دورية أكاديمية
Vascular endothelial profilin-1 drives a protumorigenic tumor microenvironment and tumor progression in renal cancer.
| العنوان: | Vascular endothelial profilin-1 drives a protumorigenic tumor microenvironment and tumor progression in renal cancer. |
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| المؤلفون: | Gau D; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: dmg40@pitt.edu., Daoud A; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Allen A; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Joy M; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Sagan A; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Lee S; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Lucas PC; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Duensing S; Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany., Boone D; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Osmanbeyoglu HU; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Roy P; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: par19@pitt.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2023 Aug; Vol. 299 (8), pp. 105044. Date of Electronic Publication: 2023 Jul 13. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Carcinoma, Renal Cell*/genetics , Kidney Neoplasms*/genetics , Profilins*/genetics , Profilins*/metabolism , Tumor Microenvironment*, Animals ; Humans ; Mice ; Endothelial Cells/metabolism ; Disease Progression |
| مستخلص: | Overexpression of actin-binding protein profilin-1 (Pfn1) correlates with advanced disease features and adverse clinical outcome of patients with clear cell renal carcinoma, the most prevalent form of renal cancer. We previously reported that Pfn1 is predominantly overexpressed in tumor-associated vascular endothelial cells in human clear cell renal carcinoma. In this study, we combined in vivo strategies involving endothelial cell-specific depletion and overexpression of Pfn1 to demonstrate a role of vascular endothelial Pfn1 in promoting tumorigenicity and enabling progressive growth and metastasis of renal carcinoma cells in a syngeneic orthotopic mouse model of kidney cancer. We established an important role of endothelial Pfn1 in tumor angiogenesis and further identified endothelial Pfn1-dependent regulation of several pro- (VEGF, SERPINE1, CCL2) and anti-angiogenic factors (platelet factor 4) in vivo. Endothelial Pfn1 overexpression increases tumor infiltration by macrophages and concomitantly diminishes tumor infiltration by T cells including CD8+ T cells in vivo, correlating with the pattern of endothelial Pfn1-dependent changes in tumor abundance of several prominent immunomodulatory cytokines. These data were also corroborated by multiplexed quantitative immunohistochemistry and immune deconvolution analyses of RNA-seq data of clinical samples. Guided by Upstream Regulator Analysis of tumor transcriptome data, we further established endothelial Pfn1-induced Hif1α elevation and suppression of STAT1 activation. In conclusion, this study demonstrates for the first time a direct causal relationship between vascular endothelial Pfn1 dysregulation, immunosuppressive tumor microenvironment, and disease progression with mechanistic insights in kidney cancer. Our study also provides a conceptual basis for targeting Pfn1 for therapeutic benefit in kidney cancer. Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | R21 EY032632 United States EY NEI NIH HHS; R01 CA248873 United States CA NCI NIH HHS; T15 LM007059 United States LM NLM NIH HHS; R00 CA207871 United States CA NCI NIH HHS; T32 HL129964 United States HL NHLBI NIH HHS; R35 GM146989 United States GM NIGMS NIH HHS; K99 CA267180 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: cytokines; immune cells; profilin; renal cancer; tumor angiogenesis |
| المشرفين على المادة: | 0 (Profilins) 0 (Pfn1 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20230714 Date Completed: 20230918 Latest Revision: 20240722 |
| رمز التحديث: | 20240722 |
| مُعرف محوري في PubMed: | PMC10432806 |
| DOI: | 10.1016/j.jbc.2023.105044 |
| PMID: | 37451478 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2023.105044 |