Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis

Cancer therapy often produces anemia, which is treated with erthropoietin (EPO) to stimulate erythrocyte production. However, concerns have recently arisen that EPO treatment may promote later tumor metastasis and mortality. The mechanisms underlying such effects are unknown, but it is clear that EPO has pleiotropic effects in cell types other than hematopoietic cells. In this study, we investigated how EPO affects lymphangiogenesis and lymph node tumor metastasis in mouse models of breast cancer and melanoma. In these models, EPO increased lymph node lymphangiogenesis and lymph node tumor metastasis in a manner associated with increased migration, capillary-like tube formation, and dose- and time-dependent proliferation of human lymphatic endothelial cells. EPO increased sprouting of these cells in a thoracic duct lymphatic ring assay. These effects were abrogated by cotreatment with specific inhibitors of phosphoinositide 3-kinase or mitogen-activated protein kinase, under conditions in which EPO increased Akt and extracellular signal-regulated kinase 1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis, and systemic treatment of EPO increased infiltration of CD11b(+) macrophages in tumor-draining lymph nodes. Finally, EPO increased VEGF-C expression in lymph node-derived CD11b(+) macrophages as well as in bone marrow-derived macrophages in a dose- and time-dependent manner. Our results establish that EPO exerts a powerful lymphangiogenic function and can drive both lymph node lymphangiogenesis and nodal metastasis in tumor-bearing animals.     

Apelin promotes lymphangiogenesis and lymph node metastasis

Whereas the role of the G-protein-coupled APJ receptor and its ligand, apelin, in angiogenesis has been well documented, the ability of the apelin/APJ system to induce lymphangiogenesis and lymphatic metastasis has been largely unexplored. To this end, we first show that APJ is expressed in lymphatic endothelial cells (LECs) and, moreover, that it responds to apelin by activating the apelinergic signaling cascade. We find that although apelin treatment does not influence the proliferation of LECs in vitro, it enhances their migration, protects them against UV irradiation-induced apoptosis, increases their spheroid numbers in 3D culture, stimulates their in vitro capillary-like tube formation and, furthermore, promotes the invasive growth of lymphatic microvessels in vivo in the matrigel plug assay. We also demonstrate that apelin overexpression in malignant cells is associated with accelerated in vivo tumor growth and with increased intratumoral lymphangiogenesis and lymph node metastasis. These results indicate that apelin induces lymphangiogenesis and, accordingly, plays an important role in lymphatic tumor progression. Our study does not only reveal apelin as a novel lymphangiogenic factor but might also open the door for the development of novel anticancer therapies targeting lymphangiogenesis.     

肿瘤淋巴管增生与淋巴结转移的研究进展

淋巴结转移是肿瘤转移的重要途径,也是判断预后的重要依据.随着淋巴管生成因子及许多淋巴管特异性标记物的发现,肿瘤新生淋巴管调控与淋巴道转移机制研究得以深入开展.临床病理学标本及动物实验模型研究也显示,肿瘤源性VEGF-C和VEGF-D可诱导肿瘤内淋巴管生成,进而促进淋巴结转移.现综述肿瘤淋巴管增生与淋巴结转移的相关研究进展.     

肿瘤淋巴管增生与淋巴结转移的研究进展

淋巴结转移是肿瘤转移的重要途径,也是判断预后的重要依据.随着淋巴管生成因子及许多淋巴管特异性标记物的发现,肿瘤新生淋巴管调控与淋巴道转移机制研究得以深入开展.临床病理学标本及动物实验模型研究也显示,肿瘤源性VEGF-C和VEGF-D可诱导肿瘤内淋巴管生成,进而促进淋巴结转移.现综述肿瘤淋巴管增生与淋巴结转移的相关研究进展.     

Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete "hotspots" of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR and immunohistochemistry revealed higher levels of mRNA in tumor tissue than in normal samples (n = 8; P = 0.017), but no obvious correlation with intratumoral lymphatics. Our results provide new evidence that proliferating lymphatics can occur in human cancers and may in some cases contribute to lymph node metastasis.     

肾细胞癌组织VEGF-C表达与淋巴管生成和淋巴转移的相关性

目的:应用特异的淋巴管内皮标志podoplanin检测肾细胞癌(RCC)组织中淋巴管,用淋巴管密度(LVD)表示淋巴管生成情况, 探讨RCC 内VEGF-C表达与淋巴管生成和淋巴转移的关系.方法:收集45例RCC和10例肾外伤致肾切除的正常肾组织标本,应用免疫组化检测VEGF-C、podoplanin 的表达,计算VEGF-C阳性表达率及淋巴管密度值,分析两者的关系.结果:RCC 组织内VEGF-C 阳性表达率(71.1%) 显著高于正常肾组织(10.0%),P<0.01,高中分化(70.6%) 和低分化(72.7%) 之间差异无统计学意义,P>0.05,淋巴结阳性组中VEGF-C阳性率(81.3 %)显著高于淋巴结阴性组(65.5%),P<0.05.RCC组织内LVD(6.8±1.3) 显著高于正常肾组织(1.2±0.3),P<0.01;VEGF-C阳性组LVD(7.6±1.5)显著高于VEGF-C 阴性组(4.7±0.9),P<0.05, 淋巴结阳性组LVD (8.3±1.4) 显著高于淋巴结阴性组(5.1±1.1),P<0.05.结论:淋巴管生成可能是RCC淋巴结转移的重要因素,VEGF-C参与RCC淋巴管生成,从而促进淋巴结转移.     

Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer

Despite our improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinomas (HNSCC) patients remains relatively unchanged at 50% for the past three decades. HNSCCs often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. Among the multiple dysregulated molecular mechanism in HNSCCs, emerging basic, preclinical, and clinical findings support the importance of the mTOR signaling route in HNSCC progression. Indeed, we observed here that the activation of mTOR is a widespread event in clinical specimens of HNSCCs invading locoregional lymph nodes. We developed an orthotopic model of HNSCC consisting of the implantation of HNSCC cells into the tongues of immunocompromised mice. These orthotopic tumors spontaneously metastasize to the cervical lymph nodes, where the presence of HNSCC cells can be revealed by histologic and immunohistochemical evaluation. Both primary and metastatic experimental HNSCC lesions exhibited elevated mTOR activity. The ability to monitor and quantitate lymph node invasion in this model system enabled us to explore whether the blockade of mTOR could impact HNSCC metastasis. We found that inhibition of mTOR with rapamycin and the rapalog RAD001 diminished lymphangiogenesis in the primary tumors and prevented the dissemination of HNSCC cancer cells to the cervical lymph nodes, thereby prolonging animal survival. These findings may provide a rationale for the future clinical evaluation of mTOR inhibitors, including rapamycin and its analogues, as part of a molecular-targeted metastasis preventive strategy for the treatment of patients with HNSCC.     

Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis

Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis.     

Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer and frequently metastasizes to the cervical lymph nodes, leading to poor survival of patients with OSCC. However, the mechanism of lymph node metastasis is not fully understood. To clarify the molecular mechanism underlying OSCC metastasis to regional lymph nodes, the highly metastatic fluorescent labeled OSCC cell line SAS-LM3 was successfully established allowing us to monitor the progression of lymph node metastases in a non-invasive manner. SAS-LM3 tumors showed increased lymphangiogenesis and elevated expression of VEGF-C, a potent stimulator of lymphangiogenesis, compared to parental SAS tumors. SAS-LM3 showed high expression of cyclooxygenase-2 (COX-2) compared to parental SAS cells and immunohistochemical analysis demonstrated intense COX-2 expression at the primary site. Inactivation of COX-2 by knockdown or the COX-2 inhibitor NS-398 decreased VEGF-C expression. Administration of COX-2 inhibitor NS-398 in SAS-LM3 tumor-bearing mice suppressed tumor lymphangiogenesis and lymphatic metastases. Collectively, our results indicate that COX-2 promotes tumor lymphangiogenesis and lymph node metastasis of OSCC. COX-2 ablation holds promise as a potential therapeutic approach for lymph node metastasis in OSCC.     

VEGF-C与肿瘤淋巴管生成和淋巴结转移关系研究进展

淋巴管生成是实体肿瘤发生淋巴结转移的重要步骤,但与肿瘤血管生成相比,目前对淋巴管生成的研究较少。随着研究的不断深入,在肿瘤的动物模型以及人类肿瘤组织和肿瘤周边组织中,均发现了新生淋巴管。目前研究已证实,血管内皮生长因子-C(VEGF-C)在肿瘤的淋巴管生成及淋巴结转移中发挥重要作用,为抗肿瘤淋巴转移治疗提供了有效的靶点,有助于改善患者预后、延长生存期。     

胃癌组织中肝细胞生长因子的表达与淋巴管生成及转移的关系

 目的　探讨人类胃癌组织中肝细胞生长因子（HGF）的表达与临床病理因素、微淋巴管密度（MLD）之间的关系。方法　应用免疫组织化学方法检测52例胃癌患者癌组织中HGF的表达并进行微淋巴管的计数。结果　HGF的表达与肿瘤组织学分级、浸润深度、临床分期、淋巴结转移显著相关（P＜0.05）,与患者年龄、肿瘤大小无关（P＞0.05）。HGF表达阳性组MLD值为22.8±10.9,阴性组为14.0±4.2,两者差异有统计学意义（P＜0.005）。结论　HGF的高表达与胃癌组织学分级、浸润深度、临床分期、淋巴结转移及MLD值密切相关,可作为判断预后的一种指标。     

VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors

The spread of cancer cells to regional lymph nodes through the lymphatic system is the first step in the dissemination of breast cancer. In several human cancers including those of the breast and prostate, the expression of vascular endothelial growth factor C (VEGF-C) is associated with lymph node metastasis. Our study was undertaken to evaluate the effect of VEGF-C on metastasis of poorly invasive, estrogen dependent human MCF-7 breast cancer cells. MCF-7 breast cancer cells transfected with VEGF-C (MCF-7-VEGF-C) were grown as tumors in the mammary fat pads of nude mice implanted with subcutaneous estrogen pellets. Tumor lymphangiogenesis and lymph node metastasis were studied immunohistochemically using antibodies against lymphatic vessel hyaluronan receptor -1 (LYVE-1), VEGF receptor-3 (VEGFR-3), PECAM-1, pan-cytokeratin and estrogen dependent pS2 protein. Overexpression of VEGF-C in transfected MCF-7 cells stimulated in vivo tumor growth in xenotransplanted mice without affecting estrogen responsiveness. The resulting tumors metastasized to the regional lymph nodes in 75% (in 6 mice out of 8, Experiment I) and in 62% (in 5 mice out of 8, Experiment II) of mice bearing orthotopic tumors formed by MCF-7-VEGF-C cells whereas no metastases were observed in mice bearing tumors of control vector-transfected MCF-7 cells (MCF-7-Mock). The density of intratumoral and peritumoral lymphatic vessels was increased in tumors derived from MCF-7-VEGF-C cells but not MCF-7-Mock cells. Taken together, our results show that VEGF-C overexpression stimulates tumor lymphangiogenesis and induces normally poorly metastatic estrogen-dependent MCF-7 tumors to disseminate to local lymph nodes. These data suggest that VEGF-C has an important role in lymph node metastasis of breast cancer even at its hormone-dependent early stage.     

Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma

BACKGROUND: Lymphatic vessel density (LVD) and microvessel density (MVD) are important parameters for assessing the malignant potential of tumors and patient survival. In this report, the authors defined LVD as the density of D2-40-positive lymphatic vessels and MVD as the density of CD105-positive microvessels per unit area of tissue. It was reported previously that vascular endothelial growth factor C (VEGF-C) is a major modulator of LVD and MVD. The objectives of this study were to clarify the clinical and prognostic significance of both LVD and MVD in oral squamous cell carcinoma (OSCC) and to elucidate the lymphangiogenic and angiogenic activities of VEGF-C in cancer tissues. METHODS: In total, 110 OSCC tissue samples were evaluated for LVD, MVD, and expression of VEGF-C using immunohistochemistry. Correlations among these parameters and clinicopathologic factors were examined. RESULTS: LVD was significantly higher in tumors that had very high expression of VEGF-C compared with tumors that had no/weak expression of VEGF-C. LVD correlated well with lymph node metastasis (P < .001). MVD was correlated significantly with positive lymph node metastasis (P < .001) but not with VEGF-C expression. In contrast, high expression of VEGF-C was correlated significantly with advanced tumor status (P = .041). Survival rates were lower in patients who had higher LVD (P < .001), higher MVD (P = .0028), and strong VEGF-C expression (P = .048). CONCLUSIONS: Lymphangiogenesis predominantly influenced metastasis-free survival. The current results suggested that LVD is a more useful tool than MVD and VEGF-C for deciding on therapeutic strategies in patients with OSCC.     

COX-2的表达与甲状腺乳头状癌中淋巴管生成及淋巴结转移的关系

目的 探讨环氧化酶-2(COX-2)对甲状腺乳头状癌淋巴管生成的影响及与淋巴结转移的关系.方法 运用Envision免疫组化法测定60例甲状腺乳头状癌患者和15例癌旁正常甲状腺组织病理标本COX-2、血管内皮生长因子C(VEGF-C)的蛋白表达,并进行评分,同时用D2 40显色淋巴管进行淋巴管密度(LVD)计数.结果 甲状腺乳头状癌中COX-2、VEGF-C较正常组织表达明显增高;有淋巴结转移的甲状腺乳头状癌患者中COX-2、VEGF-C的阳性率明显高于无转移组(P<0.05;P<0.05);转移组LVD计数显著高于无转移组(P<0.01);COX-2与LVD(r=0.71;P<0.01)、VEGF-C与LVD(r=0.68;P<0.01)、COX-2与VEGF-C之间(r=0.65,P<0.01)存在显著正相关.结论 COX-2对甲状腺乳头状癌患者的淋巴管形成起着重要的作用,可能通过上调VEGF-C的表达促进肿瘤淋巴管的形成,有利于甲状腺乳头状癌淋巴结的转移.     

p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis

The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics.     

膀胱癌组织VEGF—C表达与淋巴管生成和淋巴结转移之间关系的研究

目的：应用特异的淋巴管内皮标志物podoplanin检测膀胱移行细胞癌（BTCC）组织中淋巴管,用淋巴管密度（LVD）表示淋巴管生成情况,探讨BTCC内VEGF-C表达与淋巴管生成和淋巴结转移的关系。方法：收集45例BTCC和10例正常膀胱组织标本,应用免疫组化检测VEGF-C、podoplanin的表达,计算VEGF-C阳性表达率及淋巴管密度值,分析两者的关系。结果：BTCC组织内VEGF-C阳性表达率显著高于正常膀胱组织（71．1％vs．10．0％,P〈0．01）;BTCC高中分化和低分化之间VEGF-C阳性表达率无显著性差异（70．6％US．72．7％,P〉0．05）,而淋巴结阳性组显著高于淋巴结阴性组（81．3％vs．65．5％,P〈0．05）.BTCC组织内LVD显著高于正常膀胱组织（6．8±1．3vs．1．2±0．3,P〈0．01）;BTCC中,VEGF-C阳性组LVD显著高于VEGF-C阴性组（7．6±1．5vs．4．7±0．9,P〈0．05）,而淋巴结阳性组显著高于淋巴结阴性组（8．3±1．4vs．5．1±1．1,P〈0．05）。结论：淋巴管生成可能是BTCC淋巴结转移的重要因素,VEGF-C参与BTCC淋巴管生成,从而促进淋巴结转移。     

非小细胞肺癌VEGF-C表达与淋巴管生成和淋巴转移关系的研究

背景与目的近年来的研究表明,血管内皮生长因子C(VEGFC)通过与其配体(VEGFR3)的结合介导肿瘤淋巴管生成,是形成肿瘤淋巴道转移的最重要因素。淋巴道转移是非小细胞肺癌(NSCLC)常见的主要扩散途径。基于此,本研究用新的淋巴管内皮标志物podoplanin检测NSCLC组织中淋巴管,用淋巴管密度(LVD)表示淋巴管生成情况,探讨NSCLC内VEGFC表达与淋巴管生成和淋巴转移的关系。方法收集66例NSCLC和8例炎性假瘤组织标本,应用免疫组化检测VEGFC、podoplanin的表达,计算VEGFC阳性表达率及淋巴管密度值,分析两者的关系。结果NSCLC组织内VEGFC阳性表达率(75.8%)显著高于肺炎性假瘤(12.5%)(P<0.01),高中分化(76.3%)和低分化(75.0%)之间无显著性差异(P>0.05),淋巴结阳性组中VEGFC阳性率(86.5%)显著高于淋巴结阴性组(62.1%)(P<0.05)。NSCLC组织内LVD(20.4±5.9)显著高于肺炎性假瘤(10.9±4.9)(P<0.01);VEGFC阳性组LVD(21.3±6.0)显著高于VEGFC阴性组(17.7±5.1)(P<0.05),淋巴结阳性组LVD(21.9±5.9)显著高于淋巴结阴性组(18.5±5.5)(P<0.05)。结论淋巴管生成可能是NSCLC淋巴结转移的重要因素,VEGFC参与NSCLC淋巴管生成,从而促进淋巴结转移。     

PDGF-BB在直肠癌中的表达及其与淋巴管生成和淋巴结转移的关系

目的 探讨PDGF-BB在直肠癌组织中的表达及其与淋巴管生成和淋巴结转移的关系.方法 免疫组织化学染色技术(SP法)检测60例直肠癌组织和30例正常直肠组织中PDGF-BB和D2-40的表达;分析PDGF-BB在直肠癌组织和正常组织中的表达差异及其与淋巴管密度的关系.结果 PDGF-BB在直肠癌组织中的阳性表达率显著高于正常肠组织(55.0%vs.6.7%,P<0.001);淋巴结阳性组的PDGF-BB阳性表达率均显著高于淋巴结阴性组(77.3%vs.42.1%,P<0.05);PDGF-BB阳性表达组的LMVD显著高于阴性表达组[(12.19±2.22)vs.(7.33±3.02),P<0.05];PDGF-BB的表达与LMVD、淋巴结转移也具有显著相关性(rs=0.712,P<0.05;rs=0.501,P<0.05).淋巴结阳性组的LMVD显著高于淋巴结阴性组[(13.11±2.01)vs.(8.13±2.99),P<0.05];LMVD与淋巴结转移亦呈显著性相关(rs=0.699,P<0.05).结论 PDGF-BB在直肠癌中的阳性表达可能促进其淋巴管的生成及淋巴结转移.     

Cyclophosphamide-dependent lymph node modification in lymph node metastasis of MM48 tumor cells in syngeneic mice

We investigated the role of immunosuppressive activity induced in the regional lymph nodes (RLN, popliteal lymph nodes) in the establishment of lymph node metastasis by cyclophosphamide (CY) administration. The CY treatment led to the elimination of suppressive activity with the appearance of positive immune responses, and the inhibition of lymph node metastasis of MM48 tumor cells. In CY-treated mice, the removal of RLN together with the primary tumor lowered the survival rate compared with the mice in which the RLN remained intact. During 4 days after primary tumor resection, the proliferation of tumor cells in the RLN was significantly decreased in CY-treated mice. These results suggested that the induction of suppressive activity in the lymph node is closely associated with the establishment of lymph node metastasis.     

不同活化表型的巨噬细胞对小鼠肺癌移植瘤生长、淋巴管生成和淋巴结转移的影响

目的:探讨不同活化表型的巨噬细胞对小鼠Lewis肺癌(Lewis lung carcinoma,LLC)移植瘤生长、淋巴管生成和淋巴结转移的影响.方法:将活化的巨噬细胞与LLC细胞混合后注射至小鼠颈部背侧皮下,建立移植瘤模型,分为4组:空白对照组,经典活化的巨噬细胞(classically activated macrophages,caMphi)组,替代性活化的巨噬细胞(alternatively activated macro-phages,aaMphi)组和RAW264.7巨噬细胞组.每组10只小鼠,观察移植瘤生长情况.d 28时杀死小鼠,HE染色检测淋巴结和远处器官转移情况,免疫组织化学法检测并计数移植瘤淋巴管内皮细胞透明质酸受体-1(lymphatic vessel endothelial hyaluro-nan receptor-1,LYVE-1)阳性淋巴管密度(lymphatic vessel density,LVD).同时另取40只小鼠随机分为上述4组,观察其生存时间并计算生存率.结果:与空白对照组比较,aaMphi组和RAW264.7组移植瘤生长速度较快,淋巴结转移数和双肺转移结节数较多(P<0.01),LVD增高,荷瘤小鼠生存率降低(P<0.05).aaMphi组淋巴结转移数和LVD明显高于RAW264.7组(P<0.05),但移植瘤生长、肺转移结节数和荷瘤小鼠生存率之间差异无统计学意义(P>0.05).结论:aaMphi能够促进LLC移植瘤生长、淋巴管生成、淋巴结和肺转移,并降低荷瘤小鼠生存率.在与LLC一起形成移植瘤的过程中,未经处理的巨噬细胞可以朝着aaMphi的方向极化.