Bimodal role of Kupffer cells during colorectal cancer liver metastasis

Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3⁺ T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of pro-tumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.     

结直肠癌肝转移的治疗进展

结直肠癌肝转移是影响结直肠癌预后的重要因素，治疗方案包括手术治疗、化疗（全身静脉化疗和介入治疗）、基因治疗和局部治疗（射频消融、激光消融、无水酒精注射和冷冻切除术）等，其中手术是目前唯一有效的治愈手段，手术死亡率1％～2．8％，术后5年生存率34％-38％，但仅有10％．25％结直肠癌肝转移患者确诊时适合于手术切除，因此各种非手术治疗的作用正日益受到关注。本文对结直肠癌肝转移的综合治疗作一综述。     

Chemotherapy for liver metastasis of colorectal cancer

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. Although surgical resection is the first choice of treatment for liver metastasis of colorectal cancer, there are many cases we cannot choose the surgical treatment. The chemotherapy is very important in such cases. We examined 18 cases of unresectable liver metastases from colorectal cancer which were adapted a hepatic arterial infusion of 5-FU (HAI) with a weekly high-dose infusion method (WHF) as the first-line treatment, and then systemic chemotherapy of CPT-11 in combination with 5-FU as the second-line treatment. The response rate of this treatment is 72% (13/18) and the 1-, 2-, 3-year survival rates were 100% (16/16), 83% (10/12), and 50% (5/10), respectively. The combination chemotherapy of HAI with systemic chemotherapy using CPT-11 seemed to be an effective treatment method.     

结直肠癌肝转移外科治疗策略

目前手术切除是结直肠癌肝转移（CRLM）唯一具有治愈可能的治疗方式。近年来随着全身化疗及靶向药物的发展、肝动脉灌注化疗的应用,对于CRLM 治疗的有效率明显升高,通过手术获益的患者逐渐增多;而如射频消融、二步切除等外科技术的进步,也为更多CRLM 患者提供了治愈的机会。多学科诊疗模式（MDT ）也为更多CRLM 患者的个体化诊治创造了机会,使未来CRLM 的治疗向更加精准的方向发展。     

结直肠癌肝转移机制的研究进展

肝脏是结直肠癌转移的主要靶向器官,越来越多的研究证明,肿瘤微环境、信号传导途径、染色体的异常、增殖与凋亡调控基因的异常等为结直肠癌肝转移的重要的机制,结直肠癌肝转移是其共同作用的结果.研究其机制能为预防和治疗结直肠癌肝转移提供新思路.     

大肠癌肝转移预测指标

研究发现在大肠癌肝转移患者中,血管内皮生长因子(VEGF)、p53基因、基质金属蛋白酶(MMP)、骨桥蛋白(OPN)等生物学指标呈现高表达状态,对其检测可以预测大肠癌发生肝转移的可能性,从而对大肠癌患者提早干预,改善预后.     

结直肠癌合并糖尿病与淋巴结转移的关系

目的探讨结直肠癌合并糖尿病与淋巴结转移的关系。方法对选取2006年1月^至2011年12月间收治的313例结直肠癌患者进行病例对照研究,分析合并糖尿病的结直肠癌患者的淋巴结转移情况。结果 313例结直肠癌患者中,有45例合并糖尿病,占14.4%。45例结直肠癌合并糖尿病患者的淋巴结转移率为51.1%,268例无糖尿病结直肠癌患者的淋巴结转移率为32.5%,差异有统计学意义(P<0.05)。结论结直肠癌合并糖尿病患者的淋巴结转移率较高。     

结直肠癌肝转移的发生机制

结直肠癌的发病率及死亡率在全世界以每年递增的趋势发展着,而其主要的死亡原因是肝转移。这一事件引起了众多学者的关注,大量研究也从各方面对其机理进行了论证。我们应用PubMed和MedLine,以及中国期刊网全文数据库(CNKI)两大文献检索文库,用"结直肠癌"、"肝转移"、"分子机制"等关键词进行检索,总结了近十年间有关结直肠癌的研究,试图提供一个结直肠癌肝转移的基本框架。本文中重点分析一些可能控制此事件的关键分子,对8类13项分子指标,包括基质金属蛋白酶、尿激酶型纤溶酶原激活剂受体、整合素、骨桥蛋白、肿瘤坏死因子相关凋亡诱导配体、干扰素-β、胰岛素样生长因子Ⅰ型受体、核基质蛋白、血管上皮生长因子、过氧化物酶体增殖物激活受体、胰岛素样生长因子、细胞外信号调节激酶和蛋白酶活化受体等与结直肠癌之间的关系进行了总结和分析,以期为寻找治疗和预测结直肠癌肝转移的新靶点提供新思路。     

Immune phenotypic linkage between colorectal cancer and liver metastasis

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Microbiota in colorectal cancer related to liver metastasis

The prevalence of colorectal cancer(CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum(F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately ac...     

Endoscopic radiofrequency ablation for liver metastasis of colorectal cancer

The application of radiofrequency ablation (RFA) for liver metastasis of colorectal cancer has not yet acquired an established status in clinical cancer therapy research. Removing as much tumor tissue as possible is desirable, but some cases do not allow optimal surgical ablation due to general condition of the patient and tumor status. We introduced endoscopic RFA for liver cancer in 2003, and have applied the procedure to 6 cases with H1 or H2 liver metastases of colorectal cancer to which surgical ablation could not be applied due to the poor general health of patients. Mean tumor diameter was 22.9 mm, and mean number of tumors per patient was 1.2. Tumor location was: S4, n = 2; S5, n = 1; S4, n = 1; S7, n = 2; and S8, n = 1. Mean frequency of session was 3.0. No complications occurred in any cases, and no reoperations were required. Although no recurrence of tumors in the vicinity of ablation was observed, 2 cases of each lung metastasis and intrahepatic recurrence were identified. Intrahepatic recurrence underwent hepatic arterial infusion (HAI) chemotherapy for simultaneous metastatic hepatic tumors (H2) prior to RFA, and relapses occurred in the metastatic focus where the efficacy of HAI was observed. At this point, 2 deaths were reported, 1 each from cancer and other diseases, and mean duration of survival after the procedure was 451.2 days. These results indicate that endoscopic RFA with good local control should be an available treatment for cases involving colorectal cancer with metastasis to the liver in which surgical ablation is difficult to apply.     

Investigation of the relationship between DNA-dependent protein kinase and lymphatic metastasis in colorectal cancer

Objective  To investigate DNA-dependent protein kinase (DNA-PK) expression, and its relationship with lymphatic metastasis in colorectal cancer. Methods  Tumor tissues from 60 patients, divided into two groups according to lymphatic metastasis, were immunohistochemically stained to detect the DNA-PK expression including Ku70, Ku80 and PKcs proteins. Results  Positivity of both Ku70 and Ku80 in colorectal cancer was negatively correlated with lymphatic metastasis with an r value of −0.57 and −0.38, respectively. Similar correlation was found between Ku expression, especially Ku70, and long-term survival. PKcs, however, displayed no significant correlation. Statistical analysis failed to detect any correlation between DNAPK expression, and clinical characteristics, such as age, sex, tumor location, tumor thickness and distant metastasis (P > 0.05). Conclusion  DNA-PK expression, especially Ku70 expression, is negatively correlated with lymphatic metastasis, and the survival of patients with colorectal cancer. Ku70 expression may be a potential indicator for the preoperative evaluation, and prognosis in colorectal cancer. Supported by a grant from the Scientific Research Project of the Bureau of Health of Jiading in Shanghai (No. KYXM-2004-11-07).     

大肠癌组织淋巴管生成与淋巴转移相关性的研究

目的：探讨大肠癌组织中血管内皮生长因子-C（vascular endothelial growth factorC,VEGF：C）和-D（vascular endothelial growth factor D,VEGF—D）、癌旁淋巴管密度（lymphatic microvessel density,LMVD）的表达及其与临床病理参数的关系。方法：应用5’-Nase-酶组织化学技术及免疫组化SP法检测对50例大肠癌组织、正常肠组织测定中VEGF-C、VEGF-D和癌旁LMVD。结果：癌旁LMVD与VEGF-C、VEGF-D的表达呈正相关,大肠癌旁LMVD与VEGF-C、VEGF-D的表达与淋巴转移、Duke分期相关。结论：VEGF-C、VEGF-D／VEGFR-3信号传导机制促进淋巴管生成,导致癌旁LMVD的升高,进而促进大肠癌淋巴转移。     

DNA依赖蛋白激酶与大肠癌淋巴转移相关性研究

Objective:To investigate DNA-dependent protein kinase(DNA-PK)expression,and its relationship with lymphatic metastasis in colorectal cancer.Methods:Tumor tissues from 60 patients,divided into two groups according to lymphatic metastasis,were immunohistochemically stained to detect the DNA-PK expression including Ku70,Ku80 and PKcs proteins.Results:Positivity of both Ku70 and Ku80 in colorectal cancer was negatively correlated with lymphatic metastasis with an rvalue of-0.57 and -0.38,respectively.Similar correlation was found between Ku expression,especially Ku70.and long-term survival.PKcs,however,displayed no significant correlation.Statistical analysis failed to detect any correlation between DNA-PK expression,and clinical characteristics,such as age,sex,tumor Jocation,tumor thickness and distant metastasis(P＞0.05).Conclusion:DNA-PK expression,especially Ku70 expression,is negatively correlated with lymphatic metastasis,and the survival of patients with colorectal cancer.Ku70 expression may be a potential indicator for the preoperative evaluation,and prognosis in colorectal cancer.     

Cross-talk between gastric cancer and hepatic stellate cells promotes invadopodia formation during liver metastasis

In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia-associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet-derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto-oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross-talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRβ) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM.     

同时性结直肠癌肝转移患者治疗策略探讨

背景与目的:肝切除术是治疗同时性结直肠癌肝转移获得长期生存的希望.但如何选择肝切除术的手术时机,存在较大的争议,本研究探讨同时性结直肠癌肝转移的手术治疗策略.方法:选择上海东方肝胆外科医院和上海长海医院1995年1月至2005年12月收治的经手术治疗的83例同时性结直肠癌肝转移患者,其中37例行一期手术,46例行分期手术,比较两组手术并发症、死亡率、术中失血量、住院时间、生存率、中位生存期、无瘤生存期及肝转移癌复发率.结果:一期手术组手术并发症发生率为24.3%,分期手术组为19.6%(P=0.601).两组均没有手术死亡.一期手术组术中平均失血量为462 mL,分期手术组为574mL(P=0-312).一期手术组平均住院时间为19 d,分期手术组为36 d(P=0.001).一期手术组l、3、5年生存率分别为86.5%、54.1%和27.0%,分期手术组分别为89.1%(P-0.713)、52.2%(P=0.865)和23.9%(P=0.746).一期手术组中位生存期为40个月,分期手术组为37个月(丹0.075).一期手术组中位无瘤生存期为12个月,分期手术组为11个月(P=0.532).一期手术组肝转移癌复发率为35.1%,分期手术组为30.4% (P=0.650).结论:同时性结直肠癌肝转移患者有选择的一期手术切除原发病灶及肝转移病灶是合理的.     

结直肠癌肝转移的多因素分析

目的 探讨结直肠癌肝转移的相关因素。方法 收集结直肠癌病例1312例,建立数据库。选择性别,年龄,血型,病程,首发症状,肿瘤大小,组织类型,肠壁侵袭,淋巴结转移等临床因素。用Logistic回归（spss10.0统计软件）进行单因素和多因素分析。并对有意义的指标进行相关分析。结果 单因素分析显示,性别,病程,肿瘤大体类型,组织类型,病理分级,肠壁侵袭和淋巴结转移与肝转移有关。多因素分析显示,仅性别,肠壁侵袭和淋巴结转移与肝转移有关。结直肠癌肝转移男女性别比为1.9:1。肝转移发生与肿瘤侵袭肠壁的层次呈正相关（r=0.926,P=0.024)。肝转移发生与淋巴结转移距离的远近无关（r=0.748,P=0.252)。结论 结直肠癌肝转移的相关因素主要有性别,肿瘤侵袭深度和淋巴结转移,男性结直肠癌患者更易发生肝转移,肿瘤侵袭肠壁越深,发生肝转移的危险越大,年龄,血型,病程,首发症状,肿瘤部位,肿瘤大小,术前合并症,并发病与肝转移无关。     

Systemic chemotherapy for advanced colorectal cancer with liver metastasis

We report the progress of systemic chemotherapy for advanced colorectal cancer with liver metastasis. It must be noted that the purpose of this treatment is to prolong the symptom-free period. Review of hepatic arterial infusion (HAI) compared with systemic chemotherapy for the treatment of unresectable liver metastases from colorectal cancer showed that was attained with HAI a much higher response rate and survival benefit than systemic chemotherapy. However, systemic chemotherapy has shown progress since that time. Regarding administration methods, continuous injection is better than bolus injection for 5-FU. New modulators of 5-FU have also became available, such as leucovorin, CPT-11, and I-OHP. Futhermore, many studies of 5-FU-based combination therapy have shown that the mean survival time (MST) and response rate (RR) are now close to those of HAI. Finally, the combination with HAI with systemic chemotherapy using CPT-11 resulted in the highest RR of 74%. Further trials of such combination therapy will be performed in the future.     

Advances in therapeutics for liver metastasis from colorectal cancer

The evolution of chemotherapeutic regimens that include targeted molecular agents has resulted in a breakthrough in the management of advanced colorectal liver metastasis (CLM), improving the progression-free survival after liver resection, and rendering initially unresectable liver tumors resectable, with reported resection rates ranging from 13% to 51%. In addition, the criteria used for selecting patients for hepatectomy have been expanding because of advances in surgical techniques and improvements in chemotherapy. However, the increasing use of chemotherapy has raised concern about potential hepatotoxicities such as steatosis, chemotherapy-associated steatohepatitis, and sinusoidal obstruction syndrome, and their deleterious effects on postoperative outcome. The present review focuses on the advantages and disadvantages of chemotherapy, strategies for the prevention and diagnosis of chemotherapy-associated liver injury, and the adoption of more aggressive surgical approaches, which have changed the traditional paradigm for CLM.