Vascular Endothelial Growth Factor-C Expression and Invasive Phenotype in Ovarian Carcinomas

Ueda, Masatsugu; Hung, Yao Ching; Terai, Yoshito; Kanda, Koji; Kanemura, Masanori; Futakuchi, Hikari; Yamaguchi, Hiroyuki; Akise, Daisuke; Yasuda, Masayuki; Ueki, Minoru

doi:10.1158/1078-0432.ccr-04-1148

Cited by 57 publications

(39 citation statements)

References 35 publications

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“…In the tumor cells in both the primary cervix and the lymph node tumors, the localization pattern of CXCR4 showed positive membrane staining with cytoplasmic localization of the receptor, 37 and VEGFC showed a positive membrane stain. 38,39 uPAR staining was observed to be localized in the cytoplasm, but specific regions showed membrane staining consistent with literature reports. 40 Hdm2 stained positive in both the nucleus and cytoplasm.…”

Section: Immunolocalization Analysis Of Upregulated Genes Under Cyclisupporting

confidence: 91%

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

Chaudary

Hill

2009

Laboratory Investigation

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Solid tumors contain regions of poor oxygenation that relate to the abnormal vascular network. Clinical investigations in cervical carcinoma have shown that positive lymph node status in patients with cervical carcinoma correlates with hypoxia. Earlier, in an orthotopic cervical cancer model, we had shown that exposure to acute hypoxia enhances lymph node metastasis. This study describes a technique for sorting hypoxic cells directly from the cervical xenograft model and reports the expression of 'metastasis-related' genes in hypoxic cells from xenografted cervix and lymph node tumors. Tumor cells were sorted on the basis of DsRed fluorescence and the sub-population of hypoxic cells was sorted on the basis of carbonic anhydrase-9 (CA-9) expression. Quantitative RT-PCR was conducted to measure changes in gene expression in the hypoxic cells sorted from primary cervix tumors and lymph node metastases. Immunohistochemistry was used to track changes in protein expression in sections of the same tumors. Metastasis-related genes, CXCR4, uPAR, VEGFC, Hdm2, and OPN, were observed to be upregulated at gene and protein levels in the primary tumors and nodal metastasis from the orthotopic transplants. In particular, the hypoxic cells sorted from orthotopically transplanted cervix tumors and their lymph node metastases from mice exposed to cyclic (intermittent) hypoxia showed higher levels of expression of these genes. These results are consistent with the hypothesis that these genes may be involved in regulating lymph node metastasis in cervical cancers under hypoxic conditions and provide support to the concept cyclic hypoxia that plays an important role in this process. Our methodological study emphasizes the technique of cell sorting to identify hypoxic cells using CA-9, which may aid in improving prognostic capabilities and in designing rational therapeutic strategies by focusing on hypoxia-specific gene expression profiles of patients. The technique can be applied to identify other potential 'hypoxia-related' genes of interest for tumor growth and metastasis.

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Section: Immunolocalization Analysis Of Upregulated Genes Under Cyclisupporting

confidence: 91%

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

Chaudary

Hill

2009

Laboratory Investigation

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“…On the other hand, VEGF-C was demonstrated to induce angiogenesis in the mouse cornea (66). Although VEGF-A and VEGF-C have been shown to play various roles in both angiogenesis and lymphangiogenesis in the animal models, there have been conflicting reports regarding the relationship between VEGF-A and VEGF-C and the LVD and MVD in human cancer tissues (37,41,45,47,55,(67)(68)(69)(70). The VEGF-C expression correlated positively with both the LVD and MVD in bladder (67), gastric (41) and ovarian (45) cancers, while no significant correlation ONCOLOGY REPORTS 23: 621-630, 2010 Table VII.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer

et al. 2010

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“…[22][23][24][25][26] Some clinical studies have shown a correlation between tumor VEGF-C expression and lymph node metastasis. [27][28][29] Intrahepatic cholangiocarcinoma remains an unfortunate liver tumor with a high mortality rate, because many patients diagnosed with cholangiocarcinoma cannot be offered curative treatment. 30 One of the major hallmark of cholangiocarcinoma is its lymph node metastasis.…”

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confidence: 99%

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

et al. 2008

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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 ¼ 0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P ¼ 0.0315 and P ¼ 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 ¼ 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 ¼ 0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P ¼ 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.

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Vascular Endothelial Growth Factor-C Expression and Invasive Phenotype in Ovarian Carcinomas

Cited by 57 publications

References 35 publications

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer

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

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