定向放射治疗NSCLC寡转移是安全有效的,并能提高转移灶的局部控制率。本文旨在对SBRT治疗非小细胞肺癌寡转移的临床进展做一综述。     

Increased Expression and Aberrant Localization of Mucin 13 in Metastatic Colon Cancer

MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer.     

Adult lung stem cells and their contribution to lung tumourigenesis

The isolation and characterization of lung stem and progenitor cells represent an important step towards the understanding of lung repair after injury, lung disease pathogenesis and the identification of the target cells of transformation in lung carcinogenesis. Different approaches using prospective isolation of progenitor cells by flow cytometry or lineage-tracing experiments in mouse models of lung injury have led to the identification of distinct progenitor subpopulations in different morphological regions of the adult lung. Genetically defined mouse models of lung cancer are offering new perspectives on the cells of origin of different subtypes of lung cancer. These mouse models pave the way to further investigate human lung progenitor cells at the origin of lung cancers, as well as to define the nature of the lung cancer stem cells. It will be critical to establish the link between oncogenic driver mutations recently discovered in lung cancers, target cells of transformation and subtypes of lung cancers to enable better stratification of patients for improved therapeutic strategies.     

Tumor‐propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24‐dependent and Yap/Taz‐dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease.     

MicroRNAs associated with metastatic prostate cancer

Objective

Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis.

Methods

Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient''s primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles).

Results

Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach.

Conclusions

The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient''s cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis.     

CA19-9、CA125、CEA及Ferritin联合检测诊断非小细胞肺癌脑、骨转移的临床价值研究

目的:研究CA19-9、CA125、癌胚抗原(CEA)以及铁蛋白(Ferritin)四种肿瘤标志物联合检测用于诊断非小细胞肺癌(NSCLC)脑或(和)骨转移的临床价值。方法:选取2011年5月至2012年5月于我院就诊的NSCLC患者184例。将发现脑或(和)骨转移者归为转移组,共96例;将未发现脑、骨转移者归为无转移组,共88例,采用电化学发光免疫分析法测定各组患者血清中CA19-9、CA125、CEA以及Ferritin的水平,探讨其在NSCLC患者脑或(和)骨转移中的诊断效能。结果:在发生脑或(和)骨转移的NSCLC患者中,CA19-9、CA125、CEA及Ferritin四种肿瘤标志物的水平和阳性率均显著高于未发生骨、脑转移的患者。ROC曲线分析显示,以上四种肿瘤标志物对诊断NSCLC骨或(和)脑转移的敏感度分别为73.48%、69.13%、66.35%和61.34%;特异度分别为80.02%、32.51%、65.11%和62.58%;将四种肿瘤标志物联合进行诊断的敏感度和特异度分别为91.21%和88.64%,显著高于单一标志物诊断。结论:发生脑或(和)骨转移的NSCLC患者血清中CA19-9、CA125、CEA以及Ferritin四种肿瘤标志物水平均显著升高,以上标志物联合检测可提高NSCLC患者脑或(和)骨转移的诊断效能,可作为早期诊断NSCLC患者脑或(和)骨转移的辅助检测指标。     

外周血CTC、VEGF的水平与晚期非小细胞肺癌临床特征及化疗疗效关系的研究

摘要 目的：探讨外周血循环肿瘤细胞（CTC）、血管内皮生长因子（VEGF）的水平与晚期非小细胞肺癌临床特征及化疗疗效的关系。方法：选取我院2017年1月到2020年1月收治的80例晚期非小细胞肺癌患者作为研究对象,所有患者均采取一线方案化疗,分析外周血CTC、VEGF的水平与患者的年龄、性别等的关系,并对晚期非小细胞肺癌化疗疗效进行单因素与多因素COX分析。结果：CTC、VEGF与不同性别、年龄患者和TNM分期无明显关系（P＞0.05）,与淋巴结转移、肿瘤分化程度、肿瘤大小有关（P＜0.05）;80例患者中,客观缓解率（ORR）为51.25 %（41/80）,疾病控制率（DCR）为71.25 %（57/80）;淋巴结转移、肿瘤分化程度、CTC和血清VEGF水平为晚期非小细胞肺癌患者ORR、DCR的影响因素（P＜0.05）;COX分析分析表明：肿瘤中、低分化、CTC阴性、VEGF降低为晚期非小细胞肺癌化疗ORR和DCR提升的独立影响因素（P＜0.05）。结论：外周血CTC、VEGF检测对于晚期非小细胞肺癌化疗近远期疗效评估具有重要价值,属于预后独立影响因素。因此,CTC、VEGF可作为晚期非小细胞肺癌的预后及疗效判断的指标。     

13q14断裂重排与非小细胞肺癌转移潜能关系的研究

肿瘤转移的细胞经常存在染色体数目异常和结构畸变,在多种有转移潜能的肿瘤细胞中都涉及到13q14的异常。以往研究表明在同一组织来源但转移潜能不同的肺腺癌细胞系AGZY83-a和Anip973中存在13q14的断裂重排。采用mRNA差异展示技术（mRNA DD）分析这一对细胞系得到的差异表达基因BRI基因位于13q14。为了进一步分析肺癌细胞的转移潜能与13q14断裂重排间的关系,采用13q涂染探针对具有不同转移潜能的非小细胞肺癌细胞系PAa、SPC-1-A和95D中期分裂相进行G显带后的荧光原位杂交分析。结果发现在3个肺癌细胞系中有多种13号染色体长臂的结构异常,其中此3个细胞系均涉及13q32-33的频发断裂。但是低转移肺癌细胞系PAa、SPC-1-A均未涉及13q14的断裂,而高转移肺癌细胞系95D的两种细胞克隆均可见13q14的断裂。提示13q14断裂点与肺癌细胞的转移能力有一定的相关性,两者之间的遗传学意义需要进一步研究探索。     

系统性纵隔淋巴结清扫对非小细胞肺癌患者预后的影响

目的：探讨系统性纵隔淋巴结清扫术对非小细胞肺癌患者预后的影响。方法：选择2007年1月至2009年12月在我院住院的124例非小细胞肺癌患者为研究对象,并将其随机分为对照组和实验组,对照组60例患者采用采样式纵隔淋巴结清扫术（med．itational lymphnodesampling,LS）治疗,实验组64例患者采用系统纵隔淋巴结清扫术（systematic meditational lymphadenectomy,SML）治疗。比较两组患者的淋巴结清除总数、淋巴结转移数、淋巴结转移率,通过寿命表法和Kaplan—Meier法比较两组患者的累积3年生存率及中位生存时间。结果：两组比较淋巴结转移率无统计学差异,而与对照组相比,实验组术后并发症发生率明显下降,差异具有统计学意义（P〈0．05）。对照组和实验组患者的中位生存期、3年生存率分别为20．1和24．2个月、18．75％和43．33％,两组比较差异显著,有统计学意义（P〈0．05）。结论：系统性纵隔淋巴结清扫治疗非小细胞肺癌可显著降低患者的淋巴结转移率,并提高患者的3年生存率,延长患者的寿命。     

Metastases from metastases: comparative metastatic potential of human cancer cell lines originated from primary tumors or metastases in various tissues

Although metastases from original (primary) tumors are highly studied, metastases from metastatic sites (secondary tumors) are far less studied. Here, using data from metastasis map (MetMap) project reported in a recent study (Jin et al. in Nature 588(7837): 331–336. 10.1038/s41586-020-2969-2, 2020), we found that human cancer cell lines isolated from metastatic sites have higher potential to metastasize to another site in mice, compared to human cancer cell lines isolated from primary sites, for certain types of cancer including liver, lung and pancreas cancer. In contrast, for cancer types such as ovarian and skin cancer, human cancer cell lines originated from primary tumors have increased metastatic potential in mice, compared to human cancer cell lines originated from metastatic sites. This preliminary analysis points that the potential of metastases to further metastasize compared to that of primary tumors might be cancer type-dependent, and further research is needed to understand why certain cancer cell lines isolated from metastatic sites are more likely to spread to other organs.     

Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis

Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis.     

ERCC1和RRM1在非小细胞肺癌组织中的表达及意义

目的:观察非小细胞肺癌中ERCC1和RRM1表达,并探讨其临床意义。方法:选择本院及西安交通大学第一附属胸外二科于2013年1月-2013年6月收治的经术后病理证实为非小细胞癌肺癌患者40例作为研究对象,均采取免疫组化技术测定组织中ERCC1和RRM1表达水平,并分析ERCC1和RRM1表达水平与患者年龄、病理分期、是否淋巴结转移等相关因素之间的关系。结果:40例非小细胞肺癌患者中,ERCC1表达阴性28例(70.0%),阳性12例(30.0%);RRM1表达阴性9例(22.5%),阳性31例(77.5%)。ERCC1和RRM1表达阴性非小细胞肺患者生存期均优于表达阳性患者,均P0.05。患者非小细胞癌TNM分期及淋巴结转移转移情况与ERCC1及RRM1表达情况具有相关性,均P0.05。结论:非小细胞肺癌ERCC1和RRM1表达水平测定有助于预后情况,具有重要临床价值。