The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma
Abstract:Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.
“…It has been demonstrated that tumorigenesis will be withdrawn if the signal pathways of tumor angiogenesis are blockaded [4]. Thus, angiogenesis inhibition may be a viable treatment approach for the highly vascular tumor types, such as ovarian cancer, lung cancer and breast cancer [5][6][7]. However, targeting single factor may produce drug resistance and compensatory angiogenesis because the roles of other factors may be strengthened [8].…”
In tumor tissue, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) promote tumorigenesis by activating angiogenesis, but targeting single factor may produce drug resistance and compensatory angiogenesis. The Peptibody with bFGF/VEGFA was designed to simultaneously blockade these two factors. We were aiming to produce this Fc fusion protein in a large scale. The biological characterizations of Peptibody strains were identified as Escherichia coli and the fermentation mode was optimized in the shake flasks and 10‐L bioreactor. The fermentation was scaled up to 100 L, with wet cell weight (WCW) 126 g/L, production 1.41 g/L, and productivity 0.35 g/(L·h) of IPTG induction. The target protein was isolated by cation‐exchange, hydrophobic and Protein A chromatography, with total recovery of 60.28% and HPLC purity of 86.71%. The host cells protein, DNA, and endotoxin residues were within the threshold. In mouse model, immunization of Peptibody vaccine could significantly suppressed the tumor growth and angiogenesis, with inhibition rate of 57.73 and 39.34%. The Peptibody vaccine could elicit high‐titer anti‐bFGF and anti‐VEGFA antibodies, which inhibited the proliferation and migration of Lewis lung cancer cell cells by decreasing the Akt/MAPK signal pathways. Therefore, the Peptibody with bFGF/VEGFA might be used as a therapeutic tumor vaccine. The large‐scale process we developed could support its industrial production and pre‐clinical study in the future.
“…It has been demonstrated that tumorigenesis will be withdrawn if the signal pathways of tumor angiogenesis are blockaded [4]. Thus, angiogenesis inhibition may be a viable treatment approach for the highly vascular tumor types, such as ovarian cancer, lung cancer and breast cancer [5][6][7]. However, targeting single factor may produce drug resistance and compensatory angiogenesis because the roles of other factors may be strengthened [8].…”
In tumor tissue, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) promote tumorigenesis by activating angiogenesis, but targeting single factor may produce drug resistance and compensatory angiogenesis. The Peptibody with bFGF/VEGFA was designed to simultaneously blockade these two factors. We were aiming to produce this Fc fusion protein in a large scale. The biological characterizations of Peptibody strains were identified as Escherichia coli and the fermentation mode was optimized in the shake flasks and 10‐L bioreactor. The fermentation was scaled up to 100 L, with wet cell weight (WCW) 126 g/L, production 1.41 g/L, and productivity 0.35 g/(L·h) of IPTG induction. The target protein was isolated by cation‐exchange, hydrophobic and Protein A chromatography, with total recovery of 60.28% and HPLC purity of 86.71%. The host cells protein, DNA, and endotoxin residues were within the threshold. In mouse model, immunization of Peptibody vaccine could significantly suppressed the tumor growth and angiogenesis, with inhibition rate of 57.73 and 39.34%. The Peptibody vaccine could elicit high‐titer anti‐bFGF and anti‐VEGFA antibodies, which inhibited the proliferation and migration of Lewis lung cancer cell cells by decreasing the Akt/MAPK signal pathways. Therefore, the Peptibody with bFGF/VEGFA might be used as a therapeutic tumor vaccine. The large‐scale process we developed could support its industrial production and pre‐clinical study in the future.
“…For example, the expression of sVEGFR-1 by epithelial cells contributes to the corneal avascularity and its transfection in lacrimal glands has been shown to prevent the pathological corneal neovascularization [27,28]; the pathogenesis of pre-eclampsia, typically occurring in the last trimester of pregnancy, has been related to sVEGFR-1 production by placenta and subsequent neutralization of VEGF-A and PlGF signaling [29,30]; a low sVEGFR-1 to VEGF-A ratio has been correlated with higher tumor malignancy/invasiveness and poor patients' survival [31][32][33][34][35][36][37]. The sVEGFR-1 may also play a proangiogenic and protumoral action by activation of β1 integrin, which results in stimulation of endothelial cell adhesion and chemotaxis [38][39][40]. VEGF family members and their receptors.…”
The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process. The aim of the present review is to highlight the contribution of VEGFs/VEGFR-1 signaling in the progression of different tumor types and to provide an overview of the therapeutic approaches targeting VEGFR-1 currently under investigation.
“…Hence, in addition to the transmembrane VEGFR1, soluble isoforms of the receptor (sVEGFR1s) which arise from cleavage of full-lenght VEGFR1 or from alternative splicing of VEGFR1 pre-mRNA are produced by endothelial and also tumor cells. sVEGFR1s have been implicated in many pathological functions such as tumor progression 3,4 . In addition, several clinical trials have shown that anti-angiogenic therapies up-regulate circulating levels of sVEGFR1s 5–7 .…”
Section: Introductionmentioning
confidence: 99%
“…Together, these data support the notion that sVEGFR1-i13 exerts both pro- and anti-angiogenic functions on endothelial cells. Interestingly, we recently demonstated that sVEGFR1-i13 contributes to the progression and the response of Squamous Lung Carcinoma (SQLC) cells to anti-angiogenic therapies through the regulation of a β1 integrin/VEGFR autocrine loop 4 . Therefore, these data indicated that sVEGFR1-i13 also targets the tumor cells themselves.Figure 1VEGF 165 regulates sVEGFR1-i13 expression in SQLC cell lines.…”
Section: Introductionmentioning
confidence: 99%
“…Illustrations of a representative result are presented for each condition. ( f ) Mean levels ± SD of VEGF 165 immunohistochemical scores according to sVEGFR1-i13 status in squamous cell lung carcinoma, where SQLC are sub-divided in two classes representing tumors with high or low levels of sVEGFR1-i13 compared to normal lung tissues 4 . Statistical analyses were performed using a non parametric Mann-Whitney test (*p < 0.05; **p < 0.01; ***p < 0.001).…”
The splice variant sVEGFR1-i13 is a truncated version of the cell membrane-spanning VEGFR1 receptor that is devoid of its transmembrane and tyrosine kinase domains. We recently showed the contribution of sVEGFR1-i13 to the progression and the response of squamous lung carcinoma to anti-angiogenic therapies. In this study, we identify VEGF165, a splice variant of VEGF-A, as a regulator of sVEGFR1-i13 expression in these tumors, and further show that VEGF165 cooperates with the transcription factor SOX2 and the splicing factor SRSF2 to control sVEGFR1-i13 expression. We also demonstrate that anti-angiogenic therapies up-regulate sVEGFR1-i13 protein level in squamous lung carcinoma cells by a mechanism involving the VEGF165/SOX2/SRSF2 network. Collectively, our results identify for the first time a signaling network that controls VEGFR1 pre-mRNA alternative splicing in cancer cells.
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