Lymphatic Vessel Density and Vascular Endothelial Growth Factor Expression in Squamous Cell Carcinomas of Lip and Oral Cavity: A Clinicopathological Analysis with Immunohistochemistry Using Antibodies to D2-40, VEGF-C and VEGF-D

Background

Squamous cell carcinoma (SCC) of the oral region often metastasizes to the cervical lymph nodes. To investigate whether the risk of cervical lymph node metastasis are predictable through lymphatic vessel density (LVD) and vascular endothelial growth factor (VEGF) expression, we assessed the relationship between LVD and clinicopathological parameters, and VEGF expression in SCC of the oral region.

Methods

The subjects were 109 patients with SCC of the oral region including the lip. Clinicopathological parameters examined for the association with LVD in a peritumoral hot spot were lymph node metastasis, histological grade and disease stage. The association with VEGF expression was similarly studied. LVD was detected by immunohistochemistry using D2-40.

Results

LVD was significantly higher in lip cancer than in other oral tumors (P < 0.0001), while there were no significant differences of LVD among other cancers of the oral cavity. LVD tended to decrease with disease progression, increase of tumor size and increase of metastatic lymph node size. Eighty-four of 109 tumors were positive for VEGF-C or D. VEGF-C-positive tumor lesions were also positive for VEGF-D. Significantly higher levels of VEGF-C and D expressions were associated with large size of lymph node metastases (P = 0.02).

Conclusion

SCC of the oral region including the lip that produces VEGF-C and D is significantly more likely to cause cervical lymph node metastasis. LVD in a peritumoral hot spot does not directly indicate the risk of cervical lymph node metastasis, but instead may reflect lymphangiogenesis due to VEGF together with loss of lymphatic vessels through tumor growth and progression.     

血管内皮生长因子D的表达与乳腺癌淋巴管生成及淋巴结转移的相关性

目的 探讨乳腺癌患者不同区域淋巴管生成、淋巴管浸润特点以及与血管内皮生长因子D(VEGF-D)的表达关系,并结合腋淋巴结转移状态进行分析. 方法 选取乳腺癌根治术石蜡标本79例,分4个区域(肿瘤区、癌周区、近癌区、远癌区)取材.切片行免疫组织化学染色,采用D2-40对淋巴管进行标记,检测各区域淋巴管密度(LVD)、淋巴管浸润(LVI)及VEGF-D表达情况. 结果 癌周区LVD最高(20.25±2.03),肿瘤区VEGF-D和LVI阳性率最高,分别为87.34%和63.29%.肿瘤区VEGF-D表达与LVD之间、LVD与LVI之间、VEGF-D表达与LVI之间差异无统计学意义(P>0.05),但在其他各区域它们之间差异有统计学意义(P<0.05),且呈正相关.癌周区LVD与腋淋巴结转移状态有关(P<0.05);癌周区和近癌区的VEGF-D表达及LVI与腋淋巴结转移之间差异有统计学意义(P<0.05),但在其他区域差异无统计学意义(P>0.05). 结论 VEGF-D可能促进乳腺癌淋巴管生成,增加淋巴管浸润机会.LVD的增高易致淋巴管浸润,促进腋淋巴结转移.癌周区和近癌区在乳腺癌淋巴道转移以及评估腋淋巴结转移状态的研究中可能更具有意义.     

乳腺浸润性微乳头状癌的病理学特征与淋巴结转移的关系

目的研究乳腺浸润性微乳头状癌(IMPC)的病理学特征与淋巴结转移的关系。方法观察51例乳腺IMPC的主要病理学特征及淋巴结转移情况,采用免疫组织化学方法(LSAB法)检测IMPC中血管内皮生长因子(VEGF)-C和VEGF受体(R)-3的表达并计数淋巴管密度,分析其与淋巴结转移的关系。结果(1)乳腺IMPC病理组织学分级Ⅱ、Ⅲ级组的淋巴结转移数平均12.5个,明显高于Ⅰ级组的4.0个;(2)间质淋巴细胞浸润(+)和(++)组的淋巴结转移率(27/28,96.4%)明显高于(-)和(±)组(14/23,60.9%),且其淋巴结转移数平均14.4个,也明显高于(-)和(±)组的4.6个;(3)IMPC肿瘤细胞的VEGF-C表达在病理组织学分级Ⅱ、Ⅲ级组显著高于Ⅰ级组(P=0.03),VEGF-C的表达与淋巴结转移呈正相关(P=0.006);淋巴管密度与VEGF-C表达(P=0.009)、淋巴结转移(P=0.007)呈正相关;(4)肿瘤组织中IMPC成分的多少与淋巴结转移无显著性关系,淋巴结转移灶为纯IMPC或以IMPC成分为主;(5)28例伴有导管原位癌的IMPC中,14例为微乳头状型导管原位癌(14/28,50%)。结论乳腺IMPC的病理组织学分级、淋巴管密度及间质淋巴细胞浸润可能是影响IMPC淋巴结转移的关键性因素。VEGF-C和VEGFR-3表达增高是促使IMPC发生淋巴结转移的重要原因。微乳头状型导管原位癌可能是IMPC的早期阶段。     

VEGF-D in association with VEGFR-3 promotes nodal metastasis in human invasive lobular breast cancer

We assessed the expression of vascular endothelial growth factors (VEGF-C and VEGF-D) in breast cancer cells and the density of lymph vessels and VEGF receptor-3 (VEGFR-3)-positive vessels in and around the tumor in invasive lobular breast cancer. We found significant correlation between peritumoral lymph vessel density and presence of lymph node metastases (P=.001) and the number of metastatic lymph nodes (P<.001). A significant correlation was detected between tumor cell VEGF-D expression and lymph node status (P=.001) and density of lymphatic vessel endothelial receptor (LYVE)-1-positive vessels (P=.035). VEGFR-3+/VEGF-D+ and VEGFR-3+/VEGF-C+ tumors had a significantly higher number of metastatic lymph nodes than tumors with other staining patterns (P<.001). Tumors positive for neither VEGF-D nor VEGFR-3 had a lower density of LYVE-1+ vessels than tumors with other staining patterns (P=.033). Our results indicate that peritumoral lymph vessel density is associated with lymph node metastases in invasive lobular breast cancer and that invasive lobular cancer producing VEGF-D, surrounded by VEGFR-3+ vessels, has a significantly higher peritumoral lymph vessel density and a higher number of metastatic lymph nodes.     

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma.

Lymph node metastasis via lymphatic vessels is related with an adverse outcome in many tumors. It is unclear whether lymphatic spread needs the development of the new lymphatic vessels or the expression of lymphangiogenetic factor in intrahepatic cholangiocarcinoma. The aim of this study was to assess the role of lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression, and D2-40-positive myofibroblastic cells for lymphatic spread and patient outcome in 88 cases of intrahepatic cholangiocarcinoma. We also assessed VEGF-C expression in 15 cases of metastatic lymph nodes. There was a significant correlation between lower lymphatic vessel density in the tumor center and positive lymphatic invasion (P=0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P=0.0315 and P=0.0360, respectively). Lymphatic invasion was observed higher in the peritumoral area (63%, 24/38) and in the tumor periphery (79%, 30/38) than in the tumor center (27%, 9/38). There was no significant correlation between the proliferative lymphatic vessels and pathologic features; however, lymphatic invasion was significantly associated with VEGF-C expression (P=0.0006), and the VEGF-C expression was seen in 12 of 15 cases (80%) of metastatic lymph node. Nodal metastasis was correlated with D2-40-positive myofibroblasts (P=0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P=0.0131). Our findings suggest that VEGF-C has an important role in lymphatic invasion via the preexisting lymphatic vessels in the tumor margin, and that lymphangiogenesis does not play a direct role in lymphatic metastasis. D2-40-positive myofibroblasts may contribute to lymphatic metastasis.     

Inhibition of VEGFR-3 activation in tumor-draining lymph nodes suppresses the outgrowth of lymph node metastases in the MT-450 syngeneic rat breast cancer model

For many types of human cancer, the expression of vascular endothelial growth factor-C (VEGF-C) correlates with enhanced tumor-associated lymphatic vessel density, metastasis formation and poor prognosis. In experimental animals, VEGF-C produced by primary tumors can induce lymphangiogenesis within and/or at the periphery of the tumor, and promotes metastasis formation. Tumor-induced lymphangiogenesis is therefore thought to expedite entry of tumor cells into the lymphatic vasculature and their trafficking to regional lymph nodes, thereby fostering metastatic dissemination. Tumour-produced VEGF-C can also drain to the regional lymph nodes and induce lymphangiogenesis there. Whether this activity promotes metastasis formation remains unclear. To address this issue we manipulated VEGF-C activity and VEGFR-3 activation in the lymph nodes draining syngeneic rat breast cancers using intra-dermal delivery of either recombinant VEGF-C or VEGFR-3 blocking antibodies to induce or suppress lymph node lymphangiogenesis, respectively. Recombinant VEGF-C induced lymph node lymphangiogenesis, but was not sufficient to promote metastasis formation by poorly metastatic NM-081 breast tumours. Conversely, inhibition of lymph node lymphangiogeneis induced by highly metastatic MT-450 breast tumours suppressed the outgrowth of lymph node metastases, but not the initial colonization of the lymph nodes. Lung metastasis was also not affected. We conclude that tumor-derived VEGF-C draining to regional lymph nodes promotes the outgrowth of lymph node metastases. VEGF-C may induce lung metastasis independently of its effects on lymph node metastasis.     

血管内皮生长因子C及其受体3在人恶性黑色素瘤组织内的表达及意义

目的 观察人恶性黑色素瘤组织内血管内皮生长因子C(VEGF-C)及其受体3(VEGFR-3)的表达,探讨VEGF-C和VEGFR-3在恶性黑色素瘤淋巴管生成及淋巴道转移中的作用.方法 取人恶性黑色素瘤组织48例(石蜡标本30例,术后新鲜组织18例),应用免疫组织化学和RT-PCR技术,观察VEGF-C和VEGFR-3蛋白及mRNA在恶性黑色素瘤组织内的表达情况.以淋巴管内皮透明质酸受体(LYVE-1)标记淋巴管,计数恶性黑色素瘤组织淋巴管数密度.结果 VEGF-C和VEGFR-3蛋白主要表达于恶性黑色素瘤细胞胞浆内,在肿瘤周围的血管和淋巴管内皮上也可见VEGFR-3蛋白表达,VEGF-C和VEGFR-3蛋白在淋巴结转移组恶性黑色素瘤组织内的表达水平明显高于无淋巴结转移组(P<0.05).在18例新鲜恶性黑色素瘤中,淋巴结转移组VEGF-C和VEGFR-3mRNA的表达明显高于无淋巴结转移组(P<0.01).LYVE-1表达于肿瘤间质内的淋巴管内皮细胞,淋巴结转移组恶性黑色素瘤组织中的淋巴管数密度(LMVD)为9.845±2.454,无淋巴结转移组恶性黑色素瘤组织中的淋巴管数密度为6.534±2.193,淋巴结转移组恶性黑色素瘤组织内的淋巴管数密度明显高于无淋巴结转移组(P<0.01).结论恶性黑色素瘤组织内VEGF-C表达明显增高,并通过上调其受体VEGFR-3的表达促进恶性黑色素瘤组织内淋巴管的生成,从而促进恶性黑色素瘤的淋巴道转移.     

VEGF-C、VEGFR-3和iNOS在人乳腺癌淋巴管的表达

目的检测乳腺癌组织血管内皮生长因子-C(VEGF-C)及其受体(VEGFR-3)、iNOS基因表达的相关性及这三个基因mRNA表达水平与淋巴管密度(LVD)的相关性,为阐明乳腺癌淋巴管生成的分子机理提供实验依据。方法RT-PCR检测乳腺癌组织及正常乳腺组织VEGF-C、VEGFR-3、iNOSmRNA的表达水平;免疫组织化学染色法检测淋巴管内皮细胞上VEGFR-3的表达,测定淋巴管密度。结果乳腺癌LVD为20.35±4.23,显著高于正常对照组(P<0.05);乳腺癌组织VEGF-C、VEGFR-3、iNOSmRNA三者的表达率分别为74.0%、84.0%、82.0%,显著高于正常对照组(P<0.05);VEGF-C、VEGFR-3、iNOS阳性组中LVD分别为21.34±3.45、18.54±4.68、17.43±4.76,显著高于对照组(P<0.05)。结论VEGF-C、VEGFR-3、iNOSmRNA表达与淋巴管密度之间呈正相关,并且3者之间的表达亦具有相关性,这些基因的表达增高可能在乳腺癌淋巴管生成过程中具有重要作用。     

血管内皮生长因子C及其受体表达与肝细胞癌侵袭转移的关系

目的 研究人肝细胞癌(HCC)组织中血管内皮生长因子C(VEGF-C)、血管内皮生长因子受体2(VEGFR-2)及VEGFR-3表达与HCC临床病理特征之间的关系.方法 取HCC石蜡切片标本50例及正常肝组织标本15例,免疫组化法检测止常肝组织及HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达,分析其与HCC临床病理特征之间的关系.结果 (1)HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达阳性率高于正常肝组织(62%比26.7%,34%比6.7%,40%比0%,P均<0.05).(2)HCC组织中,VEGF-C表达与肝内转移、门静脉癌柃形成及肝门淋巴结转移有关(P<0.05);VEGFR-2表达与肝内转移及门静脉癌栓形成有关(P<0.05);VEGFR-3表达与肝门淋巴结转移有关(P<0.05).结论 HCC组织中VEGF-C、VEGFR-2及VEGFR-3表达与HCC的侵袭及转移有密切关系.     

Lymphatic Vessel Density and VEGF-C Expression are Significantly Different Among Benign and Malignant Thyroid Lesions

Thyroid cancer is the most frequent endocrine neoplasia worldwide. The route for metastasis and loco-regional invasion preferentially occurs by lymphatic vessels. For this reason, the assessment of lymphatic vessel density (LVD) is supposed to represent both a prognostic parameter and also a potential therapeutic target. In order to evaluate the value of LVD in benign and malignant thyroid lesions, we analyzed 110 thyroidectomy specimens using D2-40, a specific marker for lymphatic vessels and vascular endothelial growth factor C (VEGF-C), the most potent molecule of lymphatic proliferation. LVD was significantly different between papillary and follicular carcinomas in total (p = 0.045) and peritumoral area (p = 0.042). Follicular adenoma and follicular carcinoma showed an important difference of intra- (p = 0.019) and peritumoral (p = 0.033) LVD. VEGF-C was more markedly expressed in malignancies than in benignant lesions (p = 0.0001). Almost all cancers with high positive VEGF-C expression also exhibited increased peritumoral LVD (p = 0.049) when compared with the benignant lesions. Indeed, the high peritumoral LVD of malignant thyroid lesions is an important finding for surgery planning and supports the practice of total thyroidectomy in malignant thyroid neoplasm’s since the lymphatic peritumoral vessels definitely are an escape path for tumor cells.     

食管癌血管内皮生长因子和受体的表达及在癌转移中的作用

目的观察人食管癌组织和淋巴管中血管内皮生长因子(VEGF-C)及其受体-3(VEGFR-3)的表达,探讨食管癌的淋巴道转移机制。方法取临床手术切除的食管癌组织,用免疫组化方法检测人食管癌早期和进展期癌细胞或淋巴管对VEGF-C及其VEGFR-3的表达情况。结果在食管癌的癌细胞中可见VEGF-C阳性表达,阳性颗粒主要定位于肿瘤细胞胞浆内。淋巴管内皮细胞仅见VEGFR-3阳性表达,VEGFR-3在血管和癌细胞中也存在少量阳性表达。进展期食管癌VEGF-C和VEGFR-3的表达率和表达强度均强于早期。结论食管癌癌细胞VEGF-C的表达和淋巴管内皮细胞上VEGFR-3的表达均与肿瘤进展呈正相关,推测VEGF-C通过受体VEGFR-3促进食管癌组织淋巴管生成,从而引起癌淋巴道转移。     

VEGF-C在卵巢癌局部淋巴结内淋巴管生成中的作用

目的观察血管内皮生长因子-C(VEGF-C)在卵巢癌组织内的表达,分析其与卵巢癌局部淋巴结内淋巴管生成之间的关系。方法取卵巢癌64例,其中,有淋巴结转移40例,无淋巴结转移24例。应用免疫组化法和Western blot技术观察VEGF-C在卵巢癌组织内的表达。以D2-40作为淋巴管内皮特异性标记物,检测卵巢癌局部淋巴结内淋巴管生成情况。结果 VEGF-C主要表达于卵巢癌细胞浆和胞膜以及癌组织周围浸润的炎性细胞,在有淋巴结转移组的表达率明显高于其在无淋巴结转移组的表达率。Western blot检测结果表明,VEGF-C蛋白在有淋巴结转移的卵巢癌组织中的表达量高于其在无淋巴结转移的卵巢癌组织内的表达量。D2-40表达于卵巢癌局部淋巴结内的淋巴管内皮细胞,在有转移的淋巴结内可见大量新生的淋巴管,淋巴管腔内存在入侵的肿瘤细胞,在无转移的淋巴结内观察到新生的淋巴管。在无淋巴结转移组病例中,卵巢癌组织VEGF-C阳性者局部淋巴结内淋巴管密度明显高于VEGF-C阴性者淋巴结内的淋巴管密度。结论 VEGF-C的表达与卵巢癌淋巴结转移密切相关,卵巢癌在发生局部淋巴结转移之前存在淋巴结内淋巴管生成的现象,卵巢癌组织内VEGF-C的表达在卵巢癌局部淋巴结内的淋巴管生成中可能发挥重要作用。     

直肠腺癌VEGF-C及VEGFR-3的表达与淋巴转移的关系

目的为探讨癌细胞淋巴管转移机理,观察血管内皮生长因子-C(VEGF-C)和血管内皮生长因子受体-3(VEGFR-3)在直肠腺癌组织及淋巴管的表达。方法取人直肠腺癌手术材料30例,用免疫组化方法检测癌区和癌周正常区VEGF-C和VEGFR-3的表达情况。结果VEGF-C主要表达在直肠腺癌的癌细胞胞浆,VEGFR-3主要在淋巴管内皮细胞有阳性表达,两者在癌区的表达率均高于正常区直肠组织;癌区淋巴管的平均面密度(33.81±5.67)高于正常区平均面密度(20.13±3.27)。结论VEGF-C和VEGFR-3在人直肠腺癌中的过表达,可能与淋巴管增生和扩张,促进癌细胞的淋巴转移有关。     

Smad4和VEGF-C在喉癌中的表达及其与淋巴管生成之间的关系

目的观察Smad4与VEGF-C在喉癌组织内的表达情况,分析Smad4和VEGF-C的表达与喉癌组织内淋巴管生成及淋巴结转移之间的关系。方法取喉癌病例58例,其中淋巴结转移组34例,无淋巴结转移组24例。应用免疫组化法和Western blot技术观察Smad4和VEGF-C在喉癌组织内的表达。以D2-40特异性标检测喉癌组织内淋巴管生成情况。结果 Smad4在无淋巴结转移的喉癌组织内的表达率明显高于其在有淋巴结转移组的表达率。Smad4表达阳性组的淋巴管数密度(LVD)明显低于Smad4表达阴性组的LVD。VEGF-C在淋巴结转移组的表达率明显高于其在无淋巴结转移组的表达率。Smad4的表达与VEGF-C的表达呈显著的负相关性(r=-0.391)。结论 VEGF-C在喉癌淋巴管的发生及淋巴结转移中发挥重要作用。Smad4与VEGF-C的表达呈负相关,Smad4可能有抑制喉癌淋巴管生成和淋巴道转移的作用。     

腮腺癌中血管内皮生长因子和血管内皮生长因子受体3表达与淋巴结转移

目的:研究血管内皮生长因子C及受体3(VEGF-C、VEGFR-3)在腮腺癌中的表达及其与淋巴结转移的关系。方法:采用免疫组织化学SP法检测62例腮腺癌标本组织中VEGF-C、VEGFR-3的表达,并计算其阳性表达率。结果:VEGF-C、VEGFR-3在腮腺癌中显著表达,其阳性率分别是51.6%、48.4%,与淋巴结转移密切相关。结论:VEGF-C、VEGFR-3与淋巴结转移有相关性,为肿瘤细胞淋巴道转移提供了条件,可以作为判断腮腺癌患者预后的一个重要指标。     

肿瘤细胞分泌的VEGF-C和CCR7在恶黑淋巴道转移中的作用

目的研究血管内皮生长因子C(VEGF-C)和C-C家族趋化因子受体7(CCR7)与恶性黑色素瘤(恶黑)淋巴管浸润、淋巴结转移的关系及其预后价值。方法免疫组化方法检测56例恶黑组织中VEGF-C和CCR7的表达,淋巴管内皮细胞透明质酸受体1(LYVE-1)标记肿瘤的淋巴管,Kaplan-Meier法进行生存检验,应用Cox比例危险度模型筛选与恶黑预后有关的指标。结果肿瘤细胞胞浆中可检测到VEGF-C和CCR7的表达。CCR7表达与VEGF-C表达和淋巴管浸润有关,CCR7和VEGF-C协同增加淋巴管浸润,CCR7表达与淋巴结转移及预后无关。结论在恶黑组织中VEGF-C和CCR7诱导肿瘤细胞侵入到淋巴管,但CCR7和淋巴管浸润不能作为恶黑的预后指标。     

Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis

Formation of lymphatic metastasis is the initial step of generalized spreading of tumor cells and predicts poor clinical prognosis. Lymphatic vessels generally arise within the peritumoral stroma, although the lymphangiopoietic vascular endothelial growth factors (VEGF)-C and -D are produced by tumor cells. In a carefully selected collection of human cervical cancers (stage pT1b1) we demonstrate by quantitative immunohistochemistry and in situ hybridization that density of lymphatic microvessels is significantly increased in peritumoral stroma, and that a subset of stromal cells express large amounts of VEGF-C and VEGF-D. The density of cells producing these vascular growth factors correlates with peritumoral inflammatory stroma reaction, lymphatic microvessel density, and indirectly with peritumoral carcinomatous lymphangiosis and frequency of lymph node metastasis. The VEGF-C- and VEGF-D-producing stroma cells were identified in situ as a subset of activated tumor-associated macrophages (TAMs) by expression of a panel of macrophage-specific markers, including CD68, CD23, and CD14. These TAMs also expressed the VEGF-C- and VEGF-D-specific tyrosine kinase receptor VEGFR-3. As TAMs are derived from monocytes in the circulation, a search in peripheral blood for candidate precursors of VEGFR-3-expressing TAMs revealed a subfraction of CD14-positive, VEGFR-3-expressing monocytes, that, however, failed to express VEGF-C and VEGF-D. Only after in vitro incubation with tumor necrosis factor-alpha, lipopolysaccharide, or VEGF-D did these monocytes start to synthesize VEGF-C de novo. In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer.     

VEGF-C及VEGFR-3在乳腺癌中的表达

目的探讨乳腺癌中血管内皮生长因子-C(VEGF-C)、血管内皮生长因子受体-3(VEGFR-3)的表达及与淋巴管生成的关系。方法采用免疫组化SP法检测57例乳腺癌组织中VEGF-C及VEGFR-3的表达,并在显微镜下记数VEGFR-3标记的脉管。结果淋巴结转移组VEGF-C的阳性率(90.48%)显著高于无淋巴结转移组(47.22%)(P<0.05);淋巴结转移组VEGFR-3阳性脉管数(7.62±1.18)显著高于无淋巴结转移组(5.27±0.96)(P<0.05);VEGF-C的阳性表达与VEGFR-3阳性脉管数呈正相关,相关系数为r为0.882(P<0.05)。结论 VEGF-C及VEGFR-3与乳腺癌的生长,淋巴管的生长及淋巴结的转移有关。     

Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis

Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm²) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.     

NF-κBp65、VEGF-C及受体VEGFR-3在乳腺癌组织中的表达

目的检测乳腺癌组织内NF-κBp65、VEGF-C及受体VEGFR-3的表达水平,并观察它们与临床病理特征的关系,为乳腺癌的早期诊断、治疗提供依据。方法采用免疫组化染色法检测50例乳腺癌组织及10癌旁组织内NF-κBp65、VEGF-C及受体VEGFR-3的表达,并分析与临床病理因素的关系。结果乳腺癌组织内NF-κBp65蛋白表达的阳性率为76.0%,明显高于癌旁对照组织30.0%,二者相比差异显著(P<0.05);乳腺癌组织内VEGF-C蛋白表达的阳性率为84.0%,明显高于癌旁对照组织20.0%,二者相比差异显著(P<0.05);乳腺癌组织内VEGFR-3蛋白表达的阳性率为88.0%,明显高于癌旁对照组VEGFR-3阳性表达率20.0%,两者相比差异显著(P<0.05);乳腺癌组织内NF-κBp65、VEGF-C及受体VEGFR-3三者的表达存在显著相关性(P<0.05),均与肿瘤淋巴转移密切相关(P<0.05),而与病人年龄、肿瘤大小无关(P>0.05)。结论乳腺癌中NF-κBp65的表达可能上调VEGF-C的表达,进而导致肿瘤周围淋巴管增生、扩张,促进肿瘤细胞向区域淋巴结转移。