肝星状细胞与肿瘤肝转移的研究进展

肝脏是人体各类恶性肿瘤易于发生转移的部位,而肝星状细胞（HSC）在肿瘤肝转移中扮演着极为重要的角色。HSC能够促进和构成肿瘤细胞肝转移的微环境,肿瘤细胞又诱导HSC活化,活化的HSC又反作用于肿瘤细胞促其生长,两者双向作用呈现级联扩大效应,最终促进肿瘤侵袭、转移及生长。     

基质金属蛋白酶3基因多态性与非小细胞肺癌遗传易感性及淋巴结转移的关系

背景与目的:基质金属蛋白酶(matrixmetalloproteinases,MMPs)可能通过降解细胞外基质(extracellularmatrix,ECM)和基底膜(basementmembrane,BM)参与肿瘤的侵袭和转移。MMP-3启动子区-1171bp处5A或6A单核苷酸多态性(singlenucleotidepolymorphism,SNP)可改变该基因的转录水平,从而影响MMP-3的表达。本实验目的是研究MMP-3启动子区SNP与中国北方人非小细胞肺癌(non-smallcelllungcarcinoma,NSCLC)遗传易感性及淋巴结转移的关系。方法:采用聚合酶链反应-限制性片段长度多态性分析(polymerasechainreaction-restrictionfragmentlengthpolymorphism,PCR-RFLP)方法,分析173名NSCLC患者和350名健康对照者的MMP-3启动子区SNP位点的基因型。结果:MMP-3基因型在NSCLC病例组和健康对照组的分布均符合Hardy-Weinberg平衡(P>0.05);病例组和健康对照组的6A/6A、5A/6A和5A/5A基因型频率分别为65.3%、30.6%、4.1%和67.7%、30.0%、2.3%,6A和5A等位基因频率分别为79.3%、20.7%和82.7%、17.3%,总体分布均无显著性差异(P>0.05);根据吸烟状况及病理类型分层分析发现,吸烟患者组5A等位基因频率(21.0%)显著高于健康吸烟组(12.9%)(χ2=4.81,P=0.03),携带5A/5A或5A/6A基因型可显著增高吸烟者的NSCLC发病风险(经性别、年龄校正的OR     

非小细胞肺癌组织中VEGF-C及其受体VEGFR-3的表达与淋巴结转移的关系

 目的　研究血管内皮生长因子C（VEGF-C）及VEGF受体-3（VEGFR-3）在人类非小细胞肺癌（NSCLC）组织中的表达,并探讨其与淋巴转移之间的关系。方法　对60例NSCLC患者术后标本行VEGF-C、VEGFR-3免疫组织化学（SP法）检测,计数阳性率,并结合临床和病理资料进行分析。结果　60例NSCLC组织中VEGF-C阳性表达率为68.3 %（41／60）,VEGFR-3阳性表达率为53.3 %（32／60）,VEGF-C的表达与肺癌分化程度呈负相关（P＝0.004）,VEGF-C、VEGFR-3的表达与淋巴结转移呈正相关（P＝0.009）,肺癌组织中VEGF-C与VEGFR-3的表达亦相关（r＝0.27）。结论　NSCLC组织中VEGF-C、VEGFR-3的表达与肿瘤细胞的淋巴结转移相关。VEGF-C是促使肿瘤组织内淋巴管形成,促进肺癌淋巴结转移的重要原因。     

MicroRNAs in non-small cell lung cancer invasion and metastasis: from the perspective of the radiation oncologist

Introduction: MicroRNAs (miRs), small sequences of RNA regulating various cellular processes, are implicated to play major roles in cancer. Herein, we discuss the association of several miRs with non-small cell lung cancer (NSCLC), specifically relating to tumor invasion and metastasis to lymphatics and/or distant organs, which can often be correlated with overall prognosis.Areas covered: There exists strong evidence that presence of several miR combinations correlates with prognosis in both early- and advanced-stage NSCLCs. Principally, miR alterations could be useful in enhancing current imaging-based methods to more accurately estimate the extent of invasion/metastases.Expert Commentary: Despite the immature nature of this subject, its large ramifications on clinical oncology are clearly evident. Based on miR signature-related stratification, radiotherapy could be potentially personalized beyond current treatment standards.     

非小细胞肺癌中E-CD、CD44s和VEGF表达与淋巴结转移关系的研究

目的:研究上皮型钙粘附素(E-CD)、标准型CD44(CD44s)与血管内皮生长因子(VEGF)在NSCLC中的表达与淋巴结转移的关系。方法:应用免疫组化SP法检测53例NSCLC组织中E-CD、CD44s和VEGF的表达情况,并分析上述3项被检测物与淋巴结转移的关系。结果:E-CD在NSCLC组织中的表达显著低于正常肺组织(P<0.01),E-CD表达与淋巴结转移呈负相关(P<0.05);CD44s在NSCLC组织中的表达显著高于正常肺组织(P<0.05),CD44s与淋巴结转移呈正相关,差异有显著性(P<0.05);VEGF在NSCLC组织中的表达显著高于正常肺组织(P<0.05),且与淋巴结转移呈正相关,差异有显著性(P<0.05)。结论:E-CD、CD44s和VEGF在NSCLC中淋巴结转移过程中起重要作用,可作为判断预后的指标及靶向治疗的靶点。     

Lung cancer classification: the relationship of disease extent and cell type to survival in a clinical trials population

The staging and histologic cell type of patients in the Lung Cancer Study Group (LCSG) clinical trials program are reviewed and confirmed or resolved at the reference center for anatomic and pathologic classification of lung cancer. A high level of consistency in classification has been achieved through the use of criteria that minimize intraobserver variability. The data obtained from the review project have been used to characterize the relationship of disease extent and cell type to survival in the clinical trials population. Survival characteristics were generated for 1,121 patients who underwent apparent complete resection of nonsmall cell lung cancer and were subsequently entered into various protocols to receive either adjuvant treatment or no further therapy. The end results study provides some insight regarding the biological behavior of squamous cell carcinoma and adenocarcinoma of the lung in terms of the anatomic extent of disease at the time of apparent complete resection. Patients with squamous cell carcinoma had an outcome superior to that of patients with adenocarcinoma in every TNM subset. The differences in survival according to these major cell types were significant overall and in the T1 N0, T1 N1, and T2 N1 subsets but not in the TNM subsets in stage III disease. Histologic cell type and extent of disease are important factors in survival expectations; thus the accuracy and reproducibility of these classifications plays a significant role in the evaluation of differing modalities of treatment.     

Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy

Intrinsic or acquired drug resistance is a major limiting factor of the effectiveness of chemotherapy. Increased expression of either the MRP gene or the MDR1 gene has been demonstrated to confer drug resistance in vitro. In this study, we examined MRP and MDR1 gene expression in a panel of 17 small cell lung cancers (SCLC) xenografted into nude mice from treated and untreated patients using an RT-PCR technique. For some of them, the outcome of the corresponding patients was known and we related MDR1/MRP expression with the xenograft response to C′CAV (cyclophosphamide, cisplatin, adriamycin and etoposide) combined chemotherapy. Fifteen (88%) of the 17 cases of SCLC were found to be positive for either MDR1 or MRP. MRP gene expression was present in 12 (71%) of 17 cases, whereas MDR1 gene expression was detected in eight (50%) of 16 cases. For six SCLC, the survival duration of patients differed, with three patients surviving for more than 30 months after therapy. Among these six tumours, five expressed MRP and/or MDR1. These six xenografts responded to the C′CAV treatment but a significant rate of cure was obtained in only three cases. No obvious relationship was observed between the response to this treatment and MRP or MDR1 expression. However, the remarkably high levels and frequency of MRP expression in some SCLC samples indicate that future developments in chemotherapy of this tumour type should anticipate that drugs which are substrates of MRP may be of limited effectiveness.     

miR-409-3 p调控靶基因Beclin-1抑制小细胞肺癌细胞的自噬进而抑制其生长和转移

目的:探究miR-409-3p及其靶基因对小细胞肺癌细胞自噬、生长和转移的影响.方法:qRT-PCR检测miR-409-3p在HPAEpiC、SBC-5、NCI-H446、HOP-92细胞中的表达,SBC-5细胞中转染miR-409-3p mimic和miR-NC,CCK8法检测转染后细胞增殖,Transwell小室法...     

Spectrum of matrix metalloproteinase expression in primary and metastatic colon cancer: relationship to the tissue inhibitors of metalloproteinases and membrane type-1-matrix metalloproteinase

The matrix metalloproteinases, MMP-2 and MMP-9, are capable of degrading components of the basement membrane, a vital barrier breached during the progression of colorectal cancer. The regulation of MMP-2 activation and subsequent targets is vital to understanding the metastatic process. MMP-2 was not expressed by colorectal cancer cells (C170 and C170HM(2)) in vitro but by stromal fibroblasts (46BR.1GI). There was induction of this MMP upon transwell co-cultivation of the colon cancer cells with the fibroblasts but in vivo growth did not lead to a similar increase in the metastatic tumour cells (C170HM(2)), MMP-2 again being attributed to the stromal cells. MMP-2 mRNA was overexpressed in human colorectal tumours compared to normal colorectal tissue, which correlated with Dukes' stage and immunolocalized to the stromal compartment of the tumour tissue. The active form of the MMP-2 enzyme was also present in the colorectal tumour tissue (7/8) but essentially absent in all normal colon samples examined (1/8). MMP-2 activation was not related to an increase in MT-1-MMP mRNA or a decrease in the specific inhibitor TIMP-2 in human tissue. There was however an increase in MMP-2/TIMP-2 ratio in tumour compared to normal. MMP-9, a target of active MMP-2, was present in the metastatic cell line but expression was down-regulated in the tumour cells in vivo, gelatin analysis revealed that MMP-9 was almost entirely attributable to the murine host, confirmed by PCR. There was no increase in mRNA for MMP-9 or its specific inhibitor TIMP-1 in colorectal tumour tissue compared to normal, MMP-9 protein localized to the inflammatory infiltrate. Fibroblast cells may provide malignant epithelial cells with a ready source of enzyme which is crucial to the metastatic process.     

非小细胞肺癌中长链非编码RNA MCM3AP-AS1表达及其与顺铂敏感性关系的研究

目的:探讨长链非编码RNA（long noncoding RNA,lncRNA）微小染色体维持蛋白3相关蛋白-反义链1（MCM3AP-AS1）在非小细胞肺癌（non-small cell lung cancer，NSCLC）中的表达及其临床意义。方法:使用实时定量PCR检测MCM3AP-AS1在NSCLC组织、癌旁组织和细胞系中的表达。 CCK-8用于评估MCM3AP-AS1对NSCLC细胞顺铂敏感性的影响。使用生物信息学预测、萤光素酶报告基因测定来确定miR-195是否是MCM3AP-AS1的靶标。结果:MCM3AP-AS1在NSCLC组织和细胞系中过表达。 MCM3AP-AS1-shRNA显著增加NSCLC细胞对顺铂的敏感性。使用萤光素酶报告基因测定法证实MCM3AP-AS1可以调控miR-195的功能。此外，上调MCM3AP-AS1表达显著降低NSCLC细胞对顺铂的敏感性。结论:MCM3AP-AS1可能通过与miR-195的竞争性结合抑制NSCLC对顺铂的敏感性，并且提示了抗NSCLC治疗的潜在新策略。     

Metastatic cutaneous squamous cell carcinoma to parotid nodes: the role of bolus with adjuvant radiotherapy

Introduction: Information regarding the addition of tissue equivalent bolus to adjuvant radiotherapy (RT) for intra‐parotid metastatic head and neck cutaneous squamous cell carcinoma is lacking. This study aimed to evaluate the effect of bolus versus no bolus on the patterns of regional and distant recurrence, regional control (RC), cancer‐specific survival (CSS), overall survival, RT toxicity and RT interruption. Methods: A retrospective study was performed on consecutive patients diagnosed between 1994 and 2008 with metastatic head and neck cutaneous squamous cell carcinoma who were treated with parotidectomy ± selective neck dissection and adjuvant RT ± parotid bolus. Results: Seventy‐five patients were identified: 64 males and 11 females, with median age of 79 years (range 40–96) of which 39 had bolus during RT. Median follow up was 48 months (range 4–177). There were 23 regional recurrences – 14 dermal, six dermal + nodal and three isolated nodal – and only two systemic recurrences. Nine patients had RT interruption >6 days due to acute skin toxicity. Bolus was associated with increased grade ≥3 radiation dermatitis (P = 0.02). RT interruption >6 days was significantly associated with inferior RC and hazard ratio, 2.83 (95% confidence interval: 1.04–7.71, P = 0.042). Lympho‐vascular space invasion, positive margins and nodes >2 cm were adversely significant on CSS multivariate analysis. RC, CSS and overall survival at 5 years were 67, 66 and 52%, respectively. Conclusions: Dermal involvement dominated the pattern of regional recurrence. Bolus was associated with significantly worse skin reaction. Bolus use was not associated with a significant overall benefit on RC. This analysis does not support the use of bolus as applied in this cohort.     

Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma

Background Breast cancer, lung cancer and melanoma metastasize to the meninges in 5–15% of patients. The identification of specific biomarkers of disease may allow for earlier diagnosis and treatment. Preclinical evidence suggests the possible relevance of SDF-1 and VEGF in the homing and neoangiogenesis of metastases. We chose to measure these molecules in the cerebrospinal fluid (CSF) of melanoma, breast, and lung cancer patients being evaluated for neoplastic meningitis (NM). Materials and Methods We collected CSF from patients with these cancers who were being evaluated for possible NM. CSF was assayed for SDF-1 and VEGF levels using Enzyme-linked Immunosorbent Assay (ELISA) assays. Results CSF samples from 89 patients met criteria for analysis, including 41 with breast cancer, 35 with lung cancer and 13 with melanoma. Twenty-five percent (22/89) of all samples were positive for malignant cells; 8/41 (20%) from breast cancer, 10/35 (29%) from lung cancer and 4/13 (31%) from melanoma. CSF VEGF levels were available from 83 patients, and were elevated (>20 pg/ml) in 15/22 (68%) of patients with positive CSF cytology and normal (<20 pg/ml) in 59/61 (97%) of patients with negative CSF cytology. The two patients with negative CSF cytology who also had elevated CSF VEGF levels had MRI evidence of NM. CSF SDF-1 levels were available from 81 patients, and were elevated (>950 pg/ml) in 11/18 (61%) of patients with positive CSF cytology and normal (<950 pg/ml) in 57/63 (90%) of patients with negative CSF cytology. Conclusions Elevated CSF levels of VEGF are sensitive and highly specific for the diagnosis of NM from breast cancer, lung cancer and melanoma, and may serve as a useful biomarker of NM in high risk patients. CSF SDF-1 levels add little to the diagnostic information provided by CSF VEGF. Evaluation of CSF VEGF levels as a trigger for early treatment in high risk breast cancer, lung cancer and melanoma patients at risk for NM, is warranted.     

The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.     

The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database

BACKGROUND: This study was designed to investigate whether the mortality from heart disease, a manifestation of intercurrent disease after postoperative radiotherapy (PORT), has decreased over time for patients with nonsmall cell lung cancer (NSCLC). METHODS: The 17-registry 1973 to 2003 dataset from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program was used to create a cohort of patients with NSCLC who had evidence of ipsilateral lymph node involvement diagnosed from 1983 to 1993 and who underwent pnuemonectomy/lobectomy (n = 6148 patients). Heart disease mortality was the primary endpoint: Deaths from other causes were censored, and surviving patients were censored at 10 years. The independent variable was PORT use, and adjustment variables included age at diagnosis, sex, race, year of diagnosis, laterality, location, histology, and the operation performed. RESULTS: Multivariate analysis revealed that PORT use was associated with an increase in heart disease mortality (hazards ratio [HR], 1.30; 95% confidence interval [95% CI], 1.04-1.61; P = .0193) along with older age, male sex, African-American race, and earlier year of diagnosis. The association was confirmed in the cohort that was diagnosed from 1983 to 1988 (HR, 1.49; 95% CI, 1.11-2.01 [P = .0090]) but not for the cohort that was diagnosed from 1989 to 1993 (HR, 1.08; 95% CI, 0.79-1.48 [P = .6394]). CONCLUSIONS: The results from this study demonstrated that the risk of heart disease mortality associated with PORT has declined in more recent years. This may be secondary to improvements in the treatment planning and delivery of thoracic radiotherapy. Properly designed, prospective, adjuvant trials will be needed to verify these findings.