胃癌侵袭和转移分子机制研究进展

胃癌是我国常见的恶性肿瘤之一 ,占消化道恶性肿瘤第一位 ,癌细胞侵袭和转移是影响其疗效的主要原因。胃癌侵袭和转移的过程非常复杂 ,从分子水平可将其归纳为：粘附分子介导癌细胞与正常细胞、细胞外基质（ＥＣＭ）进行粘附 ;癌细胞释放多种蛋白水解酶降解所粘附的组织 ;水解酶使胃癌细胞粘附部位形成空隙 ,从而使胃癌细胞向纵深方向或远处运动 ;着床的癌细胞在多种促血管生成因子的作用下形成新生血管 ;癌细胞通过自身机制逃避宿主免疫监视系统的杀伤作用得以生存增殖。明确胃癌侵袭和转移具体的分子机制 ,采取有效的阻断转移 ,对估计预后…     

基质金属蛋白酶-9的表达与肾细胞癌血管生成的关系

背景与目的:基质金属蛋白酶-9(matrixmetalloproteinase-9,MMP-9)与肿瘤的侵袭、转移密切相关,近年发现它与肿瘤的血管生成也有关。本研究旨在探讨MMP-9的表达与肾细胞癌血管生成的关系及其临床意义。方法:应用免疫组化SP法检测78例肾细胞癌组织中MMP-9、血管内皮细胞生长因子(vascularendothelialgrowthfactor,VEGF)的表达及微血管密度(microvesseldensity,MVD)。结果:MMP-9的表达与肾细胞癌的病理分期和组织学分级有关(P<0.05);MMP-9表达阳性组的MVD值为110.46±50.16,明显高于阴性组的MVD值(84.77±44.52)(P<0.05),亦明显高于对照组的MVD值(74.03±36.06)(P<0.01);肾细胞癌组织中MMP-9的表达水平与VEGF的表达呈显著性正相关(r=0.4096,P<0.01)。结论:MMP-9与肾细胞癌的血管生成有关,检测MMP-9的表达可作为反映肾细胞癌侵袭和转移潜能的生物学指标。     

抗肿瘤转移治疗研究进展

近年来，癌侵袭转移的基础研究进展迅速，随之对形成转移的不同环节设计各种治疗战略，包括抗迁移机制，抑制细胞外基质的降解，抗粘附，阻断信息传递，抑制血管生成等也取得了进展。本文综述了这个领域研究进展。     

肾细胞癌血管内皮生长因子靶向治疗

肾细胞癌的生长、浸润和转移与血管生成密切相关。以血管内皮生长因子（VEGF）通路为靶点,抑制肾细胞癌血管生成,已成为肾细胞癌治疗的研究热点。目前沙利度胺已经进入Ⅱ期临床试验,单克隆抗体和小分子VEGF受体抑制剂进入了Ⅲ期临床试验。VEGF靶向治疗有可能成为肾细胞癌新的辅助治疗标准。     

肾透明细胞癌中Ang-2的表达及与血管生成的关系

目的:探讨Ang-2及CD34在肾透明细胞癌中的表达及与肾透明细胞癌血管生成的关系.方法:应用免疫组化S-P法,分别检测80例肾透明细胞癌组织及10例癌旁肾组织中Ang-2及CD34的表达.结果:肾透明细胞癌组织中Ang-2阳性表达率为61.25%(49/80),明显高于癌旁肾组织.Ang-2的表达与肾透明细胞癌患者血尿、临床分期及淋巴结转移显著相关.结论:Ang-2可能在肾透明细胞癌血管生成中起重要作用,与肾透明细胞癌的分期、转移相关.     

肾细胞癌基质金属蛋白酶-9与血管生成的关系

目的观察基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)在肾细胞癌组织中的表达特点及其与微血管密度(microvessel density,MVD)的关系,探讨MMP-9对肾细胞癌血管生成的作用和意义.方法采用SP免疫组织化学染色方法检测55例肾细胞癌组织中MMP-9和CD34的表达,并结合临床病理参数进行综合分析.结果 MMP-9蛋白在肾细胞癌组织中的阳性率为63.63%.肾癌组织中MMP-9的表达显著高于正常肾组织(P＜0.05),且与肿瘤中MVD密切正相关(r=0.456,P＜0.01).MMP-9的表达和肿瘤中MVD均与肾癌的分期、肾包膜侵袭和淋巴结转移密切相关(P＜0.05),而与肾癌组织学类型无关(P＞0.05).结论肾癌组织MMP-9高表达与MVD及肾癌的一些生物学行为、转移发生有密切关系,MMP-9可能是肾癌的重要促血管生成因子之一.     

KiSS-1和MMP-9在肾透明细胞癌中的表达及其临床意义

目的:探讨KiSS-1基因和基质金属蛋白酶-9(MMP-9)与肾脏透明细胞癌侵袭、转移的关系,为研究肾透明细胞癌的转移机制及治疗提供理论基础。方法:利用免疫组化方法检测45例肾透明细胞癌和15例正常肾组织中KiSS-1、MMP-9的表达水平。结果:KiSS-1基因产物metastin在正常肾组织和肾透明细胞癌中的阳性表达率分别为40.0%和31.1%,差异无显著性(P>0.05);metastin表达与肾透明细胞癌的临床分期和淋巴结转移有关(P<0.05),与患者性别、年龄、肿瘤大小、肿瘤组织学分级等临床病理因素无关(P>0.05)。MMP-9在正常肾组织和肾透明细胞癌中的表达率分别为20.0%和64.4%,差异有显著性(P<0.05);MMP-9表达与肾透明细胞癌组织学分级、肿瘤临床分期及淋巴结转移有关(P<0.05),与患者性别、年龄、肿瘤大小等临床因素无关(P>0.05)。结论:metastin表达与肾透明细胞癌的临床分期和淋巴结转移有关,MMP-9可能促进肾透明细胞癌的侵袭和转移过程。两者有望成为判定肾透明细胞癌侵袭和转移能力的指标。     

食管鳞状细胞癌的肿瘤血管生成机制

血管内皮生长因子、缺氧诱导因子、白细胞介素、血管生成素样蛋白、整合素和上皮间质转化在食管鳞状细胞癌血管生成中为癌细胞的生长、侵袭和转移提供了营养支持和有利环境.对食管鳞状细胞癌血管生成机制的研究将为其抗血管靶向治疗提供更多思路和潜在靶点.     

Vimentin在肾透明细胞癌中的表达及临床意义

目的:探讨波形蛋白(Vimentin)在人肾透明细胞癌(clear cell renal cell carcinoma,ccRCC)和癌旁组织样本中的表达情况,并分析其与 ccRCC 临床分期、病理分级和侵袭转移等恶性生物学特性的关系及临床意义。方法:Western blot方法检测29例新鲜肾透明细胞癌及相应癌旁组织中Vimentin的表达;免疫组织化学方法检测120例肾透明细胞癌及相应癌旁组织中Vimentin的表达情况,分析Vimentin在肾透明细胞癌组织中及癌旁正常肾脏组织中的表达水平差异及Vimentin的表达与肿瘤大小、临床分期、组织病理分级、远处转移的关系。结果:Vimentin在肾透明细胞癌及相应癌旁组织中均有表达,前者的表达水平较后者显著升高（P＜0.01）;免疫组织化学显示肾透明细胞癌组织中,Vimentin的阳性表达率高达90.0%,与癌旁组织存在明显差异（P＜0.01）;Vimentin在肾透明细胞癌组织中以胞膜表达为主,其表达随肾癌的临床分期、肾包膜受侵、癌栓形成或远处转移有升高趋势,但组间比较经统计学分析均无显著性差异。结论:Vimentin在肾透明细胞癌组织中的表达明显高于癌旁正常肾组织,提示Vimentin在肾透明细胞癌的发生发展过程中发挥重要的作用。Vimentin在肾透明细胞癌组织中过表达,与肾癌的发展密切相关,可以作为肾细胞癌早期诊断、预后和复发评估的参考指标之一。     

肿瘤侵袭机制探讨

侵袭和转移是恶性肿瘤的特征。由于人们对这些行为的分子水平机制了解甚少,分析的方法也就较粗糙。侵袭是组织屏障的丧失并伴随瘤细胞侵入邻近组织;转移是侵袭细胞进入血管或淋巴管,存活在血管内并沿管道运行,粘附在毛细血管壁上,游出毛细血管腔,并在远处生长成瘤。多数研究方法需将肿瘤和宿主在体内或体外条件下相接触,这种接触方式不同于肿瘤发展的自然过程。后者可能是单个瘤     

Radiotherapy-related typing in 842 patients in canton with nasopharyngeal carcinoma

PURPOSE: The aim of this study was to propose the clinical radiotherapy-related typing and to summarize proportional distribution of radiotherapy-related types of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: A total of 842 cases of NPC were randomly selected. According to 5-year follow-up results after radiotherapy, NPC was subdivided into four types: Type I (no primary and regional recurrence and no distant metastasis), Type II (primary or regional recurrence and no distant metastasis), Type III (no primary and regional recurrence, and distant metastasis), and Type IV (primary or regional recurrence, and distant metastasis). Proportion of the four types and relationship between this typing and Zhi-guang Xie typing were analyzed. RESULTS: Distribution of radiotherapy-related types of NPC were 50.6%, 23.2%, 20.7%, and 5.6% for Types I, II, III, and IV, respectively. For Types D and AD of Zhi-guang Xie typing system and Stage III and IV of the 1992 Fuzhou staging system, the proportion of Type III was greater than that of Type II; and for Type A and Stage I and II, there was a larger proportion of Type II than that of Type III. CONCLUSION: Radiotherapy-related typing, as a new clinical subclassification, could be supplementary for previous clinical typing and staging.     

分子分型在乳腺癌术后复发转移中的应用研究

[目的]研究乳腺癌分子分型与术后复发转移的关系。[方法]收集术后复发转移的乳腺癌患者的临床病理资料,明确患者复发转移的部位及时间,分析各分子亚型与临床病理特征以及复发转移部位、时间的关系。[结果]入组299例术后复发转移的乳腺癌患者,其中Luminal A型、Luminal B型、Her-2阳性型和Basal-like型分别为92例、79例、47例和81例。各分子亚型中年龄（P=0.034）、月经状况（P=0.013）、肿瘤组织学分级（P=0.000）、术后淋巴结转移情况（P=0.035）、术后复发转移时间（P=0.000）以及术后复发转移部位（P=0.007）存在显著差异。Cox逐步回归分析显示,组织学分级（P=0.000）和分子分型（P=0.000）是乳腺癌术后复发转移的独立预后因子。[结论]乳腺癌分子分型作为传统TNM分期的重要补充,能够很好地预测乳腺癌术后复发转移部位和时间,有助于临床医师对术后患者进行个体化随访筛查。     

Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.

We have previously detected an increased frequency of loss of heterozygosity (LOH) on chromosome 18q during progression of colorectal carcinomas. To clarify the target of 18qLOH, mutation of Smad4 and Smad2 genes was analysed in 176 colorectal tumors with different stages, including liver metastasis, from 111 sporadic, 52 familial adenomatous polyposis (FAP) and nine hereditary nonpolyposis colorectal cancer (HNPCC) patients. Mutation of other Smad gene families in the TGF-beta signaling pathway was also examined. Twenty-one Smad4 mutations and one Smad2 mutation were detected, whereas mutation of Smad3, 6 and 7 genes was not detected. Smad4 mutations included seven frameshift, one inframe deletion, four nonsense and nine missense mutations, 95% of which resulted in alteration of Smad4 protein regions included in homo-oligomer and hetero-oligomer formation. Frequencies of tumors with Smad4 mutation were 0/40 (0%) in adenoma, 4/39 (10%) in intramucosal carcinoma, 3/44 (7%) in primary invasive carcinoma without distant metastasis, 6/17 (35%) in primary invasive carcinoma with distant metastasis, and 11/36 (31%) in distant metastasis (metastatic/non-metastatic: P=0.006 approximately 0.01). Loss of the other allele was observed in 19 of 20 (95%) invasive and metastasized carcinomas with Smad4 mutations. In four cases both primary and metastasized carcinomas in the same patients showed the same mutations. The present results suggest that Smad4 gene is one of true targets of 18qLOH, and that its inactivation is involved in advanced stages, such as distant metastasis, in human colorectal carcinogenesis.     

鼻咽癌放疗分型的LDH分布及预后影响

目的 了解疗前血清LDH水平在鼻咽癌各放疗分型中分布及对预后影响。方法 搜集中山大学肿瘤防治中心2000—2005年初治鼻咽癌患者2665例资料,对疗前血清LDH检测值在放疗4种分型中变化及其与生存关系进行分析。结果 2665例患者各放疗分型分布分别为Ⅰ型(放射敏感不易转移型)1987例(74.6%)、Ⅱ型(放射抗拒不易转移型)404例(15.1%)、Ⅲ型(放射敏感易转移型)229例(8.6%)、Ⅳ型(放射抗拒易转型移型)45例(1.7%)。LDH升高者在4个分型所占比例分别为9.6%(191/1987)、15.8%(64/404)、18.8%(43/229)、35.6%(16/45);Ⅲ、Ⅳ型转移患者共274例,其81例肝转移者中LDH升高者占42%(34例)。总随访率为95.2%。总体LDH升高组的OS、LRFS、DMFS曲线均差于LDH正常组(P=0.000、0.000、0.000),而4个放疗分型中只有Ⅱ型OS的差异有统计学意义(P=0.000)。 结论 疗前血清LDH水平升高与鼻咽癌放疗分型相关,在Ⅲ、Ⅳ型患者中LDH升高以肝转移更明显,LDH升高预后变差主要表现在Ⅱ型患者。     

Malignant melanoma of soft parts (clear cell sarcoma). A study of 17 cases, with emphasis on prognostic factors

Seventeen cases of malignant melanoma of soft parts (clear cell sarcoma) are reported. The patients ranged from 9 to 70 years of age, but 13 were between 10 and 40 years of age. There were eight male patients and nine female patients. The most common tumor location (seven patients) was the foot, followed by the area around the knee (four patients). The usual histologic pattern was that of variably sized nests of uniform plump spindle cells with clear to pale cytoplasm separated by fine to coarse fibrous septa; however, variants with a substantial proportion of epithelioid cells, moderate to marked nuclear pleomorphism, predominantly diffuse growth, or a microcystic pattern were seen. Patient survival was relatively poor overall (median, 49 months; ten deaths due to tumor) and was determined mainly by distant metastasis (11 patients). Both survival and distant metastasis were correlated with tumor size (P less than 0.01 for patients with tumors greater than or equal to 5 cm versus less than 5 cm). Other clinical and pathologic factors, including patient age, sex, and race, tumor location, duration of symptoms, initial therapy, mitotic rate, tumor necrosis, proportion of epithelioid cells, and nuclear pleomorphism had no significant relation to survival or distant metastasis when tumor size was taken into account. Local recurrence and regional lymph node metastasis each occurred in four patients.     

Identifying the potential long-term survivors among breast cancer patients with distant metastasis

BackgroundWe aimed to develop a prediction model to identify long-term survivors after developing distant metastasis from breast cancer.Patients and methodsFrom the institution's database, we collected data of 547 patients who developed distant metastasis during their follow-ups. We developed a model that predicts the post-metastasis overall survival (PMOS) based on the clinicopathologic factors of the primary tumors and the characteristics of the distant metastasis. For validation, the survival data of 254 patients from four independent institutions were used.ResultsThe median duration of the PMOS was 31.0 months. The characteristics of the initial primary tumor, such as tumor stage, hormone receptor status, and Ki-67 expression level, and the characteristics of the distant metastasis presentation including the duration of disease-free interval, the site of metastasis, and the presence of metastasis-related symptoms were independent prognostic factors determining the PMOS. The association between tumor stage and the PMOS was only seen in tumors with early relapses. The PMOS score, which was developed based on the above six factors, successfully identified patients with superior survival after metastasis. The median PMOS for patients with a PMOS score of <2 and for patients with a PMOS score of >5 were 71.0 and 12 months, respectively. The clinical significance of the PMOS score was further validated using independent multicenter datasets.ConclusionsWe have developed a novel prediction model that can classify breast cancer patients with distant metastasis according to their survival after metastasis. Our model can be a valuable tool to identify long-term survivors who can be potential candidates for more intensive multidisciplinary approaches. Furthermore, our model can provide a more reliable survival information for both physicians and patients during their informed decision-making process.     

Enhancement of lymph node metastasis and distant metastasis of thyroid carcinoma

BACKGROUND: The mechanisms of local and distant metastases are imperfectly understood. The goal of the current study was to add to the body of knowledge regarding local and distant metastases of thyroid malignancies. METHODS: The authors performed multivariate analysis of 573 patients who underwent surgery between November 1994 and May 2002 for follicular (FTC; n = 100), papillary (PTC; n = 236), or medullary thyroid carcinoma (MTC; n = 237) at a university hospital. RESULTS: In multivariate analysis, extrathyroidal extension consistently evolved as the key risk factor for both lymph node metastasis and distant metastasis. This correlation was most pronounced in MTC and least pronounced in FTC. The risk of lymph node metastasis also increased with reoperative status in patients with MTC and with primary tumor diameter in patients with MTC (tumor diameter > 10 mm) and patients with PTC (tumor diameter > 20 mm). In the PTC group, lymph node metastasis was more common among patients younger than age 45. In the MTC group, extrathyroidal growth and distant metastasis were associated exclusively with lymph node metastasis. Lymph node metastasis was the only secondary risk factor for distant metastasis. In the analysis of risk factors for distant metastasis in the FTC and PTC groups, no interaction was found between extrathyroidal growth and lymph node metastasis. This finding suggests that extrathyroidal growth and lymph node metastasis of FTC and PTC, and presumably also MTC, represent separate mechanisms and routes of distant metastasis. CONCLUSIONS: Screening for both local residual disease and distant metastases should be intensified in the high-risk population of patients whose primary tumors exhibit large diameters, extrathyroidal growth, or lymph node metastasis.     

鼻咽癌后程加速超分割放射治疗失败因素分析

目的分析鼻咽癌后程加速超分割放射治疗后局部和远处失败的因素.方法对无远地转移的178例初治鼻咽低分化鳞癌行后程加速超分割放射治疗.原发灶采用60Co γ射线或6MV X射线,前4周1.2 Gy/次,2次/d,间隔≥6 h,5 d/周,48 Gy后改为1.5 Gy/次,2次/d,5 d/周,共2周.全程总剂量为78 Gy,60分次,6周,其中疗程超过47 d的病例均增加1 d的照射量(1.2 Gy/次或1.5 Gy/次,2次/d).颈部无淋巴结转移者做预防照射,有淋巴结转移者给予根治量照射,均为常规分割放射治疗.结果全组5年总生存率及无瘤生存率分别为72.4%和60.6%,5年鼻咽部及颈部控制率分别为88.9%和83.7%.5年远地转移率25.1%.5年内67例患者失败,其中单纯鼻咽部失败10例,颈部失败13例,远地转移31例,≥2项失败13例.单因素及多因素分析显示T3～T4期、年龄>50岁和颈动脉鞘区肿瘤完全占据是局部控制的不利预后因素.在单因素分析中有淋巴结转移是影响颈部控制率的不利因素,但多因素分析差异未达统计学意义(P>0.05).在影响远地转移的因素中,局部晚期T3～T4期或N2～N3期,男性不论在单因素还是多因素分析均显示有统计学意义.有上述不良预后因素的患者,远地转移明显增加.结论后程加速超分割放射治疗可以提高鼻咽癌患者的5年局部控制率和生存率.T3～T4期和(或)N2～N3期是影响局部控制率和远地转移率的重要不利因素.对局部晚期患者应联合其他全身方法进行治疗.     

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT-PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours.