血管內皮細胞在腫瘤微環境中促進透明腎細胞癌形成之研究

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：35

、訪客IP：3.138.118.250

姓名

阮陳孝輝(Hieu-Huy Nguyen-Tran) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

血管內皮細胞在腫瘤微環境中促進透明腎細胞癌形成之研究
(Study of the active role of vascular endothelial cells in the initiation and progression of clear-cell renal cell carcinoma)

相關論文

★ 由基因微陣列分析發炎與腎臟細胞癌發生之機制	★ VHL基因突變在癌前期的組織發炎機制
★ VHL剔除模型之轉錄體差異以及台灣透明細胞腎細胞癌族群之特定基因體變異之研究	★ VHL knockdown HK-2 cells induce macrophage endothelial extravasation
★ ITPR2, an ER calcium channel, regulates ER stress and inflammatory response in pre-cancerous kidney tubule cells	★ 透明腎臟細胞癌發生前期與組織發炎之關係研究
★ VHL與KIM-1的功能關係研究	★ Study of the Interaction between VHL/Vhlh Deficient Kidney Epithelial Cells and Macrophages—Relevance to the Development of Clear-Cell Renal Cell Carcinoma
★ 應用大腸桿菌與酵母菌蛋白質體晶片系統性分析抗菌肽及抗生素作用之目標蛋白質	★ Analysis of Gene Expression of Chronic Obstructive Pulmonary Disease and Chronic Kidney Disease to Illuminate Chronic Inflammation Associated with Tumor Microenvironment and Potential Treatment

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

[檢視]

[下載]

本電子論文使用權限為同意立即開放。
已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

摘要(中)

腎細胞癌 (Renal cell carcinoma, RCC) 是十大癌症之一，占腎癌的 90% 以上。其中，透明腎細胞癌 (clear-cell RCC, ccRCC) 是最為常見的一種形態，占所有 RCC 病例的 75% 以上。ccRCC組織具有豐富的血管及免疫細胞。其發生率跟 von Hippel-Lindal (VHL)抑癌基因的突變有極高的相關性。 VHL蛋白是一個 E3 泛素連接酶，在氧氣充足時辨識缺氧誘導因子α(HIF-α)，將其破壞；突變後其抑制功能缺失，導致HIF-α在細胞中累積。然而，目前尚未清楚VHL基因的突變，是如何影響組織發炎和腫瘤發生。血管內皮細胞 (Endothelial cells,ECs) 是基質細胞的一種，也是每個器官不可少的一部分。傳統上，EC 被認為是一種將血液與組織分開的惰性隔離膜。然而，近來越來越多的證據表明，EC是一個非常活躍的器官，它積極參與多數疾病，尤其是發炎相關的疾病。然而，EC是如何參與發炎反應、從而誘發腫瘤的發生並不清楚。同時 VHL突變是否在這些病理生理的相互作用中所扮演的協調角色也尚未了解。
在實驗室先前在腎小管中敲除Vhlh基因的小鼠模型 (VhlhKO)中發現被敲除Vhlh的腎小管除了有細胞增生和透明細胞的出現外，還引起嚴重的炎症和纖維化。該結果表明 VHL 的剔除可誘發慢性炎症，這可能是 ccRCC 發展的早期表現。我們意外地發現，在 Vhlh 基因敲除的組織中雖然EC沒有發生任何基因編輯但磷酸化c-Jun N末端激酶的表現量明顯增加。這發現給我們一個啟發，EC在炎症誘發腫瘤形成過程中可能會扮演重要的角色。此外，這些EC還與腫瘤血管具有相同的特徵，包括新血管生成及血管滲漏。在轉錄體研究中，從 VhlhKO組織來的 EC基因表現與對照組有很大的差異。這些有差異的基因主要是參與發炎反應以及間質轉化(mesenchymal transition)。
重要的是，我們證明oncostatin M (OSM)是VHL突變的上皮細胞與血管內皮細胞之間的主要傳導物。OSM的表現在VHL缺陷的上皮細胞中增加，從而引發EC裡的OSMR增加，進而形成一個自我延續的積極信號循環。在體外實驗中，OSM 引發EC的活化和內皮間質細胞轉化（endothelial-mesenchymal transition, EndoMT），導致血管的通透性及腎臟癌細胞侵入穿透數量增加。被OSM激活過的ECs會誘導巨噬細胞變成M2/TAM形態。在HK-2正常腎臟細胞株中敲低 VHL 後會引發OSM表現。在上皮細胞和內皮細胞的共同培養系統中，被敲低 VHL的HK-2引發EC活化。在EC敲落OSMR 或在培養液中中和OSM可以衰減VHL缺陷的在動物實驗中，敲除 Osmr來阻擋 EC中的Osm 訊息傳導可以改善EC的表型包括降低血管增生、釋放E-Selectin、血管滲露以及腫瘤血管相關的形態。同時，可以改善VhlhKO小鼠的ccRCC相關表型包括降低發炎病灶，纖維化，細胞增生及巨噬細胞浸透。在藥理治療中，Janus激酶抑製劑Tofacitini可以顯著減輕VhlhKO組織中的EC活化指數和炎症表型，與基因改造的結果一致。
最後，Vhlh突變微環境可以增強外源性腫瘤的轉移，包括小鼠黑色素瘤 (B16) 和人類 ccRCC (786-O) 細胞。因此，OSM 訊息傳導建構了VHL 缺陷腎小管細胞的發炎及致癌微環境，在 ccRCC的發生和轉移過程中扮演重要角色。我們的研究結果揭秘了EC在炎症相關癌症，並且指出OSM訊息傳導可用於預防、早發治療和ccRCC轉移治療的新標靶。

摘要(英)

Renal cell carcinoma (RCC) is among the top ten cancers worldwide and accounts for >90% of cancers in kidney. Among them, clear-cell RCC (ccRCC) is the most common histological subtype accounting for more than 75% of all RCC cases. ccRCC is a highly vascularized and immunogenic tissue that is closely associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene (found in ~80% of ccRCC patients). The VHL protein has been well-recognized as a key regulator of hypoxic response. However, it is still unclear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor (HIF-α), can coordinate tissue inflammation and tumorigenesis. Endothelial cells (ECs) are a constituent of stromal cells, which are indispensable for every organ. ECs have traditionally been considered as a non-reactive barrier that separates blood from tissues. However, recently accumulating evidence has illustrated that ECs constitute a dynamic organ that actively participates in most if not all of the disease states, particularly in inflammatory response. Yet, how these ECs are involved in inflammatory regulation and tumorigenesis is less well documented, and whether VHL plays a role in coordinating these pathophysiological interactions is also unclear.
Previously we generated a conditional mouse Vhlh gene knockout in kidney tubules (VhlhKO), which results in severe inflammation and fibrosis in addition to hyperplasia and appearance of transformed clear cells. These results imply that inactivation of VHL can induce chronic inflammation, which may be an early step in ccRCC development. Interestingly, we found that endothelial cells in Vhlh knockout kidney, although not harboring any genetic modifications, show an enrichment of phosphorylated c-Jun N-terminal kinase (p-Jnk)–an inflammatory marker–that suggested a role in inflammation induced tumorigenesis. In addition, these ECs in Vhlh knockout mice show abnormal phenotypes resembling tumor ECs, including neoangiogenesis and leakage. In the transcriptome study of these ECs, we found a profound change in gene expression program of ECs from VhlhKO tissue compared with those in wild-type mice (WT). These genes with altered expression are mainly involved in inflammatory response and mesenchymal transition.
Importantly, we demonstrate that oncostatin M (OSM) is a major regulator that mediates the interaction between VHL mutant kidney tubule cells and the ECs. The expression of OSM is upregulated in VHL-deficient epithelial cells and can induce overexpression of OSMR in ECs, thus forming a self-perpetuating positive signaling loop. In vitro, OSM induces EC activation and endothelial-mesenchymal transition (EndoMT) that leads to increase of vascular permeability and the number of invaded kidney cancer cells. These OSM-activated ECs also induce macrophage polarization toward M2/TAM like phenotype. Knockdown of VHL in renal tubule cells (HK-2) results in upregulation of OSM. In coculture system, we found that HK-2 with VHL knockdown could induce activation of EC, which could be recused by attenuating OSM pathway in ECs by knockdown of OSMR receptor or neutralizing OSM in cocultured media.
In vivo, attenuating OSM pathway in ECs by generating Osmr knockout in VhlhKO tissue (DBKO tissue) could recuse the abnormal phenotypes of ECs in VhlhKO tissue including reduced angiogenesis (CD31+ cells number), secreted E-Selectin (sSELE; marker of EC activation), vascular leakage and tumor-endothelial-cells related morphologies. In addition, DBKO also recuses the phenotypes of VhlhKO mice that are related to ccRCC, including inflammatory foci, fibrosis, proliferation index (Ki-67+ cells) and macrophage infiltration (F4/80+ cells). Consistent with the results in genetic modification, in the pharmacological treatment, tofacitinib (a Janus kinase inhibitor) could markedly alleviate the activated EC index and inflammatory phenotype of VhlhKO tissue.
Finally, the Vhlh mutant microenvironment can enhance metastasis of exogenous tumors, both of the mouse melanoma (B16) and human ccRCC (786-O) cells. Thus, OSM signaling initiates reconstitution of inflammatory and tumorigenic microenvironment of VHL-deficient renal tubule cells, which play a critical role in ccRCC initiation and metastasis. Our results provide an insight regarding ECs in inflammation related cancer, and suggest OSM pathway as a novel target for prevention and treatment of early-onset and metastasis of ccRCC.

關鍵字(中)

★ 腎細胞癌
★ von Hippel-Lindal
★ 血管內皮細胞
★ 抑癌蛋白M
★ 腫瘤微環境

關鍵字(英)

★ clear-cell renal cell carcinoma
★ von Hippel-Lindau
★ Endothelial cells
★ oncostatin M
★ Tumor microenvironment

論文目次

Abstract i
中文摘要 iii
ACKNOWLEDGEMENT v
List of Figures x
List of Tables xi
List of Glossaries And Abbreviations (alphabetical order) xiii
Chapter I 1
Literature review 1
1.1 Introduction to cancer 1
1.2 Renal cell carcinoma 2
1.2.1 Introduction to renal cell carcinoma 2
1.2.2 Papillary RCC 2
1.2.3 Chromophobe RCC 2
1.2.5 VHL tumor suppressor gene and ccRCC 4
1.3 Diagnosis and treatment of RCC 5
1.3.1 Diagnosis of RCC 5
1.3.2 Treatment of RCC 5
1.3.2.1 Treatment for local RCC 6
1.3.2.2 Treatment of metastatic RCC 6
1.4 ccRCC mouse models 7
1.5 Kidney inflammation and RCC 9
Chapter 2 20
Materials and Methods 20
2.1 Animals 20
2.2 EC isolation 20
2.3 Cell culture 21
2.4 RNA sequencing 22
2.5 Lentivirus transduction 22
2.6 Real-time PCR analysis 23
2.7 Immunoblot analysis 23
2.8 ELISA 24
2.9 Immunofluorescence and immunohistochemistry 25
2.10 Macrophage polarization 25
2.11 Flow cytometry 26
2.12 In vitro permeability, cell invasion, and ICC staining 26
2.13 In vivo vascular leakage assay 27
2.14 Pharmacological treatment 27
2.15 Kidney implantation of cancer cells 27
2.16 Tissue specimens 28
2.17 Statistical analysis 28
2.18 mRNA transcriptome data 29
Chapter 3 30
Abnormal vascular phenotype in pre-malignant ccRCC mouse model and human ccRCC tissue 30
3.1 Introduction 30
3.1.1 Renal endothelial cells under physiological conditions 30
3.1.2 Jun N-terminal kinase 31
3.2 Results 32
3.2.1 Conditional Vhlh knock out mice exhibit ccRCC-related inflammatory phenotypes 32
3.2.2 Abnormal vascular signature of ECs in VhlhKO tissue 33
3.3 Discussion 33
Chapter 4 41
Activation signature of ECs in pre-malignant ccRCC 41
4.1 Introduction 41
4.1.1 Tumor microenvironment (TME) 41
4.1.2 Renal ECs under inflammatory condition 41
4.1.3 Tumor endothelial cells (TEC) 42
4.2 Results 44
4.3 Discussion 46
Chapter 5 57
The activation of ECs is mainly mediated by OSM in VHL mutant microenvironment 57
5.1 Introduction 57
5.2 Results 57
5.2.1 The activation of ECs is mainly regulated by OSM in Vhlh mutant microenvironment 57
5.2.2 The interaction of VHL mutant renal tubule cells and ECs in vitro 58
5.2.3 OSM induces endothelial-mesenchymal transition (EndoMT). 59
5.2.4 Activated ECs by OSM could induce alternative activation of macrophages 60
5.3 Discussion 60
Chapter 6 79
OSM pathway is important for the pathogenesis of VhlhKO tissue 79
6.1 Results 79
6.2 Discussion 81
Chapter 7 88
Vhlh mutant microenvironment promotes cancer cells metastasis 88
7.1 Introduction 88
7.2 Results 89
7.3 Discussion 91
Chapter 8 100
Conclusion remarks and perspective 100
8.1 Conclusion remarks 100
8.2 Perspective 103
References 106
Publication list 138

參考文獻

Rothschild, B.M., Tanke, D.H., Helbling, M., 2nd & Martin, L.D. Epidemiologic study of tumors in dinosaurs. Naturwissenschaften 90, 495-500 (2003).
2. Schultz, M., Parzinger, H., Posdnjakov, D.V., Chikisheva, T.A. & Schmidt-Schultz, T.H. Oldest known case of metastasizing prostate carcinoma diagnosed in the skeleton of a 2,700-year-old Scythian king from Arzhan (Siberia, Russia). Int J Cancer 121, 2591-2595 (2007).
3. Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71, 209-249 (2021).
4. Alberts, B. Molecular Biology of the Cell. (W.W. Norton, 2017).
5. Lodish, H.F. et al. Molecular Cell Biology. (W.H. Freeman, New York; 2008).
6. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
7. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424 (2018).
8. Bhatt, J.R. & Finelli, A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat Rev Urol 11, 517-525 (2014).
9. Foot, N.C., Humphreys, G.A. & Whitmore, W.F. Renal tumors: pathology and prognosis in 295 cases. J Urol 66, 190-200 (1951).
10. Cohen, H.T. & McGovern, F.J. Renal-cell carcinoma. N Engl J Med 353, 2477-2490 (2005).
11. Hsieh, J.J. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017).
12. Delahunt, B. & Eble, J.N. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10, 537-544 (1997).
13. Cancer Genome Atlas Research, N. et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med 374, 135-145 (2016).
14. Klatte, T. et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clinical Cancer Research 15, 1162-1169 (2009).
15. Sun, M. et al. HNF1B Loss Exacerbates the development of chromophobe renal cell carcinomas. Cancer Research 77, 5313-5326 (2017).
16. Caleb et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319-330 (2014).
17. Gudbjartsson, T. et al. Effect of incidental detection for survival of patients with renal cell carcinoma: results of population-based study of 701 patients. Urology 66, 1186-1191 (2005).
18. Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 46, 225-233 (2014).
19. Mitchell, T.J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell 173, 611-623 e617 (2018).
20. Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx Renal. Cell 173, 595-610 e511 (2018).
21. Beuselinck, B. et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clinical Cancer Research 21, 1329-1339 (2015).
22. D′Avella, C., Abbosh, P., Pal, S.K. & Geynisman, D.M. Mutations in renal cell carcinoma. Urol Oncol 38, 763-773 (2020).
23. Cowey, C.L. & Rathmell, W.K. VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep 11, 94-101 (2009).
24. v. Hippel, E. Über eine sehr seltene Erkrankung der Netzhaut. Albrecht von Graefes Archiv für Ophthalmologie 59, 83-106 (1904).
25. Lindau, A. Zur frage der angiomatosis retinae und ihrer hirncomplikation. Acta Ophthalmol. Scand 4, 193–226 (1927).
26. Maher, E.R., Neumann, H.P. & Richard, S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 19, 617-623 (2011).
27. Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317-1320 (1993).
28. Schoenfeld, A., Davidowitz, E.J. & Burk, R.D. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A 95, 8817-8822 (1998).
29. Kibel, A., Iliopoulos, O., DeCaprio, J.A. & Kaelin, W.G., Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 269, 1444-1446 (1995).
30. Duan, D.R. et al. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269, 1402-1406 (1995).
31. Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M. & Krek, W. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev 13, 1822-1833 (1999).
32. Maxwell, P.H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271-275 (1999).
33. Iliopoulos, O., Kibel, A., Gray, S. & Kaelin, W.G., Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1, 822-826 (1995).
34. Zbar, B., Brauch, H., Talmadge, C. & Linehan, M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 327, 721-724 (1987).
35. Young, A.C. et al. Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res 15, 7582-7592 (2009).
36. Mandriota, S.J. et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1, 459-468 (2002).
37. Yao, M. et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 94, 1569-1575 (2002).
38. Gimenez-Bachs, J.M. et al. Determination of Vhl gene mutations in sporadic renal cell carcinoma. Eur Urol 49, 1051-1057 (2006).
39. Choueiri, T.K. et al. The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Cancer Res 19, 5218-5226 (2013).
40. Volpe, A. et al. Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. J Urol 178, 379-386 (2007).
41. Leveridge, M.J. et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol 60, 578-584 (2011).
42. Volpe, A. et al. Contemporary results of percutaneous biopsy of 100 small renal masses: a single center experience. J Urol 180, 2333-2337 (2008).
43. Bradley, A.J., Lim, Y.Y. & Singh, F.M. Imaging features, follow-up, and management of incidentally detected renal lesions. Clin Radiol 66, 1129-1139 (2011).
44. Huang, W.C., Elkin, E.B., Levey, A.S., Jang, T.L. & Russo, P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes? J Urol 181, 55-61; discussion 61-52 (2009).
45. Gill, I.S. et al. Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. J Urol 178, 41-46 (2007).
46. Aron, M. & Gill, I.S. Minimally invasive nephron-sparing surgery (MINSS) for renal tumours. Part II: probe ablative therapy. Eur Urol 51, 348-357 (2007).
47. Kunkle, D.A. & Uzzo, R.G. Cryoablation or radiofrequency ablation of the small renal mass : a meta-analysis. Cancer 113, 2671-2680 (2008).
48. Zagoria, R.J. et al. Oncologic efficacy of CT-guided percutaneous radiofrequency ablation of renal cell carcinomas. AJR Am J Roentgenol 189, 429-436 (2007).
49. Motzer, R.J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356, 115-124 (2007).
50. Rini, B.I. et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26, 5422-5428 (2008).
51. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356, 2271-2281 (2007).
52. Sternberg, C.N. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28, 1061-1068 (2010).
53. Motzer, R.J. et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 33, 1430-1437 (2015).
54. Motzer, R.J. et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 378, 1277-1290 (2018).
55. Paraf, F. et al. Renal lesions in von Hippel-Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins. Histopathology 36, 457-465 (2000).
56. Droz, D. et al. Expression of the human nephron differentiation molecules in renal cell carcinomas. Am J Pathol 137, 895-905 (1990).
57. Straube, T. et al. Changes in the expression and subcellular distribution of galectin-3 in clear cell renal cell carcinoma. J Exp Clin Cancer Res 30, 89 (2011).
58. Gnarra, J.R. et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A 94, 9102-9107 (1997).
59. Rankin, E.B., Tomaszewski, J.E. & Haase, V.H. Renal cyst development in Mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Research 66, 2576-2583 (2006).
60. Schley, G. et al. Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury. J Am Soc Nephrol 22, 2004-2015 (2011).
61. Schietke, R.E. et al. Renal tubular HIF-2 expression requires VHL inactivation and causes fibrosis and cysts. PLoS One 7, e31034 (2012).
62. Harlander, S. et al. Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. Nat Med 23, 869-877 (2017).
63. Pritchett, T.L., Bader, H.L., Henderson, J. & Hsu, T. Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene 34, 2631-2639 (2015).
64. Virchow, R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI--Atheromatous affection of arteries. 1858. Nutr Rev 47, 23-25 (1989).
65. de Vivar Chevez, A.R., Finke, J. & Bukowski, R. The role of inflammation in kidney cancer. Adv Exp Med Biol 816, 197-234 (2014).
66. Diaz-Montero, C.M., Rini, B.I. & Finke, J.H. The immunology of renal cell carcinoma. Nat Rev Nephrol 16, 721-735 (2020).
67. Greten, F.R. & Grivennikov, S.I. Inflammation and cancer: triggers, cechanisms, and consequences. Immunity 51, 27-41 (2019).
68. Jöhrer, K. et al. Up-Regulation of functional chemokine receptor CCR3 in human renal cell carcinoma. Clinical Cancer Research 11, 2459-2465 (2005).
69. Yoshida, N. et al. Interleukin-6, tumour necrosis factor α and interleukin-1β in patients with renal cell carcinoma. British Journal of Cancer 86, 1396-1400 (2002).
70. Fitzgerald, J.P. et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS One 7, e30712 (2012).
71. Petrella, B.L. & Brinckerhoff, C.E. Tumor cell invasion of von Hippel Lindau renal cell carcinoma cells is mediated by membrane type-1 matrix metalloproteinase. Mol Cancer 5, 66 (2006).
72. Song, M., Bode, A.M., Dong, Z. & Lee, M.H. AKT as a Therapeutic target for cancer. Cancer Res 79, 1019-1031 (2019).
73. Kondo, K. et al. PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int J Cancer 91, 219-224 (2001).
74. Qi, H. & Ohh, M. The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway. Cancer Res 63, 7076-7080 (2003).
75. Loh, C.Y. et al. Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol 9, 48 (2019).
76. Wang, Y. et al. G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas. Cell Death Dis 9, 501 (2018).
77. Bardia, A. et al. Association of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs with cancer incidence and mortality. J Natl Cancer Inst 99, 881-889 (2007).
78. Sawaoka, H. et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 79, 1469-1477 (1999).
79. Khurana, V., Caldito, G. & Ankem, M. Statins might reduce risk of renal cell carcinoma in humans: case-control study of 500,000 veterans. Urology 71, 118-122 (2008).
80. Alberts, B. Molecular biology of the cell. (2015).
81. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436-444 (2008).
82. Weng, P.H. et al. Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort. Clin J Am Soc Nephrol 6, 1121-1128 (2011).
83. Christensson, A. et al. Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years. Int J Cancer 133, 1452-1458 (2013).
84. Lowrance, W.T., Ordonez, J., Udaltsova, N., Russo, P. & Go, A.S. CKD and the risk of incident cancer. J Am Soc Nephrol 25, 2327-2334 (2014).
85. Stewart, J.H. et al. Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand. J Am Soc Nephrol 14, 197-207 (2003).
86. Denton, M.D. et al. Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis. Kidney Int 61, 2201-2209 (2002).
87. Peired, A.J. et al. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells. Sci Transl Med 12 (2020).
88. Peired, A.J., Lazzeri, E., Guzzi, F., Anders, H.-J. & Romagnani, P. From kidney injury to kidney cancer. Kidney International 100, 55-66 (2021).
89. Tanaka, M. et al. Targeted disruption of oncostatin M receptor results in altered hematopoiesis. Blood 102, 3154-3162 (2003).
90. Huleihel, L. et al. Macrophage phenotype in response to ECM bioscaffolds. Semin Immunol 29, 2-13 (2017).
91. Savitri, C., Ha, S.S., Liao, E., Du, P. & Park, K. Extracellular matrices derived from different cell sources and their effect on macrophage behavior and wound healing. J Mater Chem B 8, 9744-9755 (2020).
92. Sellmayr, M. et al. Only hyperuricemia with crystalluria, but not asymptomatic hyperuricemia, drives progression of chronic kidney disease. J Am Soc Nephrol 31, 2773-2792 (2020).
93. Tracz, A., Mastri, M., Lee, C.R., Pili, R. & Ebos, J.M. Modeling spontaneous metastatic renal cell carcinoma (mRCC) in mice following nephrectomy. J Vis Exp (2014).
94. Lanzer, P. Panvascular medicine. (2015).
95. Satchell, S. The role of the glomerular endothelium in albumin handling. Nat Rev Nephrol 9, 717-725 (2013).
96. Rafii, S., Butler, J.M. & Ding, B.S. Angiocrine functions of organ-specific endothelial cells. Nature 529, 316-325 (2016).
97. Arnout, J., Hoylaerts, M.F. & Lijnen, H.R. Haemostasis. Handb Exp Pharmacol, 1-41 (2006).
98. Davenport, A.P. et al. Endothelin. Pharmacol Rev 68, 357-418 (2016).
99. Siragusa, M. & Fleming, I. The eNOS signalosome and its link to endothelial dysfunction. Pflugers Arch 468, 1125-1137 (2016).
100. Behrens, A., Sibilia, M. & Wagner, E.F. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21, 326-329 (1999).
101. Bubici, C. & Papa, S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 171, 24-37 (2014).
102. Dong, C., Davis, R.J. & Flavell, R.A. MAP kinases in the immune response. Annu Rev Immunol 20, 55-72 (2002).
103. Chen, F. JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res 72, 379-386 (2012).
104. Maeda, S. et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19, 725-737 (2003).
105. Han, Z. et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108, 73-81 (2001).
106. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743-756 (2008).
107. Hui, L., Zatloukal, K., Scheuch, H., Stepniak, E. & Wagner, E.F. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 118, 3943-3953 (2008).
108. Chang, Q. et al. JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma. Mol Cancer 8, 64 (2009).
109. Liu, J. et al. Analysis of drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer. Science 323, 1218-1222 (2009).
110. Chaudhury, H. et al. c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis. Arterioscler Thromb Vasc Biol 30, 546-553 (2010).
111. Uchida, C., Gee, E., Ispanovic, E. & Haas, T.L. JNK as a positive regulator of angiogenic potential in endothelial cells. Cell Biol Int 32, 769-776 (2008).
112. Miho, N. et al. Role of the JNK pathway in thrombin-induced ICAM-1 expression in endothelial cells. Cardiovasc Res 68, 289-298 (2005).
113. Sun, Y.B., Qu, X., Li, X., Nikolic-Paterson, D.J. & Li, J. Endothelial dysfunction exacerbates renal interstitial fibrosis through enhancing fibroblast Smad3 linker phosphorylation in the mouse obstructed kidney. PLoS One 8, e84063 (2013).
114. Ozcan, A. et al. PAX-2 in the diagnosis of primary renal tumors: immunohistochemical comparison with renal cell carcinoma marker antigen and kidney-specific cadherin. Am J Clin Pathol 131, 393-404 (2009).
115. Kraus, S. et al. MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis. Hum Pathol 33, 60-67 (2002).
116. Kuo, C.Y., Lin, C.H. & Hsu, T. VHL inactivation in precancerous kidney cells induces an inflammatory response via ER stress-activated IRE1alpha signaling. Cancer Res 77, 3406-3416 (2017).
117. Jourde-Chiche, N. et al. Endothelium structure and function in kidney health and disease. Nat Rev Nephrol 15, 87-108 (2019).
118. Wagner, E.F. & Nebreda, A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9, 537-549 (2009).
119. Bejarano, L., Jordao, M.J.C. & Joyce, J.A. Therapeutic Targeting of the Tumor Microenvironment. Cancer Discov 11, 933-959 (2021).
120. Liao, J.K. Linking endothelial dysfunction with endothelial cell activation. J Clin Invest 123, 540-541 (2013).
121. Pober, J.S. & Cotran, R.S. The role of endothelial cells in inflammation. Transplantation 50, 537-544 (1990).
122. Birch, K.A., Ewenstein, B.M., Golan, D.E. & Pober, J.S. Prolonged peak elevations in cytoplasmic free calcium ions, derived from intracellular stores, correlate with the extent of thrombin-stimulated exocytosis in single human umbilical vein endothelial cells. J Cell Physiol 160, 545-554 (1994).
123. Stevens, T., Garcia, J.G., Shasby, D.M., Bhattacharya, J. & Malik, A.B. Mechanisms regulating endothelial cell barrier function. Am J Physiol Lung Cell Mol Physiol 279, L419-422 (2000).
124. Mako, V. et al. Proinflammatory activation pattern of human umbilical vein endothelial cells induced by IL-1beta, TNF-alpha, and LPS. Cytometry A 77, 962-970 (2010).
125. Ley, K. & Reutershan, J. Leucocyte-endothelial interactions in health and disease. Handb Exp Pharmacol, 97-133 (2006).
126. Rezaie, A.R. Protease-activated receptor signalling by coagulation proteases in endothelial cells. Thromb Haemost 112, 876-882 (2014).
127. Ehling, J. et al. Quantitative micro-Computed tomography imaging of vascular dysfunction in progressive kidney diseases. J Am Soc Nephrol 27, 520-532 (2016).
128. Recio-Mayoral, A., Banerjee, D., Streather, C. & Kaski, J.C. Endothelial dysfunction, inflammation and atherosclerosis in chronic kidney disease--a cross-sectional study of predialysis, dialysis and kidney-transplantation patients. Atherosclerosis 216, 446-451 (2011).
129. Tumur, Z., Shimizu, H., Enomoto, A., Miyazaki, H. & Niwa, T. Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-kappaB activation. Am J Nephrol 31, 435-441 (2010).
130. Folkman, J. Tumor angiogenesis: therapeutic implications. N Engl J Med 285, 1182-1186 (1971).
131. Weis, S.M. & Cheresh, D.A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17, 1359-1370 (2011).
132. Goveia, J. et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37, 21-36 e13 (2020).
133. Franses, J.W., Baker, A.B., Chitalia, V.C. & Edelman, E.R. Stromal endothelial cells directly influence cancer progression. Sci Transl Med 3, 66ra65 (2011).
134. Franses, J.W., Drosu, N.C., Gibson, W.J., Chitalia, V.C. & Edelman, E.R. Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis. Int J Cancer 133, 1334-1344 (2013).
135. Neiva, K.G. et al. Endothelial cell-derived interleukin-6 regulates tumor growth. BMC Cancer 14, 99 (2014).
136. Wieland, E. et al. Endothelial Notch1 Activity Facilitates Metastasis. Cancer Cell 31, 355-367 (2017).
137. Zabel, B.A. et al. Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 183, 3204-3211 (2009).
138. Mancuso, P. et al. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97, 3658-3661 (2001).
139. Aran, D., Hu, Z. & Butte, A.J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 18, 220 (2017).
140. Pircher, A. et al. Synergies of Targeting Tumor angiogenesis and immune checkpoints in non-small cell lung cancer and renal cell cancer: from basic soncepts to clinical reality. Int J Mol Sci 18 (2017).
141. Albiges, L., Salem, M., Rini, B. & Escudier, B. Vascular endothelial growth factor-targeted therapies in advanced renal cell carcinoma. Hematol Oncol Clin North Am 25, 813-833 (2011).
142. Niinivirta, M. et al. Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib. BMC Cancer 20 (2020).
143. Yao, X. et al. Two distinct types of blood vessels in clear cell renal cell carcinoma have contrasting prognostic implications. Clin Cancer Res 13, 161-169 (2007).
144. Seeber, A. et al. High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma. Cancer Sci 109, 1583-1591 (2018).
145. Ricketts, C.J. & Linehan, W.M. Gender specific mutation incidence and survival associations in clear cell renal cell carcinoma (ccRCC). PLoS One 10, e0140257 (2015).
146. van Beijnum, J.R., Rousch, M., Castermans, K., van der Linden, E. & Griffioen, A.W. Isolation of endothelial cells from fresh tissues. Nat Protoc 3, 1085-1091 (2008).
147. Dejana, E., Orsenigo, F. & Lampugnani, M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121, 2115-2122 (2008).
148. Zanetta, L. et al. Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications. Thromb Haemost 93, 1041-1046 (2005).
149. Petrova, T.V. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21, 4593-4599 (2002).
150. Hirakawa, S. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162, 575-586 (2003).
151. Podgrabinska, S. et al. Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U.S.A 99, 16069-16074 (2002).
152. Durante, W. Role of arginase in vessel wall remodeling. Front Immunol 4, 111 (2013).
153. Li, H. et al. Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280, E75-82 (2001).
154. Pernow, J. & Jung, C. Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal? Cardiovasc Res 98, 334-343 (2013).
155. Luczak, A., Madej, M., Kasprzyk, A. & Doroszko, A. Role of the eNOS uncoupling and the nitric oxide metabolic pathway in the pathogenesis of autoimmune rheumatic diseases. Oxid Med Cell Longev 2020, 1417981 (2020).
156. Yang, Z. & Ming, X.F. Arginase: the emerging therapeutic target for vascular oxidative stress and inflammation. Front Immunol 4, 149 (2013).
157. Zhu, C., Yu, Y., Montani, J.-P., Ming, X.-F. & Yang, Z. Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling. BMC Research Notes 10 (2017).
158. Yepuri, G. et al. Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. Aging Cell 11, 1005-1016 (2012).
159. Wang, L. et al. Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia. Microvasc Res 98, 1-8 (2015).
160. Wetzel, M.D. et al. Selective inhibition of arginase-2 in endothelial cells but not proximal tubules reduces renal fibrosis. JCI Insight 5 (2020).
161. Mendoza, F.A., Piera-Velazquez, S., Farber, J.L., Feghali-Bostwick, C. & Jimenez, S.A. Endothelial cells expressing endothelial and mesenchymal cell gene products in lung tissue from patients with systemic sclerosis-associated interstitial lung disease. Arthritis Rheumatol 68, 210-217 (2016).
162. Ma, J., Sanchez-Duffhues, G., Goumans, M.J. & Ten Dijke, P. TGF-beta-induced endothelial to mesenchymal transition in disease and tissue engineering. Front Cell Dev Biol 8, 260 (2020).
163. Kovacic, J.C. et al. Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol 73, 190-209 (2019).
164. Sabbisetti, V.S. et al. Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol 25, 2177-2186 (2014).
165. Moschen, A.R., Adolph, T.E., Gerner, R.R., Wieser, V. & Tilg, H. Lipocalin-2: a master mediator of intestinal and metabolic inflammation. Trends Endocrinol Metab 28, 388-397 (2017).
166. Scelo, G. et al. KIM-1 as a blood-based marker for early detection of kidney cancer: A prospective nested case-control study. Clin Cancer Res 24, 5594-5601 (2018).
167. Jones, S.A. & Jenkins, B.J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 18, 773-789 (2018).
168. Wang, Q. et al. Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2alpha. Nat Commun 9, 559 (2018).
169. Khan, S. et al. EndoDB: a database of endothelial cell transcriptomics data. Nucleic Acids Res 47, D736-D744 (2019).
170. Phua, Y.L., Martel, N., Pennisi, D.J., Little, M.H. & Wilkinson, L. Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. J Pathol 229, 685-696 (2013).
171. Martin, T.A., Harrison, G.M., Mason, M.D. & Jiang, W.G. HAVcR-1 reduces the integrity of human endothelial tight junctions. Anticancer Res 31, 467-473 (2011).
172. Van de Velde, M. et al. Tumor exposed-lymphatic endothelial cells promote primary tumor growth via IL6. Cancer Lett 497, 154-164 (2021).
173. Zeisberg, E.M., Potenta, S.E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19, 2282-2287 (2008).
174. Dejana, E., Hirschi, K.K. & Simons, M. The molecular basis of endothelial cell plasticity. Nat Commun 8, 14361 (2017).
175. Modur, V. et al. Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. J Clin Invest 100, 158-168 (1997).
176. Ruprecht, K. et al. Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions. J Neuropathol Exp Neurol 60, 1087-1098 (2001).
177. Brown, T.J., Rowe, J.M., Liu, J.W. & Shoyab, M. Regulation of IL-6 expression by oncostatin M. J Immunol 147, 2175-2180 (1991).
178. Stawski, L. & Trojanowska, M. Oncostatin M and its role in fibrosis. Connect Tissue Res, 1-10 (2018).
179. West, N.R., Owens, B.M.J. & Hegazy, A.N. The oncostatin M-stromal cell axis in health and disease. Scand J Immunol 88, e12694 (2018).
180. West, N.R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med 23, 579-589 (2017).
181. Junk, D.J. et al. Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene 36, 4001-4013 (2017).
182. Lindberg, R.A. et al. Cloning and characterization of a specific receptor for mouse oncostatin M. Mol Cell Biol 18, 3357-3367 (1998).
183. Linsley, P.S. et al. Identification and characterization of cellular receptors for the growth regulator, oncostatin M. J Biol Chem 264, 4282-4289 (1989).
184. Tawara, K. et al. OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung. Breast Cancer Res 20, 53 (2018).
185. Abe, H. et al. Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nat Commun 10, 2824 (2019).
186. Brown, T.J., Lioubin, M.N. & Marquardt, H. Purification and characterization of cytostatic lymphokines produced by activated human T lymphocytes. Synergistic antiproliferative activity of transforming growth factor beta 1, interferon-gamma, and oncostatin M for human melanoma cells. J Immunol 139, 2977-2983 (1987).
187. Grenier, A. et al. Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood 93, 1413-1421 (1999).
188. Hurst, S.M. et al. Secretion of oncostatin M by infiltrating neutrophils: regulation of IL-6 and chemokine expression in human mesothelial cells. J Immunol 169, 5244-5251 (2002).
189. Suda, T. et al. Oncostatin M production by human dendritic cells in response to bacterial products. Cytokine 17, 335-340 (2002).
190. Zarling, J.M. et al. Oncostatin M: a growth regulator produced by differentiated histiocytic lymphoma cells. Proc Natl Acad Sci U S A 83, 9739-9743 (1986).
191. Ranchoux, B. et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131, 1006-1018 (2015).
192. Zeisberg, E.M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67, 10123-10128 (2007).
193. Hsu, T., Nguyen-Tran, H.H. & Trojanowska, M. Active roles of dysfunctional vascular endothelium in fibrosis and cancer. J Biomed Sci 26, 86 (2019).
194. Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15, 423-430 (2014).
195. Marden, G. et al. The role of the oncostatin M/OSM receptor beta axis in activating dermal microvascular endothelial cells in systemic sclerosis. Arthritis Res Ther 22, 179 (2020).
196. van Keulen, D. et al. Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE*3Leiden.CETP mice. PLoS One 13, e0204911 (2018).
197. Ma, Y., Streiff, R.J., Liu, J., Spence, M.J. & Vestal, R.E. Cloning and characterization of human oncostatin M promoter. Nucleic Acids Res 27, 4649-4657 (1999).
198. Mosley, B. et al. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem 271, 32635-32643 (1996).
199. Blanchard, F. et al. Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. J Biol Chem 276, 47038-47045 (2001).
200. Miles, S.A. et al. Oncostatin M as a potent mitogen for AIDS-Kaposi′s sarcoma-derived cells. Science 255, 1432-1434 (1992).
201. Fearon, U. et al. Oncostatin M induces angiogenesis and cartilage degradation in rheumatoid arthritis synovial tissue and human cartilage cocultures. Arthritis Rheum 54, 3152-3162 (2006).
202. Vasse, M. et al. Oncostatin M induces angiogenesis in vitro and in vivo. Arterioscler Thromb Vasc Biol 19, 1835-1842 (1999).
203. Repovic, P., Fears, C.Y., Gladson, C.L. & Benveniste, E.N. Oncostatin-M induction of vascular endothelial growth factor expression in astroglioma cells. Oncogene 22, 8117-8124 (2003).
204. Wijelath, E.S. et al. Oncostatin M induces basic fibroblast growth factor expression in endothelial cells and promotes endothelial cell proliferation, migration and spindle morphology. J Cell Sci 110 ( Pt 7), 871-879 (1997).
205. Rychli, K. et al. The inflammatory mediator oncostatin M induces angiopoietin 2 expression in endothelial cells in vitro and in vivo. J Thromb Haemost 8, 596-604 (2010).
206. Gurluler, E. et al. Oncostatin-M as a novel biomarker in colon cancer patients and its association with clinicopathologic variables. Eur Rev Med Pharmacol Sci 18, 2042-2047 (2014).
207. Koskela, K., Pelliniemi, T.T., Rajamaki, A., Pulkki, K. & Remes, K. Serum oncostatin M in multiple myeloma: impact on disease severity and prognosis. Eur J Haematol 65, 52-56 (2000).
208. Lilja, A., Nordborg, C., Brun, A., Salford, L.G. & Aman, P. Expression of the IL-6 family cytokines in human brain tumors. Int J Oncol 19, 495-499 (2001).
209. Torres, C. et al. Serum cytokine profile in patients with pancreatic cancer. Pancreas 43, 1042-1049 (2014).
210. Robak, T., Wierzbowska, A., Blasinska-Morawiec, M., Korycka, A. & Blonski, J.Z. Serum levels of IL-6 type cytokines and soluble IL-6 receptors in active B-cell chronic lymphocytic leukemia and in cladribine induced remission. Mediators Inflamm 8, 277-286 (1999).
211. Liang, H. et al. Interleukin-6 and oncostatin M are elevated in liver disease in conjunction with candidate hepatocellular carcinoma biomarker GP73. Cancer Biomark 11, 161-171 (2012).
212. Luyckx, V.A., Cairo, L.V., Compston, C.A., Phan, W.L. & Mueller, T.F. Oncostatin M pathway plays a major role in the renal acute phase response. Am J Physiol Renal Physiol 296, F875-883 (2009).
213. Elbjeirami, W.M. et al. Early differential expression of oncostatin M in obstructive nephropathy. J Interferon Cytokine Res 30, 513-523 (2010).
214. Yamashita, S. et al. Essential roles of oncostatin M receptor beta signaling in renal crystal formation in mice. Sci Rep 10, 17150 (2020).
215. Zhang, Y. et al. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proceedings of the National Academy of Sciences 118, e2103240118 (2021).
216. West, N.R., Murray, J.I. & Watson, P.H. Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer. Oncogene 33, 1485-1494 (2014).
217. Kucia-Tran, J.A. et al. Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival. Br J Cancer 115, 212-222 (2016).
218. Piera-Velazquez, S., Mendoza, F.A. & Jimenez, S.A. Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases. J Clin Med 5 (2016).
219. Lovisa, S. et al. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis. Sci Signal 13 (2020).
220. Zeisberg, E.M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13, 952-961 (2007).
221. Masjedi, A. et al. Oncostatin M: A mysterious cytokine in cancers. Int Immunopharmacol 90, 107158 (2021).
222. Nakamura, K., Nonaka, H., Saito, H., Tanaka, M. & Miyajima, A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 39, 635-644 (2004).
223. Ichihara, M., Hara, T., Kim, H., Murate, T. & Miyajima, A. Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood 90, 165-173 (1997).
224. Humphreys, B.D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176, 85-97 (2010).
225. Lapeire, L. et al. Cancer-associated adipose tissue promotes breast cancer progression by paracrine oncostatin M and Jak/STAT3 signaling. Cancer Res 74, 6806-6819 (2014).
226. Hanlon, M.M. et al. STAT3 Mediates the Differential Effects of Oncostatin M and TNFalpha on RA Synovial Fibroblast and Endothelial Cell Function. Front Immunol 10, 2056 (2019).
227. Kucia-Tran, J.A. et al. Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma. J Pathol 244, 283-295 (2018).
228. Steeg, P.S. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895-904 (2006).
229. Paget, S. The Distribution of secondary growths in cancer of the brest. The Lancet 133, 571-573 (1889).
230. Luzzi, K.J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153, 865-873 (1998).
231. Mack, G.S. & Marshall, A. Lost in migration. Nat Biotechnol 28, 214-229 (2010).
232. Chiang, A.C. & Massague, J. Molecular basis of metastasis. N Engl J Med 359, 2814-2823 (2008).
233. Laubli, H. & Borsig, L. Selectins promote tumor metastasis. Semin Cancer Biol 20, 169-177 (2010).
234. Taftaf, R. et al. ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer. Nature Communications 12 (2021).
235. Vestweber, D. Relevance of endothelial junctions in leukocyte extravasation and vascular permeability. Ann N Y Acad Sci 1257, 184-192 (2012).
236. Carman, C.V. & Springer, T.A. Trans-cellular migration: cell-cell contacts get intimate. Curr Opin Cell Biol 20, 533-540 (2008).
237. Teicher, B.A. & Fricker, S.P. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16, 2927-2931 (2010).
238. Kukreja, P., Abdel-Mageed, A.B., Mondal, D., Liu, K. & Agrawal, K.C. Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res 65, 9891-9898 (2005).
239. Gassmann, P. et al. CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. Neoplasia 11, 651-661 (2009).
240. Strilic, B. et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536, 215-218 (2016).
241. Tavora, B. et al. Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis. Nature 586, 299-304 (2020).
242. Motzer, R.J. et al. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer 113, 1552-1558 (2008).
243. Rini, B.I., Campbell, S.C. & Escudier, B. Renal cell carcinoma. Lancet 373, 1119-1132 (2009).
244. Goyal, R., Gersbach, E., Yang, X.J. & Rohan, S.M. Differential diagnosis of renal tumors with clear cytoplasm: clinical relevance of renal tumor subclassification in the era of targeted therapies and personalized medicine. Arch Pathol Lab Med 137, 467-480 (2013).
245. Sinha, R. et al. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection. Nat Commun 8, 15165 (2017).
246. Smigiel, J.M., Parameswaran, N. & Jackson, M.W. Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer. Mol Cancer Res 15, 478-488 (2017).
247. Reymond, N., d′Agua, B.B. & Ridley, A.J. Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13, 858-870 (2013).
248. Brugarolas, J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol 32, 1968-1976 (2014).

指導教授

徐沺(Tien Hsu)

審核日期

2021-12-14

推文