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. 2021 Jun;21(6):554.
doi: 10.3892/etm.2021.9986. Epub 2021 Mar 26.

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

Xiuming Li  1 , Dianbin Song  1 , Hui Liu  2 , Zhiyong Wang  1 , Guang Ma  1 , Man Yu  1 , Yong Zhang  3 , Yu Zeng  4
Affiliations

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

Xiuming Li et al. Exp Ther Med. 2021 Jun.

Abstract

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.

Keywords: lymph node metastasis; lymphatic vessel density; renal cell carcinoma; vascular endothelial growth factor receptor 3; vascular endothelial growth factor-C.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Relative mRNA levels of VEGF-C. VEGF-C mRNA expression was analyzed by reverse transcription-semiquantitative PCR in (A) normal renal tissues (n=10) and RCC (n=40) tissues, and (B) LNM (n=11) and no LNM (n=29) groups. β-actin was used as an internal control. Data are presented as the mean ± SD. Significance was determined using the Mann-Whitney U test. *P<0.05. RCC, renal cell carcinoma; LNM, lymph node metastasis; VEGF-C, vascular endothelial growth factor-C.
Figure 2
Figure 2
Immunohistochemical staining of VEGF-C expression in RCC and normal renal tissues. (A) Negative VEGF-C expression in RCC. (B) Weak positive expression of VEGF-C in RCC. (C) Moderate positive expression of VEGF-C in RCC. (D) Strong positive expression of VEGF-C in RCC. (E) VEGF-C expression in glomerular epithelial cells (arrowheads). Scale bars, 100 µm. (F) Statistical analysis of the VEGF-C positive expression rate. Statistical significance was determined using the χ2 test. *P<0.05. RCC, renal cell carcinoma; VEGF-C, vascular endothelial growth factor-C.
Figure 3
Figure 3
Immunohistochemical staining of VEGFR-3 expression. VEGFR-3 immunohistochemical staining in (A) normal renal tissues and (B) RCC tissues. (C) Lymphatic endothelial cells in RCC tissues were VEGFR-3+ (indicated by arrows). Scale bars, 100 µm. (D) Correlation between VEGF-C and VEGFR-3 expression in RCC tissues. Statistical significance was determined by Spearman's correlation test. RCC, renal cell carcinoma; VEGF-C, vascular endothelial growth factor-C; VEGFR-3, VEGF receptor-3.
Figure 4
Figure 4
LVD in RCC and normal renal tissues. Lymphatic tubes were stained with D2-40. (A) Representative morphological structure of lymphatic vessels (indicated by arrows) in normal renal tissues. (B) Lymphatic capillaries were often irregularly shaped and collapsed in RCC tissues (indicated by arrows). (C) LVD around the tumor was higher than that in the tumor tissues; lymphatic vessels around the tumor were functionally dilated with an enlarged diameter (indicated by arrows). Scale bars, 100 µm. (D) Quantification of LVD in normal renal, RCC and peritumoral tissues. One-way ANOVA with Bonferroni post-hoc test was used for statistical analysis. (E) Statistical analysis of LVD in the LNM and no LNM groups. Significance was determined using an unpaired t-test. Data are presented as the mean ± SD. *P<0.05. RCC, renal cell carcinoma; LVD, lymphatic vessel density; LNM, lymph node metastasis.
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Grants and funding

Funding: The present study was supported by The Science and Technology Research and Development Project of Chengde, Hebei province (grant no. 201801A101).