Correlation between vascular endothelial growth factor‐C expression and invasion phenotype in cervical carcinomas

Ueda, Masatsugu; Terai, Yoshito; Yamashita, Yoshiki; Kumagai, Koji; Ueki, Ken; Yamaguchi, Hiroyuki; Akise, Daisuke; Hung, Yao Ching; Ueki, Minoru

doi:10.1002/ijc.10193

Cited by 77 publications

(59 citation statements)

References 34 publications

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“…Evidence suggests a strong correlation between VEGF-C expression and lymph node metastasis formation (Yonemura et al, 1999). Most recent reports suggest that VEGF-C plays an extremely important role in invasion in breast (Mattila et al, 2002), cervical (Ueda et al, 2002), colon (Furudoi et al, 2002), and gastric cancer (Takahashi et al, 2002). In our study, VEGF-C was highly overexpressed in most of the mutants, and in fibrosarcoma HT1080, glioma T98G, and prostate cancer DU145 cells.…”

Section: Discussionsupporting

confidence: 64%

Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer

et al. 2003

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The constitutive activation of nuclear factor jB (NFjB) helps a variety of tumors to resist apoptosis and desensitizes them to chemotherapy, but the causes are still largely unknown. We have analysed this phenomenon in eight mutant cell lines derived from human 293 cells, selected for NFjB-dependent expression of a marker gene, and also in seven tumor-derived cell lines. Conditioned media from all of these cells stimulated the activation of NFjB (up to 30-fold) in indicator cells carrying an NFjB-responsive reporter. Therefore, secretion of extracellular factors as the cause of constitutive activation seems to be general. The mRNAs encoding several different cytokines and growth factors were greatly overexpressed in the tumor and mutant cells. The pattern of overexpression was distinct in each cell line, indicating that the phenomenon is complex. Two secreted factors whose roles in the constitutive activation of NFjB are not well defined were investigated further as pure proteins: transforming growth factor b2 (TGFb2) and fibroblast growth factor 5 (FGF5) were both highly expressed in some mutant clones and tumor cell lines, each activated NFjB alone, and the combination was synergistic. Our data indicate that a group of different factors, expressed at abnormally high levels, can contribute singly and synergistically to the constitutive activation of NFjB in all of the mutant and tumor cell lines we studied. Since several NFjB target genes encode secreted proteins that induce NFjB, autocrine loops are likely to be ubiquitously important in the constitutive activation of NFjB in cancer. We provide the first evidence of the general, complex, and synergistic activation of NFjB in tumor and mutant cell lines through the action of secreted factors and suggest that the same explanation is likely for the constitutive activation of NFjB in cancers.

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Section: Discussionsupporting

confidence: 64%

Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer

et al. 2003

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“…Overexpression of vascular endothelial growth factor C (VEGF-C) has been detected in numerous cancers (34)(35)(36)(37), and the role of VEGF-C in promoting lymphatic metastasis has been demonstrated in several VEGF-C overexpression animal models of mammary carcinoma (38)(39)(40). Previous study revealed that Six1 could coordinate with transforming …”

Section: Six1 Expression N -----------------------------------------mentioning

confidence: 99%

Six1 expression is associated with a poor prognosis in patients with glioma

Zhang

2017

Oncology Letters

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Abstract. Glioma is the most common human brain cancer and has poor prognosis. Messenger RNA profiling identified that sineoculis homeobox homolog 1 (Six1) is dysregulated in glioma tumor progenitor cells from glial progenitor cells isolated from normal white matter. However, the expression and role of Six1 in glioma remains unclear. The purpose of the present study was to investigate the expression level of Six1 in glioma tissues and the association between Six1 expression and clinicopathological characteristics and prognosis of gliomas. The Six1 protein was detected by immunohistochemistry in 163 glioma tissues of distinct malignancy grades, and Kaplan-Meier survival analysis was performed to assess the prognosis of the patients. The Six1 protein was stained in 49.1% (80 out of 163) of the glioma tissues, including 34.2% of low-grade [World Health Organization (WHO) I/II] gliomas and 80.8% of high-grade (WHO III/IV) gliomas. Normal brain tissues rarely expressed the Six1 protein. In addition, Six1 expression was significantly associated with WHO grade (P<0.001). According to the log-rank test and Cox regression model, Six1 may be suggested as an independent prognostic factor, in addition to the WHO grade. Overall, Six1 protein expression varies between different grades of glioma and is associated with the WHO grade. Upregulation of Six1 is more frequent in high-grade glioma and is an independent prognostic factor of poor clinical outcome.

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“…Overexpression of VEGF-C has been implicated in a number of cancers (35)(36)(37)(38), and its role in promoting lymphatic metastasis has been demonstrated in several VEGF-C overexpression animal models of mammary carcinoma (25)(26)(27). Although growth factors have been found to regulate the expression of VEGF-C (39,40), here, we demonstrate for what we believe to be the first time that SIX1 can directly upregulate VEGFC through transcription and stimulate VEGF-C-mediated lymphangiogenesis in breast cancer cells, thereby contributing to lymphatic dissemination and distant metastasis.…”

Section: Six1 Is Overexpressed In 50% Of Primary Tumors and In An Evenmentioning

confidence: 99%

SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

Wang¹,

Jedlicka²,

Patrick³

et al. 2012

J. Clin. Invest.

107

110

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An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood. Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in breast cancer with lymph node positivity, was involved in lymphangiogenesis and lymphatic metastasis. In a model in which human breast cancer cells were injected into immune-compromised mice, we found that SIX1 expression promoted peritumoral and intratumoral lymphangiogenesis, lymphatic invasion, and distant metastasis of breast cancer cells. SIX1 induced transcription of the prolymphangiogenic factor VEGF-C, and this was required for lymphangiogenesis and lymphatic metastasis. Using a mouse mammary carcinoma model, we found that VEGF-C was not sufficient to mediate all the metastatic effects of SIX1, indicating that SIX1 acts through additional, VEGF-Cindependent pathways. Finally, we verified the clinical significance of this prometastatic SIX1/VEGF-C axis by demonstrating coexpression of SIX1 and VEGF-C in human breast cancer. These data define a critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer, resulting in lymphangiogenesis and metastasis.

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Correlation between vascular endothelial growth factor‐C expression and invasion phenotype in cervical carcinomas

Cited by 77 publications

References 34 publications

Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer

Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer

Six1 expression is associated with a poor prognosis in patients with glioma

SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

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