Endothelial Metabolic Control of Lymphangiogenesis

Yu, Pengchun; Wu, Guosheng; Lee, Heon-Woo; Simons, Michael

doi:10.1002/bies.201700245

Cited by 13 publications

(14 citation statements)

References 58 publications

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“…Some studies have indicated the presence of lymphatic vessels in tumors, while others have demonstrated contrasting results ( 10 , 39 ). Although it remains controversial whether tumors can induce the genesis of lymphatic vessels, it has been demonstrated that the excessive expression of lymphogenerative factors, such as VEGF-C, can induce more lymphatic vessels and facilitate metastasis through tumor lymphatic vessels ( 14 ). In experiments using mouse tumor models, it has been demonstrated that VEGF-C induces lymphangiogenesis and that tumor cells enter the capillary lymphatic vessels ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

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Expression levels of VEGF‑C and VEGFR‑3 in renal cell carcinoma and their association with lymph node metastasis

Song

Liu

et al. 2021

Exp Ther Med

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Renal cell carcinoma (RCC) is the most common form of kidney cancer. Vascular endothelial growth factor-C (VEGF-C) and its receptor, VEGFR-3, are involved in lymphangiogenesis. The aim of the present study was to investigate the expression levels of VEGF-C and VEGFR-3 in RCC, and their association with lymphatic vessel density (LVD) and lymph node metastasis. The mRNA expression levels of VEGF-C in 40 RCC tissues and 10 normal renal tissues were determined by reverse transcription-semiquantitative PCR. The differential expression of VEGF-C and VEGFR-3 was examined by immunohistochemistry. Using an anti-D2-40 antibody as a lymphatic marker, the morphology and structure of lymphatic vessels in tissues was examined, and the LVD was calculated. VEGF-C mRNA expression in RCC tissues was higher than that in normal renal tissues, and VEGF-C mRNA expression in the lymph node metastasis group was higher than that in the non-lymph node metastasis group. The positive expression rate of VEGF-C and VEGFR-3 in RCC tissues was significantly higher than that in normal renal tissues. VEGF-C expression in the lymph node metastasis group was significantly higher than that in the non-lymph node metastasis group, and the positive expression of VEGF-C was associated with the clinical staging of RCC. In addition, there was a correlation between VEGF-C and VEGFR-3 expression in tumor cells. The LVD around the tumor was higher than that in the center of the tumor tissues and normal renal tissues, and it was closely associated with lymphatic invasion and lymph node metastasis. Overall, the current findings demonstrated that the VEGF-C/VEGFR-3 signaling pathway promoted lymphangiogenesis around the tumor and provided an approach for tumor lymphatic invasion and lymph node metastasis. Therefore, VEGFC and VEGFR-3 expression may serve an important role in the initiation and development of RCC.

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Section: Discussionmentioning

confidence: 99%

“…Lymphangiogenesis is a complex process regulated by a number of factors ( 14 ). It has been reported that vascular endothelial growth factor-C (VEGF-C) and its receptor, VEGFR-3, are the basis of lymphatic vessel formation ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Expression levels of VEGF‑C and VEGFR‑3 in renal cell carcinoma and their association with lymph node metastasis

Song

Liu

et al. 2021

Exp Ther Med

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“…Despite lesser ATP generation compared with oxidative phosphorylation, the up-regulated glycolysis meets the metabolic requirements of cell proliferation by affording adequate energy and sufficient glycolytic intermediates for macromolecular synthesis (eg, amino acids, phospholipids, and nucleic acids). 2,3 Moreover, the findings from a previous study 4 showed that the glycolysis level in endothelial cells (ECs) was much higher than that in other noncancer type of cells and largely comparable to that in tumor cells. EC metabolism has recently emerged as an important regulator of angiogenesis and lymphangiogenesis.…”

mentioning

confidence: 94%

Pyruvate Kinase M2 Mediates Glycolysis in the Lymphatic Endothelial Cells and Promotes the Progression of Lymphatic Malformations

Jiang

Zou

Zhao

et al. 2021

The American Journal of Pathology

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“…Recent advances have identified endothelial cell metabolism as a novel regulator of lymphatic vessel formation [17][18][19][20]. We and others found that glycolysis, which refers to a series of biochemical processes that convert glucose to pyruvate, provides more than 70% of ATP in LECs [21,16].…”

Section: Introductionmentioning

confidence: 99%

FGFR Signaling Coordinates the Balance Between Glycolysis and Fatty Acid β-Oxidation in Lymphatic Endothelial Cells

Song

Zhu

Fang

et al. 2020

Preprint

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The balance between glycolysis and oxidative phosphorylation is believed to be critical for maintaining cellular bioenergetics, yet the regulation of such balance in lymphatic endothelial cells (LECs) remains unclear. Here we found that chemical inhibition of fibroblast growth factor receptor (FGFR) activity or knockdown of FGFR1, which has been shown to suppress glycolysis and consequently ATP production, induces substantial upregulation of fatty acid b-oxidation (FAO), but not glucose oxidation or glutamine oxidation in LECs. Mechanistically, blockade of FGFR-AKT signaling promotes the expression of CPT1A, a rate-limiting enzyme of FAO, in a PPARadependent manner. Metabolic analysis further showed that CPT1A depletion impairs ATP generation in FGFR1-deficient rather than wild-type LECs. This result suggests that FAO, which makes a minor contribution to cellular energy under normal conditions, can compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified an FGFR-regulated metabolic balance that is important for LEC growth.

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Endothelial Metabolic Control of Lymphangiogenesis

Cited by 13 publications

References 58 publications

Expression levels of VEGF‑C and VEGFR‑3 in renal cell carcinoma and their association with lymph node metastasis

Expression levels of VEGF‑C and VEGFR‑3 in renal cell carcinoma and their association with lymph node metastasis

Pyruvate Kinase M2 Mediates Glycolysis in the Lymphatic Endothelial Cells and Promotes the Progression of Lymphatic Malformations

FGFR Signaling Coordinates the Balance Between Glycolysis and Fatty Acid β-Oxidation in Lymphatic Endothelial Cells

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