Molecular mechanisms and clinical relevance of endothelial cell cross-talk in clear cell renal cell carcinoma
Keywords:
Kidney cancer, clear cell renal cell carcinoma, tumor microenvironment, vasculature, endothelial cells, immune cells
Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer in adults and stands out as one of the most vascularized and immune-infiltrated solid tumors. Overproduction of vascular endothelial growth factor A promotes uncontrolled growth of abnormal vessels and immunosuppression, and the tumor microenvironment (TME) has a prominent role in disease progression, drug targeting and drug response, and for patient outcome.
Methods: Studies of experimental models, large-scale omics approaches, and patient prognosis and therapy prediction, using gene expression signatures and tissue biomarker analysis, have been reviewed for enhanced understanding of the endothelium in ccRCC and the interplay with the surrounding TME.
Results: Preclinical and clinical studies have discovered molecular mechanisms of endothelial cross-talk of relevance for disease progression, patient prognosis, and therapy prediction. There is, however, a lack of representative ccRCC experimental models. Omics approaches have identified clinically relevant subsets of angiogenic and immune-infiltrated tumors with distinct molecular signatures and distinct endothelial cell and immune cell populations in patients.
Conclusions: Recent genetically engineered ccRCC mouse models together with emerging evidence from single cell RNA sequencing data open up for future validation studies, including multiplex imaging of ccRCC patient cohorts. These studies are of importance for therapy benefit and personalized treatment of ccRCC patients.
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References
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12. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–57. doi: 10.1038/s41591-018-0053-3
13. Augustin HG, Koh GY. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science. 2017;357(6353):eaal2379. doi: 10.1126/science.aal2379
14. Apelt K, Bijkerk R, Lebrin F, Rabelink TJ. Imaging the renal microcirculation in cell therapy. Cells. 2021;10:1087. doi: 10.3390/cells10051087
15. Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18:195–203. doi: 10.1038/nri.2017.145
16. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51. doi: 10.1016/j.cell.2010.03.014
17. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99. doi: 10.1038/nri3862
18. Braun DA, Street K, Burke KP, Cookmeyer DL, Denize T, Pedersen CB, et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell. 2021;39:632–48.e8. doi: 10.1016/j.ccell.2021.02.013
19. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15:2148–57. doi: 10.1158/1078-0432.CCR-08-1332
20. Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. 2008;14:6674–82. doi: 10.1158/1078-0432.CCR-07-5212
21. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–103. doi: 10.1038/nm1096-1096
22. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212:139–48. doi: 10.1084/jem.20140559
23. Wolf MM, Kimryn Rathmell W, Beckermann KE. Modeling clear cell renal cell carcinoma and therapeutic implications. Oncogene. 2020;39:3413–26. doi: 10.1038/s41388-020-1234-3
24. Wang T, Lu R, Kapur P, Jaiswal BS, Hannan R, Zhang Z, et al. An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. Cancer Discov. 2018;8:1142–55. doi: 10.1158/2159-8290.CD-17-1246
25. Gu YF, Cohn S, Christie A, McKenzie T, Wolff N, Do QN, et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. 2017;7:900–17. doi: 10.1158/2159-8290.CD-17-0292
26. Bailey ST, Smith AM, Kardos J, Wobker SE, Wilson HL, Krishnan B, et al. MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma. Nat Commun. 2017;8:15770. doi: 10.1038/ncomms15770
27. Harlander S, Schonenberger D, Toussaint NC, Prummer M, Catalano A, Brandt L, et al. Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. Nat Med. 2017;23:869–77. doi: 10.1038/nm.4343
28. Sjoberg E, Melssen M, Richards M, Ding Y, Chanoca C, Chen D, et al. Endothelial VEGFR2-PLCgamma signaling regulates vascular permeability and anti-tumor immunity through eNOS/Src. J Clin Invest. 2023;133(20):e161366. doi: 10.1172/JCI161366
29. Nguyen-Tran HH, Nguyen TN, Chen CY, Hsu T. Endothelial reprogramming stimulated by oncostatin M promotes inflammation and tumorigenesis in VHL-deficient kidney tissue. Cancer Res. 2021;81:5060–73. doi: 10.1158/0008-5472.CAN-21-0345
30. Li R, Ferdinand JR, Loudon KW, Bowyer GS, Laidlaw S, Muyas F, et al. Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer. Cancer Cell. 2022;40:1583–99.e10. doi: 10.1016/j.ccell.2022.11.001
31. Aggen DH, Ager CR, Obradovic AZ, Chowdhury N, Ghasemzadeh A, Mao W, et al. Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model: multidimensional analyses. Clin Cancer Res. 2021;27:608–21. doi: 10.1158/1078-0432.CCR-20-1610
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33. Koch S, van Meeteren LA, Morin E, Testini C, Westrom S, Bjorkelund H, et al. NRP1 presented in trans to the endothelium arrests VEGFR2 endocytosis, preventing angiogenic signaling and tumor initiation. Dev Cell. 2014;28:633–46. doi: 10.1016/j.devcel.2014.02.010
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Published
2024-05-08
How to Cite
Sjöberg E. (2024). Molecular mechanisms and clinical relevance of endothelial cell cross-talk in clear cell renal cell carcinoma. Upsala Journal of Medical Sciences, 129(S1), e10632. https://doi.org/10.48101/ujms.v129.10632
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