Lymphatic metastasis is a continuous and complicated process. The detailed mechanisms of lymphatic metastasis are still not very clear, despite considerable research efforts in recent years. Previously, it was commonly accepted that there were no lymphatic vessels in the primary tumor. However, recent studies have demonstrated that lymphatic vessels are detectable in certain types of cancer, and more and more evidence has shown that cancer cells invade into local lymph nodes mainly via peritumoral lymphatic vessels. Moreover, activated endothelial cells may also be important, having an influence on lymphatic metastasis of cancer cells. This article, based on recent research findings, provides an in-depth discussion of the relationship between lymphangiogenesis, tumor-derived lymphatic endothelial cells and lymphatic metastasis in head and neck cancer.
Carcinoma, Squamous Cell ; pathology ; secondary ; Endothelial Cells ; pathology ; physiology ; Endothelium, Lymphatic ; pathology ; physiopathology ; Head and Neck Neoplasms ; pathology ; Humans ; Lymphangiogenesis ; physiology ; Lymphatic Metastasis ; pathology ; Neoplasm Invasiveness

Animals ; Humans ; Lymph Nodes ; pathology ; Lymphangiogenesis ; physiology ; Lymphatic Metastasis ; Lymphatic Vessels ; metabolism ; pathology ; Neoplasms ; metabolism ; pathology ; Vascular Endothelial Growth Factor C ; metabolism ; physiology ; Vascular Endothelial Growth Factor D ; metabolism ; physiology

Cell Culture Techniques ; Endothelial Cells ; cytology ; Humans ; Lymphangiogenesis ; physiology ; Lymphatic Metastasis ; Lymphatic Vessels ; pathology ; Neoplasms ; blood supply ; metabolism ; physiopathology ; Vascular Endothelial Growth Factor C ; metabolism ; physiology ; Vascular Endothelial Growth Factor Receptor-3 ; metabolism

PURPOSE: To correlate tumor stiffness and lymphangiogenesis in breast cancer and to find its clinical implications. MATERIALS AND METHODS: A total of 140 breast cancer patients were evaluated. Tumor stiffness was quantitatively measured by shear-wave elastography in preoperative ultrasound examination, calculated as mean elasticity value (kPa). Slides of resected breast cancer specimens were reviewed for most fibrotic area associated with tumor. D2-40 immunohistochemical staining was applied for fibrotic areas to detect the lymphatic spaces. Microlymphatic density, tumor stiffness, and clinicopathologic data were analyzed. RESULTS: Higher elasticity value was associated with invasive size of tumor, microlymphatic density, histologic grade 3, absence of extensive intraductal component, presence of axillary lymph node metastasis, and Ki-67 labeling index (LI) in univariate regression analysis, and associated with Ki-67 LI and axillary lymph node metastasis in multivariate regression analysis. Microlymphatic density was associated histologic grade 3, mean elasticity value, and Ki-67 LI in univariate regression analysis. In multivariate regression analysis, microlymphatic density was correlated with mean elasticity value. CONCLUSION: In breast cancer, tumor stiffness correlates with lymphangiogenesis and poor prognostic factors.
Adult ; Aged ; Aged, 80 and over ; Breast/pathology ; Breast Neoplasms/*diagnostic imaging/*pathology ; Elasticity Imaging Techniques/*methods ; Female ; Humans ; Lymph Nodes/pathology ; Lymphangiogenesis/*physiology ; Lymphatic Metastasis/*pathology ; Middle Aged ; Multivariate Analysis ; Neoplasm Invasiveness ; Neoplasm Staging ; Regression Analysis

BACKGROUNDTwist is a highly conserved epithelial-mesenchymal transcription factor that has been reported to be a key factor in tumor malignancy, including lymph node metastasis. It represents the major step of dissemination and serves as a chief prognostic indicator of disease progression. However, the mechanism by which Twist regulates lymph node metastasis remains incompletely understood. Studies on the mechanism of metastasis are thus required for determining appropriate therapeutic strategies.

METHODSImmunohistochemistry for lymphatic vessel endothelial receptor 1 (LYVE-1), Ki-67, Twist, vascular endothelial growth factor C (VEGF-C), and vascular endothelial growth factor receptor 3 (VEGFR-3) was performed to detect lymphatic vessel density (LVD), cell proliferation levels and the expressions of Twist, VEGF-C, and VEGFR-3 were determined from 66 primary supraglottic carcinoma tissue samples from 36 patients with lymph node metastasis (pathological N+, pN+) and 30 patients without metastasis (pathological N0, pN0). Western blotting analysis of the proteins in pN+ and pN0 primary tumors was used to characterize the expressions of Twist, VEGF-C, and VEGFR-3 further.

RESULTSThe LVD was 22.4 ± 10.3 in pN+ patients and 6.8 ± 4.1 in pN0 ones. For Ki-67, the number of proliferous cells in pN+ patients was greater than that in pN0 ones. Both, however, were associated with their clinical nodal stages. In pN+ patients, Twist, VEGF-C, and VEGFR-3 expressions were 86.11% (31/36), 80.56% (29/36), and 58.33% (21/36), respectively. These values were higher than those found for pN0 patients (i.e., 13/30, 11/30, and 7/30, respectively) (P < 0.05). Among the samples with Twist expression, 88.64% were VEGF-C-positive and 59.09% were VEGFR-3-positive. The pN0 counterparts were 4.55% and 9.09%, respectively (P < 0.05). The expressions of Twist, VEGF-C, and VEGFR-3 in pN+ patients obtained through Western blotting analysis were significantly higher than those in pN0 patients, and the levels of VEGF-C and VEGFR-3 were positively correlated with that of Twist.

CONCLUSIONSTwist expression correlates with lymph node metastasis. The mechanism involved in such a correlation may be related to lymphangiogenesis.

Adult ; Aged ; Blotting, Western ; Female ; Humans ; Immunohistochemistry ; Laryngeal Neoplasms ; complications ; metabolism ; Lymphangiogenesis ; genetics ; physiology ; Lymphatic Metastasis ; genetics ; pathology ; Male ; Middle Aged ; Twist-Related Protein 1 ; genetics ; metabolism ; Vascular Endothelial Growth Factor C ; metabolism ; Vascular Endothelial Growth Factor Receptor-3 ; metabolism

OBJECTIVETo study the effect of cyclooxygenase-2 (COX-2) on lymphangiogenesis in breast cancer.

METHODSBy the means of immunohistochemistry, COX-2, vascular endothelial growth factor-C (VEGF-C) and D2-40 were examined in the tissue samples of primary tumors from 94 patients underwent surgical resections for breast cancer from November 1998 to March 2002. Eighty-three patients were followed-up. The expressions of VEGF-C mRNA and protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot in MDA-MB-231 cell lines by the treatment of selective COX-2 inhibitor Nimesulide at different doses. The expressions of VEGF-C protein were evaluated in MDA-MB-231 cells treated by PGE2 (1 microg/ml) and Trastuzumab (1 microg/ml), respectively.

RESULTSCOX-2 over-expression was observed in 46.8% of surgical specimens (44/94), while VEGF-C overexpression occurred in 51.1% of tumor samples (48/94). COX-2 was strongly correlated with VEGF-C expression (P < 0.01), micro-lymphatic vessels (P = 0.032) and metastatic lymph nodes (P = 0. 035). Patients with COX-2 positive tumors had a significant shorter survival time than those with negative tumors did, including disease-free survival (P = 0.010) and overall survival (P = 0.040). Nimesulide could down-regulate the expressions of VEGF-C mRNA and protein in a does-dependent manner, while PGE2 could up-regulate the expressions. The expression of VEGF-C protein up-regulated by PGE2 treatment was decreased by Trastuzumab.

CONCLUSIONSCOX-2 over-expression can up-regulate the expression of VEGF-C. VEGF-C might promote lymph node metastasis by a lymph-angiogenic pathway, then affect the prognosis of the patients with breast cancer.

Adolescent ; Adult ; Aged ; Breast Neoplasms ; metabolism ; pathology ; Cyclooxygenase 2 ; metabolism ; physiology ; Female ; Follow-Up Studies ; Humans ; Lymphangiogenesis ; Lymphatic Metastasis ; Middle Aged ; Prognosis ; Vascular Endothelial Growth Factor C ; genetics ; metabolism

OBJECTIVE: To study the function of lymphangiogenesis and the expression of Cathepsin D (Cath-D) in laryngeal carcinoma metabasis and clinical pathology character. METHOD: The expression of Cath-D were detected in 76 laryngeal carcinoma with immunohistochemistry (SP method). Podoplanin was used as the marker of lympgatic vessel endotheliocytes to label lympgatic vessel in 76 laryngeal carcinoma,lymphatic microvessel density were measured,and the paraneoplastic tissues was used as control group. RESULT: The positive rate of Cath-D in paraneoplastic tissue, laryngeal carcinoma and in pathology classification, in clinical stage, in cervicale lymphonode metastasis negative and positive group were significantly different. However, there had no difference between the positive rate of Cath-D in the age specific and clinical classification. c) The lymphatic microvessel density in paraneoplastic tissue, laryngeal carcinoma and clinical stage, in glottic carcinoma and supraglottic carcinoma, in cervical lymphonode metastasis negative and positive group were significantly different; but there had no difference in age-specific and pathology classification. CONCLUSION (1) The high expression of lymphatic microvessel density and the increasing expression of Cath-D could promote cervical lymphonode metastasis in aryngeal carcinoma. (2) There had a correlation between the high expression of lymphangiogenesis and Cath-D in laryngeal carcinoma, and had cooperation in aryngeal carcinoma lymphonode metastasis.
Biomarkers, Tumor ; metabolism ; Carcinoma ; metabolism ; pathology ; physiopathology ; Cathepsin D ; metabolism ; Female ; Glottis ; Humans ; Immunohistochemistry ; Laryngeal Neoplasms ; metabolism ; pathology ; physiopathology ; Lymphangiogenesis ; physiology ; Lymphatic Metastasis ; Lymphatic Vessels ; metabolism ; Male ; Membrane Glycoproteins ; metabolism

OBJECTIVETo study the mechanism of interleukin 7/interleukin 7 receptor (IL-7/IL-7R) in promoting cell proliferation and inducing lymphangiogenesis of non-small cell lung cancer (NSCLC) in vivo and in vitro.

METHODSImmunohistochemical study for IL-7, IL-7R, cyclin D1 and vascular endothelial growth factor-D (VEGF-D) was carried out in NSCLC tissues from 95 patients. The relationship between IL-7/IL-7R expression and various parameters was analyzed. The mechanism of IL-7/IL-7R in promoting cell proliferation and inducing lymphangiogenesis was studied by methylthiazolyldiphenyl-tetrazolium bromide, fluorescence-activated cell sorting, reverse transcriptase-PCR, Western blot, co-immunoprecipitation, chromatin immunoprecipitation and nude mice experiments with xenograft tumors.

RESULTSIL-7 (63.2%, 60/95), IL-7R (61.1%, 58/95), cyclin D1 (52.6%, 50/95) and VEGF-D (58.9%, 56/95) showed that high level of expression in NSCLC. IL-7/IL-7R over-expression correlated with cyclin D1 expression (P < 0.01, P < 0.01), VEGF-D expression (P < 0.01, P < 0.01), increased lymphovascular density (P = 0.005, P = 0.013), advanced clinical stage (P = 0.008, P = 0.005) and presence of lymph node metastasis (P < 0.01, P < 0.01). IL-7/IL-7R could promote proliferation of A549 cell, increase cyclin D1 and VEGF-D expression, and enhance c-Fos/c-Jun expression and phosphorylation, resulting in formation of heterodimer. Furthermore, IL-7/IL-7R could induce binding of c-Fos/c-Jun to cyclin D1/VEGF-D promoters and regulate their transcription. IL-7/IL-7R could also promote proliferation and lymphangiogenesis of lung cancer xenograft tumors.

CONCLUSIONSIL-7/IL-7R promotes c-Fos/c-Jun expression and activity in NSCLC. This further facilitates cyclin D1 expression and accelerates proliferation of cells and VEGF-D-induced lymphovascular formation.

Animals ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; Cyclin D1 ; metabolism ; Female ; Humans ; Interleukin-7 ; metabolism ; physiology ; Lung Neoplasms ; metabolism ; pathology ; Lymphangiogenesis ; Lymphatic Metastasis ; Male ; Mice ; Mice, Nude ; Middle Aged ; Neoplasm Staging ; Neoplasm Transplantation ; Proto-Oncogene Proteins c-fos ; metabolism ; Proto-Oncogene Proteins c-jun ; metabolism ; Receptors, Interleukin-7 ; metabolism ; physiology ; Vascular Endothelial Growth Factor D ; metabolism

Cardiac lymphatic system in the remodeling after acute myocardial infarction (AMI) has been overlooked. We wanted to investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) and their contribution to lymphatic distribution in myocardial remodeling after AMI. Mouse (C57bl/6J) MI models were created by ligation of the left anterior descending coronary artery and were treated with phosphate buffered saline (PBS) or EPCs. Real-time RT-PCR with 2- to 4-week myocardial tissue samples revealed that lymphangiogenetic factors such as vascular endothelial growth factor (VEGF)-C (8.5 fold, P < 0.05), VEGF-D (6.1 fold, P < 0.05), Lyve-1 (15 fold, P < 0.05), and Prox-1 (11 fold, P < 0.05) were expressed at significantly higher levels in the PBS group than the EPC group. The PBS group also showed a significantly higher density of lymphatic vessels in the peri-infarction area. Echocardiography showed that from 2 weeks after the treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (P < 0.01) and LV fractional shortening was higher in the EPC group accordingly (P < 0.01). Lymphangiogenic markers increased in a mouse MI model. EPC transplantation decreased lymphangiogenesis and adverse ventricular remodeling after AMI. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium, and may be involved in adverse myocardial remodeling after AMI.
Animals ; Cell Transplantation ; Endothelial Cells/*cytology ; Homeodomain Proteins/genetics/metabolism ; Immunohistochemistry ; Lymphangiogenesis/genetics/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardial Infarction/metabolism/physiopathology/*therapy ; Real-Time Polymerase Chain Reaction ; *Stem Cell Transplantation ; Tumor Suppressor Proteins/genetics/metabolism ; Vascular Endothelial Growth Factor A/genetics/metabolism ; Vascular Endothelial Growth Factor D/genetics/metabolism