Endostatin gene therapy stimulates upregulation of ICAM-1 and VCAM-1 in a metastatic renal cell carcinoma model

Abstract

One of the greatest challenges in urological oncology is renal cell carcinoma (RCC), which is the third leading cause of death in genitourinary cancers. RCCs are highly vascularized and respond positively to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential of ES-based antiangiogenic therapy to activate tumor-associated endothelial cells in metastatic RCC (mRCC). Balb/c-bearing Renca cells were treated with NIH/3T3-LendSN or, as a control, with NIH/3T3-LXSN cells. The T-cell subsets and lymphocyte populations of tumors, mediastinal lymph nodes and the spleen were assessed by flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was assessed by real-time PCR, flow cytometry and immunohistochemistry analysis. ES gene therapy led to an increase in the percentage of infiltrating CD4-interferon (IFN)-g cells (Po0.05), CD8-IFN-g cells (Po0.01) and CD49b-tumor necrosis factor-a cells (Po0.01). In addition, ES therapy caused an increase at the mRNA level of ICAM-1 (1.4-fold; Po0.01) and VCAM-1 (1.5-fold) (control vs treated group; Po0.001). Through flow cytometry, we found a significant increase in the CD34/ICAM-1 cells (8.1-fold; Po0.001) and CD34/VCAM-1 cells (1.6-fold; Po0.05). ES gene therapy induced a significant increase in both T CD4 and CD8 cells in the lymph nodes and the spleen, suggesting that ES therapy may facilitate cell survival or clonal expansion. CD49b cells were also present in increased quantities in all of these organs. In this study, we demonstrate an antitumor inflammatory effect of ES in an mRCC model, and this effect is mediated by an increase in ICAM-1 and VCAM-1 expression in tumor-associated endothelial cells.

Involvement of the NF-кB/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma

“…Our data are corroborated by the study of Feldman et al in 2002, where it was demonstrated that the plasma levels of ES in patients with RCC in stage IV were elevated compared to levels of ES in healthy volunteers [28]. Treatment with gene therapy caused a significant increase in circulating levels of ES, which led to changes in the tumor microenvironment, such as decreases in the number of intranodular vessels and increases in inflammatory infiltrates [21][22][23][24][25]. In turn, these changes lead to changes in the pattern of gene expression in both stromal and tumor cells.…”

“…NIH/3T3-LendSN-clone 3 was utilized for ES expression, and NIH/3T3-LXSN was used as a control, as described in previous work [23,26]. Both cell lines were maintained in high-glucose (4.5 g/L at 25 mM) DMEM medium (Life Technologies Corporation 1 , Grand Island, NY, USA) supplemented with 100 U/mL penicillin, 100 mg/ mL streptomycin (Gibco 1 ), and 10% fetal bovine serum (FBS).…”

“…ES showed antiangiogenic and antitumor activities. Furthermore, it was shown that ES caused exhibits potent immunomodulatory effects [20][21][22][23][24][25][26].…”

Impact of Endostatin Gene Therapy on Myeloid-Derived Suppressor Cells From a Metastatic Renal Cell Carcinoma

“…Accordingly, we previously demonstrated that ES gene therapy elicits a pleotropic effect in the mRCC model, primarily as a potent pro-inflammatory and antitumor response, as observed on day 17 [43,44]. The production of ES by fibroblasts was 2.5-fold higher than that of non-producing fibroblasts, and the administration of these cells promoted a reduction in the metastatic foci number, corroborating our previous data [45].…”

MicroRNA-181a-5p Impedes IL-17-Induced Nonsmall Cell Lung Cancer Proliferation and Migration through Targeting VCAM-1

“…VCAM-1 is a critical molecule which contributes to cancer cell adhesion. Abnormal VCAM-1 expression has been studied in patient with gastric cancer and renal cell carcinoma [24, 25]. The expression of VCAM-1 was also elevated in NSCLC (Fig.…”