Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma

English, William R.; Lunt, Sarah Jane; Fisher, Mike; Lefley, Diane V.; Dhingra, Mohit; Lee, Yu-Chin; Bingham, Karina; Hurrell, Jack E.; Lyons, Scott K.; Kanthou, Chryso; Tozer, Gillian M.

doi:10.1158/0008-5472.can-16-0255

Cited by 27 publications

(26 citation statements)

References 42 publications

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“…In the present study, we further revealed that ETV5 directly promoted transcription of proangiogenic factor VEGFA in CRC. Some previous studies reported cancers with high levels of VEGFA were particularly sensitive to VEGFA inhibition, including liver cancer, sarcoma and breast cancer [26][27][28]. Now that ETV5 could strongly induced VEGA expression in CRC, we speculated that the ETV5 + CRCs should be extremely sensitive to VEGFA.…”

Section: Discussionmentioning

confidence: 89%

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Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Feng

Liu

Liang

et al. 2020

Preprint

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Background ETV5 mediated angiogenesis was dependent on PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC) in our previous study. However, whether ETV5 affects effect of antiangiogenic therapy in CRC requires further investigation. Methods GSEA analysis and a series of experiments were performed to identify the critical candidate gene involved in bevacizumab resistance, and further explored whether the treatment targeting the candidate gene enhanced bevacizumab sensitivity in vitro and in vivo. Results ETV5 could directly bind to VEGFA promoter and promote translation of VEGFA. However, by in vitro and in vivo experiments, ETV5 actually accelerated anti-VEGF therapy (bevacizumab) resistance. GSEA analysis and further assays confirmed that ETV5 could promote angiogenesis by enhancing secretion of another tumor angiogenesis factor CCL2 in CRC cells, which resulted in bevacizumab resistance. ETV5 induced VEGFA and CCL2 were mutually independent to induce angiogenesis by activating PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells. In CRC tissues, ETV5 protein level was positively associated with CD31, CCL2, VEGFA protein expression. CRC patients with high expression of ETV5/VEGFA or ETV5/CCL2 showed inferior prognosis than other patients. Combination of anti-CCL2 and anti-VEGFA (Bevacizumab) treatment could more effectively inhibited tumor angiogenesis and growth than single treatment did in CRCs with high expression of ETV5 (ETV5 + CRCs). Conclusions Our results not only revealed ETV5 as a novel biomarker for antiangiogenic therapy, but also indicated a potential combined therapy strategy by simultaneously targeting CCL2 and VEGFA in ETV5 + CRC.

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Section: Discussionmentioning

confidence: 89%

“…1a). In cancers, high expression of VEGFA was particularly related to sensitivity of VEGFA inhibition, including liver cancer, sarcoma and breast cancer [26][27][28]. However, by chick embryo chorioallantoic membrane (CAM) assay, ETV5 upregulation in RKO promoted bevacizumab resistance (Fig.…”

Section: Statisticsmentioning

confidence: 99%

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Feng

Liu

Liang

et al. 2020

Preprint

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“…Our results indicated that the model can be used to identify sarcoma patients at high risk and enabling early interventions to improve the prognosis. Among 19 IRGs enrolled in risk signature, VEGFA, CYR61, and RHOA have con rmed to be related to the pathogenesis or prognosis of sarcoma [38][39][40][41]. It was reported that VEGFA is a potential neovascular regulatory factor that promotes tumor growth and metastasis through its receptor.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that VEGFA is a potential neovascular regulatory factor that promotes tumor growth and metastasis through its receptor. Differential expression of VEGFA subtypes regulates sarcoma metastasis and response to anti-VEGFA [38]. Besides, the VEGF family can not only promote tumor-associated immunode ciency by interfering with the growth of early hematopoietic progenitor T cells but promote Treg cell proliferation [42,43].…”

Section: Discussionmentioning

confidence: 99%

Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma

Shen

Meng

et al. 2020

Preprint

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Background Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs. Methods We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed. Results A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis(P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs. Conclusions In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.

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“…At a third stage, 14 mice were intraperitoneally injected with 200 μL of sodium chloride 0.9% or 25 mg/kg of bevacizumab 10,11 (Avastin, Roche, Basel, Switzerland) as pre-treatment 2 days before and after bacterial challenge; challenge was 5 × 10 6 cfus of P. aeruginosa intratracheally; mice were sacrificed 124 h after challenge.…”

Section: Experimental Animal Studymentioning

confidence: 99%

Early increase of VEGF‐A is associated with resolution of ventilator‐associated pneumonia: Clinical and experimental evidence

et al. 2018

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Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma

Cited by 27 publications

References 42 publications

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma

Early increase of VEGF‐A is associated with resolution of ventilator‐associated pneumonia: Clinical and experimental evidence

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