Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

Purpose Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. Methods We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. Results A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). Conclusions Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer. *Deceased. The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006. Reprints are not available.     

HGF在大肠癌中的表达及其与淋巴管生成及转移的关系

目的探讨肝细胞生长因子（HGF）在大肠癌淋巴管生成及转移中的作用。方法应用免疫组织化学（SABC）法检测52例大肠癌、20例大肠息肉组织和20例正常对照组织中HGF的表达,并应用podoplanin标记淋巴管,检测各组织中的淋巴管密度,结合大肠癌患者的临床病理资料,分析其相关性。结果大肠癌组织中HGF被染成棕黄褐色,其阳性表达率和相对表达量均明显高于大肠息肉组织和正常大肠组织[75％、30％、15％;（0．36±0．07）、（0．24±0．06）、（O．23±0．06）,P〈0．01]。其微淋巴管密度（LMVD）也明显增多[（4．13±1．99）、（2．59±1．46）、（2．40±1．44）,P〈0．01]。大肠癌组织中HGF的相对表达量和LMVD两者间呈正相关。39例HGF表达阳性的大肠癌,其LMVD明显大于HGF蛋白表达阴性者[（4．25±2．13）w（2．73±1．54）,t=3．051,P=0．003]。HGF和LMVD的表达与大肠癌患者年龄、性别及肿瘤分化程度无关（P〉0．05）,但与Dukes分期（P=0．034,P=0．006）、淋巴管有无转移明显相关（P=0．015,P=0．001）。结论HGF与大肠癌的淋巴管生成及转移有一定的相关性,并可能通过直接或间接促进淋巴管增生,从而促进肿瘤细胞的淋巴转移。     

Podoplanin阳性淋巴管密度与非小细胞肺癌预后的关系

目的探讨非小细胞肺癌(NSCLC)患者淋巴管生成(lymphangiogenesis)与预后的关系。方法应用免疫组织化学的方法,检测68例NSCLC和8例肺炎症性肌纤维母细胞瘤(PIMT)组织标本中CD31、podoplanin和血管内皮生长因子受体-3(VEGFR-3)的表达,进行淋巴管密度及微血管密度计数;与血管内皮标志物CD31比较,评价VEGFR-3和podoplanin标志物的表达;分析淋巴管密度与患者临床病理改变及预后的关系。结果Podoplanin阳性淋巴管密度与CD31阳性血管密度、VEGFR-3阳性血管密度无相关性;VEGFR-3与CD31阳性血管密度有相关性。镜下见VEGFR-3阳性管多数有血管,而podoplanin阳性管未发现血管。淋巴管密度在NSCLC组为(22.4±8.6)支/mm2,明显高于PIMT组的(10.9±4.9)支/mm2;与淋巴结转移阴性组[(20.4±8.2)支/mm2]比较,淋巴结转移阳性组淋巴管密度[(24.8±9.0)支/mm2]明显增高;临床Ⅲ+Ⅳ期患者组织淋巴管密度[(27.2±9.2)条/mm2]明显高于Ⅰ+Ⅱ期的(19.5±6.9)支/mm2;淋巴管密度与NSCLC的组织类型、细胞分化、患者的年龄和性别无关。多因素分析结果显示,淋巴管密度是影响NSCLC患者预后的独立危险因素,高淋巴管密度较低淋巴管密度患者预后差。结论Podoplanin是较为特异的淋巴管内皮标志物,淋巴管密度可作为NSCLC患者预后有意义的预测指标之一。     

血小板源性生长因子受体-β在大肠癌间质中的表达及与淋巴管生成的关系

目的检测血小板源性生长因子受体－β（PDGFR—β）在大肠癌间质组织中的表达,探讨其与淋巴管生成的关系。方法应用免疫组化SP法检测90份大肠癌间质及20份正常大肠组织中PDGFR—β的表达,用D2-40标记微淋巴管,计数微淋巴管密度（LMVD）,分析PDGFR—β的表达与LMVD和临床病理参数之间的关系。结果大肠癌间质组织中PDGFR—β的表达及LMVD明显高于癌旁正常组织（P均〈0．05）;有淋巴结转移者LMVD均明显高于无淋巴转移者,PDGFR-β阳性表达者的LMVD明显高于阴性表达者。间质组织中PDGFR-β的阳性表达与淋巴结转移相关（P〈0．05）。结论PDGFR—β在大肠癌间质组织中表达与肿瘤淋巴管的形成密切相关并可促进淋巴结转移。     

血管生成抑制剂抗胃癌微淋巴管生成的实验研究

目的 通过建立未分化人胃腺癌SGC-7901原位移植裸鼠模型,应用2-(8-羟基-6-甲氧基-1-氧-1-氢-2-苯并吡喃-3-羟基)丙酸(NM-3)和卡铂的腹腔化学治疗,观察其对裸鼠原位移植人胃癌微淋巴管生成的影响.方法 建立人胃癌SGC-7901原位种植BALB/C裸鼠模型28只,随机分为4组,每组7只,分别腹腔内注射0.9%氯化钠溶液、NM-3(10 mg/kg)、卡铂(5 mg/kg)和NM-3+卡铂,2次/周.8周后处死裸鼠,采用定量免疫组化染色检测淋巴管内皮细胞透明质酸受体(LYVE)-1、肾小球足突细胞膜黏蛋白、同源异型盒转录因子(Prox)-1;计数微淋巴管密度(LMVD)值.结果 卡铂组、NM-3组及NM-3+卡铂组LYVE-1表达值均较0.9%氯化钠溶液组下降,但差异无统计学意义(P值均＞0.05);NM-3组及NM-3+卡铂组肾小球足突细胞黏蛋白、Prox-1值较0.9%氯化钠溶液组及卡铂组均显著下降(P＜0.05).NM-3组及NM-3+卡铂组LMVD值分别为4.72±0.50和4.78±0.38,较0.9%氯化钠溶液组及卡铂组均显著下降[7.35±0.55和6.98±0.35,P＜0.05].结论 NM-3能抑制胃癌微淋巴管生成,抑制肿瘤的生长和转移.     

COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer

Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via multiple mechanisms including inactivation of host antitumor immunity and promotion of tumor cell migration, tumor cell invasiveness and tumor-associated angiogenesis and lymphangiogenesis. We previously demonstrated an association between COX-2 and VEGF-C in an in vitro model of lung cancer. However, little is known about the regulation of VEGF-C by COX-2 in cervical cancer. In this study, we measured the COX-2 and VEGF-C expressions by immunohistochemistry in 23 LNM-positive and 20 LNM-negative cervical cancer specimens. We then examined the correlations among the expressions and the lymphatic microvessel density (LMVD) and ultrastructural changes to the lymphatic vessel walls by enzyme histochemical staining and electron microscopy. In addition, we used the HeLa cervical cancer cell line to explore the in vitro regulation of VEGF-C by COX-2 and its metabolite, PGE₂, using siRNA-mediated gene silencing and EP receptor blockade. The LNM-positive specimens exhibited significantly higher VEGF-C expression, COX-2 expression and LMVD than the LNM-negative specimens. Furthermore, there were strong correlations between the levels of COX-2 expression and the levels of VEGF-C expression and secretion and a significant positive association between the LMVD and LNM. siRNA-mediated knockdown of COX-2 expression inhibited VEGF-C mRNA expression while EP1 and EP4 receptor antagonists reduced the VEGF-C protein level and tyrosine phosphorylation of Src kinase. Moreover, inhibition of Src kinase with the tyrosine kinase inhibitor PP1 attenuated VEGF-C expression. Collectively, our data provide evidence for a clinical association between COX-2 and VEGF-C expressions in cervical cancer. EP1 and EP4 receptors may be involved in the COX-2-mediated regulation of VEGF-C protein and mRNA expressions. Src may be a downstream mediator of EP1 and EP4 receptors. COX-2 inhibition may diminish LNM by suppressing VEGF-C-mediated lymphangiogenesis.     

Relationship of mast cell density with lymphangiogenesis and prognostic parameters in breast carcinoma

In many cancers, mast cell density (MCD) in the tumor microenvironment is associated with tumor progression and, to a greater extent, angiogenesis. Our study was designed to investigate the correlation between MCD, tumor lymphangiogenesis, and several well-established prognostic parameters in breast cancer. One hundred and four cases of invasive breast carcinoma diagnosed in our clinic between 2007 and 2011 were included. Mast cells and lymphatic vessels were stained with toluidine blue and D2-40, respectively, and their densities were calculated in various areas of tumors and lymph nodes. The variables of MCD and lymphatic vessel density (LVD) were compared using prognostic parameters as well as with each other. As tumor size and volume increased, MCD increased comparably in metastatic lymph nodes; intratumoral and peritumoral LVD also increased. Lymphovascular invasion, lymphatic invasion, perineural invasion, and estrogen receptor positivity were positively related to intratumoral MCD. The relationship between peritumoral MCD and nontumoral breast tissue MCD was statistically significant. Stage was correlated with MCD in metastatic lymph nodes. Metastatic lymph node MCD and intratumoral MCD were also significantly related. Stage, lymphatic invasion, perineural invasion, lymphovascular invasion, and metastatic lymph node MCD were all correlated with intratumoral and/or peritumoral LVD. As nuclear grade increased, intratumoral LVD became higher. In breast carcinoma, MCD, depending on its location, was related to several prognostic parameters. Notably, mast cells may have at least some effect on lymphangiogenesis, which appears to be a predictor of tumor progression.     

Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer

Purpose Lymph node metastasis is an important factor that influences curability after endoscopic treatment of submucosal colorectal cancer. This study was designed to determine the usefulness of identification of lymphatic vessels by immunohistochemistry in predicting lymph node metastasis of submucosal colorectal cancer. Methods Lymphatic involvement was assessed by hematoxylin and eosin staining and podoplanin immunostaining on samples resected from 268 patients with submucosal colorectal cancer. Lymphatic vessel density was estimated by two investigators by average count of three fields (×200) in the area of greatest number of podoplanin-positive capillaries at the site of deepest submucosal penetration. Relations with other clinicopathologic parameters also were investigated. Results Lesions with high lymphatic vessel density (≥9 vessels per field) showed a significantly greater incidence of lymph node metastasis than did those with low lymphatic vessel density (<9 vessels per field; 23.3 vs. 8.4 percent). By multivariate analysis, lymphatic vessel density was determined to be an independent risk factor for lymph node metastasis of submucosal colorectal cancer (P = 0.0044). Lymphatic vessel density also correlated with tumor budding and the degree of inflammation at the invasive front. Conclusions Identification of lymphatic vessels by podoplanin immunostaining provides objective and accurate evaluation of lymphatic involvement. Lymphatic vessel density at the site of deepest penetration is a useful predictor of lymph node metastasis of submucosal colorectal cancer. Supported by a grant from the Japanese Society of Gastroenterological Endoscopy, Chugoku Branch. Presented at the meeting of The Japanese Society of Gastroenterology, Kokura, Fukuoka, Japan, April 20 to 22, 2006. Reprints are not available.     

Expression of vascular endothelial growth factor-C and the relationship between lymphangiogenesis and lymphatic metastasis in colorectal cancer

AIM: To investigate the expression of vascular endothelial growth factor-C (VEGF-C) and the relationship between VEGF-C and lymphangiogenesis, lymph node metastasis in colorectal cancer. METHODS: Fifty six cases of colorectal cancer were selected randomly. Expression of VEGF-C was detected by immunohistochemistry, and lymphatic vessels were stained by enzyme histochemical method. RESULTS: VEGF-C expression was found in 66.7% (37/56) patients. In VEGF-C positive and negative patients, the lymphatic vessel density was 25.16+/-7.52 and 17.14+/-7.22, respectively (P<0.05). The rate of lymph node metastasis in VEGF-C positive patients (81.1%) was significantly higher than that in the negative group (42.1%). CONCLUSION: VEGF-C expression may induce lymphangiogenesis in colorectal cancer, as a result, tumor cells can entry the lymphatic vessels easily. VEGF-C may serve as a useful prognotic factor in colorectal carcinoma.     

罗格列酮对人胃癌细胞裸鼠移植瘤生长和淋巴管生成的影响

背景:血管内皮生长因子-C(VEGF-C)可激活淋巴管内皮细胞表面的VEGFR-3,诱导淋巴管生成。体外研究显示PPARγ配体罗格列酮(ROS)可通过抑制VEGF-C表达抑制人胃癌细胞的淋巴管生成。目的:明确ROS在体内能否抑制胃癌生长及其淋巴管生成。方法:建立人胃癌细胞株SGC7901裸鼠皮下移植瘤模型,成瘤裸鼠随机分为模型组和3组ROS组,后者分别予50、75、100 mg.kg-1.2 d-1ROS灌胃42 d。处死裸鼠,测定移植瘤体积,D2-40淋巴管内皮免疫组化染色计数微淋巴管密度(LMVD),RT-PCR和蛋白质印迹法检测VEGF-C mRNA和蛋白表达。结果:50、75、100 mg/kg ROS组移植瘤体积、肿瘤组织LMVD以及VEGF-C mRNA和蛋白表达依次降低并均显著低于模型组(P<0.05),作用呈浓度依赖性(P<0.05)。结论:ROS可呈浓度依赖性地抑制人胃癌细胞祼鼠移植瘤生长,并通过下调VEGF-C表达抑制肿瘤淋巴管生成。     

Correlation of caveolin-1 expression with microlymphatic vessel density in colorectal adenocarcinoma tissues and its correlation with prognosis

Objective: To study the expression of caveolin-1 in colorectal adenocarcinoma tissues and its correlation with microlymphatic vessel density(LMVD), and to investigate the clinical pathological prognostic significance of caveolin-1 and LMVD in patients with colorectal cancer. Methods: The expression of caveolin-1 and LMVD in 45 specimens of normal colorectal tissues, and 90 specimens of colorectal adenocarcinoma tissues were detected by immunohistochemistry technique. The correlation between their expression and the clinicopathologic features was analyzed. Muhivariable Cox regression was used to analyze the association between the laboratory indices and overall survival time. Results: The positive rates of caveolin-1 in colorectal adenocarcinoma tissues were significantly higher than those in normal colorectal tissues(P0.01). LMVD in colorectal adenocarcinoma tissues were significantly higher than those in normal colorectal tissues(P0.01). Mean LMVD in group with caveolin-1 positive was significantly higher than in that with caveolin-1 negative. The median survival time was 26.7 months. Cox regression analysis showed that the caveolin-1 expression, invation depth, lymph nodemetastasis, TNM stage, liver metastasis and LMVD were independent risk factors of overall survival time of patients with colorectal carcinoma. Conclusions: Caveolin-1 may contribute to the lymphangiogenesis in the tumor. During the occurrence and development of colorectal adenocarcinoma, there is a close relationship between the expression of caveolin-1 and lymphatic microvessel of tumor. Caveolin-1 expression and microlymphatic vessel density are significant prognostic value of colorectal carcinoma.     

Potential therapeutic strategies for lymphatic metastasis

Physiologically, the lymphatic system regulates fluid volume in the interstitium and provides a conduit for immune cells to travel to lymph nodes, but pathologically, the lymphatic system serves as a primary escape route for cancer cells. Lymphatic capillaries have a thin discontinuous basement membrane, lack pericyte coverage and often contain endothelial cell gaps that can be invaded by immune cells (or tumor cells). In addition, tumor cells and stromal cells in the tumor microenvironment secrete factors that stimulate lymphangiogenesis, the growth of lymphatic endothelial cells and the sprouting of lymphatic capillaries. As a result, many tumors are surrounded by large, hyperplastic, peri-tumoral lymphatic vessels and less frequently are invaded by intra-tumoral lymphatic vessels. Carcinoma cells commonly metastasize through these lymphatic vessels to regional lymph nodes. The presence of metastatic cells in the sentinel lymph node is a prognostic indicator for many types of cancer, and the degree of dissemination determines the therapeutic course of action. Lymphangiogenesis is currently at the frontier of metastasis research. Recent strides in this field have uncovered numerous signaling pathways specific for lymphatic endothelial cells and vascular endothelial cells. This review will provide an overview of tumor lymphangiogenesis and current strategies aimed at inhibiting lymphatic metastasis. Novel therapeutic approaches that target the tumor cells as well as the vascular and lymphatic endothelial compartments are discussed.     

Potential therapeutic strategies for lymphatic metastasis

Physiologically, the lymphatic system regulates fluid volume in the interstitium and provides a conduit for immune cells to travel to lymph nodes, but pathologically, the lymphatic system serves as a primary escape route for cancer cells. Lymphatic capillaries have a thin discontinuous basement membrane, lack pericyte coverage and often contain endothelial cell gaps that can be invaded by immune cells (or tumor cells). In addition, tumor cells and stromal cells in the tumor microenvironment secrete factors that stimulate lymphangiogenesis, the growth of lymphatic endothelial cells and the sprouting of lymphatic capillaries. As a result, many tumors are surrounded by large, hyperplastic, peri-tumoral lymphatic vessels and less frequently are invaded by intra-tumoral lymphatic vessels. Carcinoma cells commonly metastasize through these lymphatic vessels to regional lymph nodes. The presence of metastatic cells in the sentinel lymph node is a prognostic indicator for many types of cancer, and the degree of dissemination determines the therapeutic course of action. Lymphangiogenesis is currently at the frontier of metastasis research. Recent strides in this field have uncovered numerous signaling pathways specific for lymphatic endothelial cells and vascular endothelial cells. This review will provide an overview of tumor lymphangiogenesis and current strategies aimed at inhibiting lymphatic metastasis. Novel therapeutic approaches that target the tumor cells as well as the vascular and lymphatic endothelial compartments are discussed.     

Enzyme histochemical analysis of lymphatic vessels in colon carcinoma: occurrence of lymphangiogenesis within the tumor

BACKGROUND/AIMS: While it is generally recognized that the lymph vessel is absent in solid carcinoma, a few papers have reported the presence of intratumoral lymph vessels. The present study was carried out to clarify whether or not intratumoral lymphangiogenesis occurs. METHODOLOGY: To identify lymphatics in colon carcinomas, tumor-adjoining and normal submucosa, we tried using an enzymatic histochemistry procedure to examine the specific high activity of 5'-nucleotidase that is seen in lymphatic endothelial cells. Additionally, arterioles and venules were identified by alkaline phosphatase and dipeptidyl (amino) peptidase IV staining, respectively. RESULTS: Intratumoral lymphatic vessels were observed in 30 of 34 colon carcinomas (91%), and arterioles were found in all cases. However, no venules were identified within the tumor. The lymphatic density (mean +/- SD vessels/mm2) increased in the order of the submucosa near the tumor (21.9 +/- 9.5), normal submucosa (27.9 +/- 13.8) and tumor tissue (33.9 +/- 25.1). Intratumoral lymphatic density was significantly higher than that in the submucosa near the tumor (P<0.05). Intratumoral lymphatic density is related to arteriolar density (r=0.284, P=0.0012). The ratio of lymphatic/arteriolar density in the tumor was significantly higher than that seen in the submucosa near the tumor (0.78 +/- 0.76 vs. 0.51 +/- 0.36, P<0.05). Intratumoral lymphatic density was relatively higher in cases with lymph node metastasis than in those without metastasis, but was not related to tumor size, depth of tumor invasion, distant metastasis and TNM stage. CONCLUSIONS: Enzyme histochemistry revealed active lymphangiogenesis and the absence of venules within the tumor. Intratumoral lymphatic density was relatively correlated to arteriolar density. Enzyme histochemistry is a simple and quickly processed method that can be used to differentiate lymphatics from arterioles and venules.     

Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action

Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumor cells. Here, we demonstrate that HGF is a lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel expressing the lymphatic vessel endothelial specific marker hyaluronan receptor-1 (Lyve-1). Unlike blood vessels, the Lyve-1-positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1-positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.     

Role of podoplanin expression in esophageal squamous cell carcinoma: a retrospective study

Lymphatic metastasis is the predominant cause of the low overall survival of patients with esophageal squamous cell carcinoma (ESCC), as there are no faithful methods available predicting early metastasis. Recent studies suggest an effect of podoplanin expression on metastatic spreading to lymph nodes. The purpose of this study was to investigate the influence of podoplanin expression on lymphatic metastasis and tumor cells, and to find the relationship between podoplanin expression and prognosis of patients with ESCC. We evaluated the level of podoplanin expression on tumor cells and the lymphatic vessel density change of tumor mass compared with normal tissue from the same patient through D2-40 immunohistochemistry staining, and analyzed associations between these two variables and various clinicopathologic parameters individually or conjunctively. There was an association between podoplanin expression and the frequency of lymph node metastases. In 45 patients (80%), podoplanin was expressed on the tumor cells. Twenty-one patients (37.5%) showed high levels of expression. The 5-year disease-free survival rate (5%) for patients with high levels of podoplanin expression was significantly lower (P < 0.001) than for patients with low and moderate expression of podoplanin (54% and 27%, respectively). We concluded that podoplanin is expressed frequently in ESCC, and that the expression of podoplanin on cancer cells, lymphatics, or both is correlated with lymphatic metastasis and clinical outcome.     

整合素β3与VEGFR-3在胃癌组织中的表达及意义

目的探讨整合素β3、血管内皮细胞生长因子受体-3（VEGFR-3）在胃癌发生、发展中的作用。方法用免疫组织化学SP法检测65份胃癌术后癌组织标本（观察组）中整合素β3、VEGFR-3表达[定量以淋巴管密度（LMVD）表示],并与20份距胃癌组织10 cm的正常胃黏膜组织标本（对照组）作对比。结果观察组整合素β3阳性表达率及LMVD均明显高于对照组（P均〈0.01）。观察组整合素β3阳性表达者LMVD明显高于阴性表达者（t=4.30,P〈0.01）,整合素β3阳性表达与LMVD呈正相关（r=0.473,P〈0.01）。结论整合素β3和VEGFR-3与胃癌的淋巴管形成及浸润转移密切相关,可作为胃癌预后综合性评估的有效指标。     

Lymphangiogenesis: A new player in cancer progression

Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymph...     

Lymph node evaluation in colorectal cancer

BACKGROUND: In Brazil, colorectal carcinoma is the third cause of death by malignant tumors among women, and the fifth among men. Lymph node involvement is one of the most relevant prognostic maker in these tumors. AIM: To study lymph node involvement in colorectal carcinoma in relationship to biological behavior and tumor location. PATIENTS AND METHODS: One hundred and eight five colorectal carcinoma cases were studied. Lymph node involvement was analyzed according to tumor location, diameter, vessel invasion, and TNM staging. RESULTS: Three thousand nine hundred and six lymph nodes were harvested in 185 patients (21.1 lymph nodes/patient). Metastasis were detected in 399/2,573 peritumoral lymph nodes (15.5%) and in 72/1,333 non-peritumoral lymph nodes (5.4%). Eighty-six patients presented metastasis; in these patients 471/1942 lymph nodes were compromised. In 26 patients peritumoral and non-peritumoral lymph nodes were involved; in 57 cases metastasis were detected only in peritumoral lymph nodes and in 3, only non-peritumoral lymph nodes were involved. The number of lymph node was higher among cecal tumors and smaller in the rectum and sigmoid. There was a positive correlation between the number of metastatic lymph node and pT, tumor diameter and lymphatic and venous invasion; there was a negative correlation between lymph node involvement and lymphocytic response; pN was significantly associated with pT. CONCLUSIONS: Colorectal carcinoma involves preferentially peritumoral lymph node, but in 29 patients (15,7%) non-peritumoral lymph nodes were affected, which is important for tumor staging and prognosis. pN and the number of metastatic lymph nodes were associated with other behaviour markers.     

Feasible endoscopic therapy for early gastric cancer

AIM: To analyze the relationship between lymph node metastasis and clinical pathology of early gastric cancer(EGC) in order to provide criteria for a feasible endoscopic therapy.METHODS: Clinical data of the 525 EGC patients who underwent surgical operations between January 2009 and March 2014 in the West China Hospital of Sichuan University were analyzed retrospectively. Clinical pathological features were compared between different EGC patients with or without lymph node metastasis, and investigated by univariate and multivariate analyses for possible relationships with lymph node metastasis.RESULTS: Of the 2913 patients who underwent gastrectomy with lymph node dissection, 529 cases were pathologically proven to be EGC and 525 cases were enrolled in this study, excluding 4 cases of gastric stump carcinoma. Among 233 patients with mucosal carcinoma, 43(18.5%) had lymph node metastasis. Among 292 patients with submucosal carcinoma, 118(40.4%) had lymph nodemetastasis. Univariate analysis showed that gender, tumor size, invasion depth, differentiation type and lymphatic involvement correlated with a high risk of lymph node metastasis. Multivariate analysis revealed that gender(OR = 1.649, 95%CI: 1.091-2.492, P = 0.018), tumor size(OR = 1.803, 95%CI: 1.201-2.706, P = 0.004), invasion depth(OR = 2.566, 95%CI: 1.671-3.941, P = 0.000), histological differentiation(OR = 2.621, 95%CI: 1.624-4.230, P = 0.000) and lymphatic involvement(OR = 3.505, 95%CI: 1.590-7.725, P = 0.002) wereindependent risk factors for lymph node metastasis. Comprehensive analysis showed that lymph node metastasis was absent in patients with tumor that was limited to the mucosa, size ≤ 2 cm, differentiated and without lymphatic involvement.CONCLUSION: We propose an endoscopic therapy for EGC that is limited to the mucosa, size ≤ 2 cm, differentiated and without lymphatic involvement.