肿瘤起始细胞及上皮-间质转化在肿瘤转移及耐药中的作用

目的总结肿瘤起始细胞(tumor initiating Cells,TICs)和上皮-间质转化(epithelial-mesenchymal transition,EMT)及其在肿瘤转移和耐药中的研究现状。方法检索近年来国内外有关TICs和EMT及其与肿瘤转移和耐药关系的文献并做综述。结果 TICs是肿瘤细胞中一小群具有自我更新、高度增殖及多向分化能力的细胞,表达多种表面标志物,如CD133、CD44等,在肿瘤的侵袭、转移和耐药中起着重要的作用。EMT是肿瘤上皮细胞失去极性转变为间质细胞的一种现象,常见于胚胎发育及组织修复,能够促进肿瘤的侵袭、转移以及逃避宿主的免疫反应,EMT可能是TICs所致肿瘤转移和复发的根源。靶向TICs或EMT的治疗可能有效预防肿瘤的复发及改善患者的预后。结论 EMT是TICs致肿瘤转移及耐药的重要机理,对于TICs和EMT的研究可用于探索更有效的针对肿瘤的靶向治疗策略。     

Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.     

Impact of Identification of Internal Mammary Sentinel Lymph Node Metastasis in Breast Cancer Patients

Background

Accurate assessment of the internal mammary (IM) nodal basin can impact prognosis and treatment in breast cancer. The goal of this study was to identify characteristics associated with positive IM sentinel lymph nodes (SLNs) and the impact on adjuvant treatment.

Methods

Clinically node-negative breast cancer patients who underwent SLN dissection including removal of IM SLNs were identified and medical records were reviewed. Statistical analysis was performed using Fisher’s exact test and rank-sum tests with a significance level of 0.05.

Results

IM SLNs were removed in 71 patients, 60 (85 %) had negative IM SLNs, whereas 11 (15 %) had positive IM SLNs. Clinicopathologic characteristics were similar between the groups. The majority of patients in both groups had axillary SLNs removed (95 % in the node-negative group vs. 91 % in the node-positive group). Four patients (36 %) with positive IM SLNs had axillary metastasis; thus, IM nodal metastases were the only nodal metastases in 64 % of patients with positive IM SLNs. The identification of IM metastases altered adjuvant therapy in 5 (45 %) patients with positive IM SLNs.

Conclusions

Patients with positive IM SLNs have clinicopathologic features similar to those of patients with negative IM SLNs limiting the ability to predict IM nodal metastasis preoperatively. The identification of IM nodal metastases significantly impacts treatment decisions, especially when IM nodes are the only site of nodal metastasis. Removal of IM SLNs should be considered when lymphoscintigraphy reveals IM drainage.     

Physiologic and Antinociceptive Effects of Intrathecal Resiniferatoxin in a Canine Bone Cancer Model

Background: Resiniferatoxin is a potent capsaicin analog. Intrathecal administration leads to selective, prolonged opening of the transient receptor potential V1 ion channel, which is localized mainly to C-fiber primary afferent nociceptive sensory neurons. Following work in laboratory animals, the authors explored the use of intrathecal resiniferatoxin to control spontaneous bone cancer pain in companion (pet) dogs.

Methods: Normal canine population: Behavioral testing was performed to establish baseline paw withdrawal latency; subsequently, general anesthesia was induced and resiniferatoxin was administered intrathecally while hemodynamic parameters were recorded. Behavior testing was repeated for 12 days after administration of resiniferatoxin. Clinical canine population: Twenty companion dogs with bone cancer pain were recruited. The animal's baseline level of discomfort and analgesic use were recorded. Resiniferatoxin was administered intrathecally and hemodynamic parameters were monitored while the dogs were under general anesthesia. Dogs were reevaluated up to 14 weeks after resiniferatoxin administration.

Results: Normal canine population: In the first minutes after resiniferatoxin injection, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate from baseline. Two days after injection, limb withdrawal latencies increased to the point of cutoff in the dogs that received at least 1.2 [mu]g/kg resiniferatoxin. Clinical canine population: From baseline, there were significant (P < 0.05) increases in mean arterial blood pressure and heart rate after resiniferatoxin injection. Comfort scores were significantly improved at 2, 6, 10, and 14 weeks after resiniferatoxin administration (P < 0.0001). There was decreased or discontinued use of supplemental analgesics in 67% of the dogs 2 weeks after resiniferatoxin administration.     

结直肠癌肝转移的治疗进展

目前,结直肠癌正逐渐成为一个越来越影响当今世界人类健康的问题.而结直肠癌肝转移是结直肠癌患者最主要的死亡原因,肝转移灶无法切除患者的中位生存期仅6.9个月,5年生存率接近0[1],而肝转移灶能根治性切除患者的中位生存期为35个月,5年生存率达30％～50％[2].故结直肠癌肝转移已成为目前结直肠癌治疗的重点和难点之一.     

^89Sr联合放疗和帕米膦酸二钠治疗肺癌多发骨转移

目的：探讨89Sr联合放疗和帕米膦酸二钠治疗肺癌多发骨转移的临床疗效。方法：选取478例肺癌多发骨转移患者,采用89Sr、博宁和放疗3种方法进行联合治疗。结果：疼痛缓解率为82.4%,78例骨转移灶消退,206例治疗结束6个月以内未出现新的转移灶,总有效率59.4%。结论：89Sr联合放疗和帕米膦酸二钠治疗肺癌骨转移简便,无痛苦,无创伤,副作用较低,治疗效果较好。     

Prognostic Significance of Epithelial-Mesenchymal Transition of Extracapsular Spread Tumors in Lymph Node Metastases of Head and Neck Cancer

Background and Purpose

The extracapsular spread (ECS) of lymph node metastasis (LNM) reflects tumor aggressiveness and is associated with poor survival and risk of distant metastasis. In this study, we aimed to explore the prognostic significance of epithelial-mesenchymal transition (EMT) of ECS tumors in LNM of head and neck cancers.

Methods

We collected LNM samples from head and neck cancer patients (follow-up >2 years) and made 20 ECS(?): ECS(+) pairs (1:2) of LNM (N = 60), matched by the primary sites and by T and N classifications. Immunostaining of cytokeratin, E-cadherin, vimentin, and CD31 were performed and quantified to determine the epithelial-mesenchymal transition percent (EMT%), defined as vimentin(+)/cytokeratin(+) area of ECS. Univariate and multivariable analyses of clinic-pathologic factors, including EMT% of ECS, were conducted to identify the significant prognosticators. In addition, the anatomical relationship between CD31 vessels and ECS tumors was analyzed.

Results

Rather than the presence of ECS in LNM, higher EMT% (>50 %) of ECS strongly correlated with the worse overall and disease-free survival and had more frequent recurrence and distant dissemination in their clinical courses. ECS tumors intermingled closely with Ki-67(?) CD31(+) non-proliferating perinodal blood vessels. Particularly, vimentin(+) ECS areas exhibited a higher density of CD31(+) perinodal vessels than did vimentin(?) ECS.

Conclusion

High EMT scores of ECS tumors in LNM predict an unfavorable prognosis and systemic dissemination more accurately than the simple presence of ECS in LNM in head and neck cancer patients.     

前列腺癌的跳跃式转移

目的:提高对仅有骨外器官转移的晚期前列腺癌患者的诊治水平。方法:2例因体检发现肺脏和肝脏有转移癌灶的患者,进一步检查仅发现血PSA升高。经前列腺穿刺活检,病理证实为前列腺癌,MRI示前列腺包膜连续性消失,ECT检查骨骼无异常。遂用LHRHa联合抗雄药物行诊断性内分泌治疗,一例病人在12个月时行手术去势。分别于15个月和18个月时行前列腺调强放疗一疗程(80Gy)。结果:经内分泌治疗3个月时,肝、肺多发转移灶消失或明显缩小,6个月时转移灶均消失,PSA水平1例维持在0.02μg/L以下,1例维持在0.5μg/L左右。放疗后停用药物治疗,随访12个月,肝、肺扫描正常,骨扫描正常,PSA均维持在1.0μg/L以下。结论:前列腺癌的远处转移可首先出现在骨骼以外器官,在诊断时应重视对骨外器官的检查。患者经综合治疗后效果良好。     

Surgical Treatment of Bone Metastasis Followed by a Primary Lung Cancer Lesion: Report of a Case

In August 1997, a 68-year-old man presented with right pelvic pain. Pelvic computed tomography (CT) and bone scintigraphy showed a huge tumor of the right iliac bone. No other lesion was detected, in spite of a high serum carcinoembryonic antigen level (CEA, 963ng/ml). In October 1997, the iliac bone tumor was widely resected, and thereafter was diagnosed to be a metastatic adenocarcinoma of unknown origin. After a resection, the serum CEA level dropped as low as 6.4ng/ml, but gradually went up to 80ng/ml in October 1999. Next, a lung tumor in the left upper lobe was detected by routine chest CT. In January 2000, a left upper lobectomy was performed, and based on not only the pathological findings but also on an immunohistochemical analysis for napsin A expression, the tumor was diagnosed to be lung adenocarcinoma. The histological and immunohistochemical findings in the previously resected bone lesion were completely compatible with those in the pulmonary tumor, which was finally regarded as M1 lung cancer. In October 2002, the patient was alive without any symptoms, although the serum CEA level was elevated again. We consider this case worthy of presentation because of its unique clinical course as well as the successful long-term survival after surgical treatment alone, for both the primary and metastatic lesions.     

Epithelial-Mesenchymal Transition (EMT) and Activated Extracellular Signal-regulated Kinase (p-Erk) in Surgically Resected Pancreatic Cancer

Background EMT or transformation to the mesenchymal phenotype plays an important role in tumor invasion and metastasis. In vitro data suggest that mesenchymal transformation may correlate with the activation of PI3 kinase and Ras/Erk pathways. We investigated the expression of EMT markers (low E-cadherin, high fibronectin, and vimentin) and their association with p-Erk in resected pancreatic cancer. Methods Clinical data/surgical specimens from 34 consecutive pancreatic cancer patients (pts) who underwent pancreatectomy were included. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissues using monoclonal antibodies against vimentin, fibronectin, E-cadherin, and p-Erk. The results were correlated with clinicopathological parameters and survival. Survival analysis (log-rank test, Cox proportional hazard model), categorical data analysis (Pearson’s chi-square, Fisher’s exact test) and Kendall’s tau were performed at a significance level of 0.05. Results The patient population was formed from 13 males and 21 females, with a median age of 66 years (range 38–84 years); American Joint Committee on Cancer (AJCC) stage 1 (n = 2), 2 (n = 27), 3 (n = 5); histological grade 1 (n = 4), 2 (n = 13), 3 (n = 16), 4 (n = 1). Median survival was 15 months (95% CI: 11–24 months). Fibronectin overexpression correlated with the presence of vimentin (p = 0.0048) and activated Erk (p = 0.0264). There was a borderline association of fibronectin with worsening grade (p = 0.06). A negative association between vimentin and E-cadherin was noted (p = 0.0024). Increased fibronectin or vimentin and decreased E-cadherin correlated with poor survival. Conclusion EMT is associated with poor survival in surgically resected pancreatic adenocarcinoma. A correlation between activated Erk and fibronectin was identified that may open avenues for targeted therapy for this subgroup.     

Haemangiosarcoma with a Metastasis of a Malignant Mixed Mammary Gland Tumour in a Dog

An 11‐year‐old dog with a history of weight loss, anorexia, anaemia, epistaxis and a nodule in the mammary gland showed multifocal lung masses during radiography. At necropsy as well as in the histological examination two different tumours were identified in several organs including the right heart auricle. By immunohistochemistry, using a double‐staining DAKO® kit (DAKO Diagnostics, Zug, Switzerland), it was possible to identify the two components as haemangiosarcoma and metastasizing malignant mixed mammary gland tumour.     

乳腺内乳淋巴结在乳腺癌诊治中的临床意义

目的探讨乳腺内乳淋巴结在乳腺癌诊治中的临床意义.方法通过分析国内、外关于内乳淋巴结的相关研究,总结乳腺癌中乳腺内乳淋巴结的分布、转移、检测及临床治疗的效果. 结果乳腺内乳淋巴结主要分布在胸骨附近,沿胸内乳动、静脉走行,在乳腺癌中能够发生早期转移且转移率随腋淋巴结转移数目的增多而增加,对内乳淋巴结的活检和治疗能影响乳腺癌患者的预后.结论内乳淋巴结的活检和治疗有助于乳腺癌的精确分期、治疗和预后判断, 同时也是防止乳腺癌复发的有效手段.     

女性大肠癌卵巢转移的高危因素及治疗探讨

探讨女性大肠癌卵巢转移的高危因素。方法:对我院1990年4月至1996年4月经手术及病理证实的77例女性大肠癌进行临床及病理因素的单因素。多因素分析。结果:具有年龄≤50岁、肿瘤细胞分化程度低及肿瘤侵犯浆膜层三个因素者卵巢转移率明显增高。结论:上述三个因素是女性大肠癌卵巢转移的高危因素。建议女性大肠癌手术前常规作妇科及盆腔B超检查,术中认真探查双侧卵巢,高度重视卵巢的囊性改变。对未切除卵巢者,术后应密切随访卵巢情况。     

Silencing of TLR4 Increases Tumor Progression and Lung Metastasis in a Murine Model of Breast Cancer

Background

Toll-like receptor 4 (TLR4) is a member of a family of pattern recognition receptors that are involved in the host defense against microbial infection. Little research has investigated the link between TLR4 and cancer. We thus addressed the effect of TLR4 in both the host immune system and cancer cells with regard to its effect on breast cancer progression and metastasis.

Methods

Adult female Balb/c mice aged 6–8 weeks were divided into three groups. In group 1, 15 each wild-type and TLR4^?/? mice were inoculated with 4T1 cells; in group 2, wild-type mice were inoculated with 4T1 cells (n = 15), 4T1 cells transduced with TLR4 lentivirus (n = 15) or with control lentivirus (n = 15); and in group 3, 15 TLR4^?/? mice were inoculated with 4T1 cells transduced with TLR4 lentivirus. Flank tumor volume was measured with calipers during weeks 2–5. Animals were then humanely killed and the number of macroscopic lung nodules counted.

Results

There was a significant increase in tumor volume in weeks 2, 3 and 4 after inoculation of TLR4^?/? mice with 4T1 cells compared with wild-type mice (p < 0.05). The number of metastatic lung nodules was significantly higher in TLR4^?/? mice (p < 0.05), and survival of tumor-bearing TLR4^?/? mice was substantially reduced compared with wild-type mice (p = 0.004). Knockdown of TLR4 from the 4T1 cells led to a relative reduction in lung metastasis, although it did not reach statistical significance.

Conclusions

TLR4 exerts both a defensive role at the host level and a negative role at the cancer cell level in this murine metastatic breast tumor model. Further evaluation of the role of TLR4 in breast cancer is warranted.