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Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells.

ABSTRACT: Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D were adopted for experiments. Stable transformants of dominant-negative (dn) SAS cells were established in which the cytoplasmic domain-deleted FLT-4 was exogenously overexpressed, which can lead to inactivation of endogenous FLT-4 through competitive antagonism and is associated with down-activation of endogenous FLT-4-related intracellular signals. In vitro and in vivo proliferation assays showed lower proliferative activity of dn-SAS cells. An immunohistochemical study revealed that the tumor lymphangiogenesis was significantly suppressed, and the level of human VEGF-C mRNA was significantly lower in dn-SAS cell-derived tumor tissues. Moreover, in vitro studies demonstrated that the significant suppression of VEGF-C and VEGF-A expression was evident in dn-SAS cells or wild-type SAS cells treated with either the FLT-4 kinase inhibitor MAZ51 or the inhibitor of FLT-4-related signals. These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy.

SUBMITTER: Matsuura M

PROVIDER: S-EPMC2751566 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells.

Matsuura Masaki M Onimaru Mitsuho M Yonemitsu Yoshikazu Y Suzuki Hanako H Nakano Toshiaki T Ishibashi Hiroaki H Shirasuna Kanemitsu K Sueishi Katsuo K

The American journal of pathology 20090924 4

Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D w ...[more]

PMID: 19779139

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Project description:Vascular endothelial growth factor A (VEGF) is involved in all the essential biology of endothelial cells, from proliferation to vessel function, by mediating intercellular interactions and monolayer integrity. It is expressed as three major alternative spliced variants. In mice, these are VEGF120, VEGF164, and VEGF188, each with different affinities for extracellular matrices and cell surfaces, depending on the inclusion of heparin-binding sites, encoded by exons 6 and 7. To determine the role of each VEGF isoform in endothelial homeostasis, we compared phenotypes of primary endothelial cells isolated from lungs of mice expressing single VEGF isoforms in normoxic and hypoxic conditions. The differential expression and distribution of VEGF isoforms affect endothelial cell functions, such as proliferation, adhesion, migration, and integrity, which are dependent on the stability of and affinity to VEGF receptor 2 (VEGFR2). We found a correlation between autocrine VEGF164 and VEGFR2 stability, which is also associated with increased expression of proteins involved in cell adhesion. Endothelial cells expressing only VEGF188, which localizes to extracellular matrices or cell surfaces, presented a mesenchymal morphology and weakened monolayer integrity. Cells expressing only VEGF120 lacked stable VEGFR2 and dysfunctional downstream processes, rendering the cells unviable. Endothelial cells expressing these different isoforms in isolation also had differing rates of apoptosis, proliferation, and signaling via nitric oxide (NO) synthesis. These data indicate that autocrine signaling of each VEGF isoform has unique functions on endothelial homeostasis and response to hypoxia, due to both distinct VEGF distribution and VEGFR2 stability, which appears to be, at least partly, affected by differential NO production. This study demonstrates that each autocrine VEGF isoform has a distinct effect on downstream functions, namely VEGFR2-regulated endothelial cell homeostasis in normoxia and hypoxia.

Project description:The aim of the present study was to explore the effects of BRAF-activated non-protein coding RNA (BANCR) on pancreatic microlymphangiogenesis in pancreatic cancer (PC) and its molecular mechanism under hypoxic conditions. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the expression of BANCR in SW1990 and PANC-1 PC cell lines under normoxic and hypoxic conditions. Subsequently, the expression of BANCR in the PC cells was knocked down using small interfering RNAs (siRNAs). Western blotting and RT-qPCR analyses were performed to detect the expression of hypoxia-inducible factor (HIF-1α), VEGF-C and VEGFR-3 in the transfected cells. In addition, the transfected PC cells were co-cultured with human lymphatic endothelial cells and the lymphatic microvessel density (MLVD) was detected under normal and hypoxic conditions. Furthermore, HIF-1α expression in the PC cells was knocked down using siRNAs, and VEGF-C and VEGFR-3 mRNA expression in the HIF-1α knockdown cells was detected using RT-qPCR. The results showed that the expression of BANCR in the SW1990 and PANC-1 PC cell lines was significantly higher than that in human pancreatic duct endothelial cells. Additionally, the expression of BANCR was significantly increased in PC cells under hypoxic conditions compared with normoxic conditions. The MLVD of PC cells under hypoxic conditions was significantly higher compared with that under normoxic conditions, and the MLVD in the si-BANCR group was lower than that in the si-NC group, indicating that si-BANCR downregulated MLVD. These results indicate that BANCR positively regulated the expression of HIF-1α in PC cells at the transcriptional and translational levels. Finally, the expression levels of VEGF-C and VEGFR-3 in PC cells were significantly reduced when BANCR or HIF-1α expression was knocked down. In conclusion, the results demonstrate that the expression of BANCR in PC cells was significantly increased under hypoxic conditions and suggest that BANCR promoted tumor cell lymphangiogenesis by upregulating the HIF-1α/VEGF-C/VEGFR-3 pathway, which plays an important role in the process of PC lymph node metastasis.

Dataset Information

Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells.

Publications

Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells.

Similar Datasets

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