Study of the Interaction between VHL/Vhlh Deficient Kidney Epithelial Cells and Macrophages—Relevance to the Development of Clear-Cell Renal Cell Carcinoma

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阮氏玉(Thi-Ngoc Nguyen) 查詢紙本館藏

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生醫科學與工程學系

論文名稱

(Study of the Interaction between VHL/Vhlh Deficient Kidney Epithelial Cells and Macrophages—Relevance to the Development of Clear-Cell Renal Cell Carcinoma)

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摘要(中)

腎細胞癌 (renal cell carcinoma) 由腎小管上皮細胞惡化而來，佔 90%的腎臟惡性腫瘤，其中又以腎透明細胞癌 (clear-cell renal cell carcinoma， ccRCC) 類型最多，約佔所有腎細胞癌的 70%以上。腫瘤抑制基因 von Hippel-Lindau (VHL，位於染色體 3p25-
26) 的突變和 ccRCC 的發生率有非常密切的關係，若此基因突變失去功能，將無法抑制細胞不正常的增生而形成腫瘤。 70% 以上的散發性腎透明细胞癌 (sporadic ccRCC) 攜帶VHL 基因突變或 VHL 表觀遺傳失活，且幾乎 100% 的遺傳性 ccRCC（在 VHL 疾病中）
皆有 VHL 突變。越來越多研究結果證實， VHL 的突變可誘發慢性發炎，這可能是ccRCC 發展的早期表徵，而且重要的是 ccRCC 實體腫瘤含有大量浸潤的免疫細胞。這表示 ccRCC 的發生，極可能是帶有 VHL 基因突變或失活的腎小管細胞，與發炎微環境之間的相互作用誘導而成。
單核球 (monocyte) 是免疫系統中的一種白血球，單核球產生於骨髓，在血管內為單核球，血管外就分化成巨噬細胞(macrophages)，它們是發炎和癌症形成的關鍵連接者。雖然科學家已發現在 VHL 突變的 ccRCC 中有大量巨噬細胞浸潤現象，然而針對VHL 喪失功能的細胞在 ccRCC 形成過程中如何激活巨噬細胞的機制仍不清楚。
透過本論文研究，我們闡明了 VHL/Vhlh 缺陷型腎小管細胞，如何與巨噬細胞互動，進而引發、促進腫瘤相關發炎與 ccRCC 形成。活體內與活體外的研究結果證實，在癌症早期階段， VHL/Vhlh 缺陷的腎上皮細胞分泌大量 IL-6 來誘導巨噬細胞浸潤，隨後刺激分化成能促腫瘤發生的腫瘤依附性巨噬細胞（ tumor-associated macrophage; TAM)。被刺激分化的巨噬細胞反饋地分泌出誘導腎小管細胞的上皮間質轉化 (EMT) 的CCL18 和 TGF-β1 兩個重要細胞激素，促進 ccRCC 發展。在條件性 Vhlh 基因剔除小鼠中，阻斷 IL-6 顯著地抑制巨噬細胞外滲和分化，並減少發炎和增生現象。另一方面，在 VHL 缺失的細胞中，阻斷巨噬細胞分泌的 CCL18 和 TGF-β，也明顯抑制細胞 EMT的現象。特別是在小鼠異種移植模式中，抑制巨噬細胞 CCL18 的表現可明顯減緩腫瘤生長和癌細胞轉移。我們的研究結果揭示了微環境中， VHL/Vhlh 缺陷型腎小管細胞和巨噬細胞互動時參與調控反饋機制的分子。未來這些分子可成爲 ccRCC 早期偵測、與治療藥物的新標靶。

摘要(英)

Clear-cell renal cell carcinoma (ccRCC), the most prevalent subtype of renal cell carcinoma (up to 70% of all RCC types), is characterized by malignant tubule epithelial cells with clear cytoplasm. There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up
to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL, and nearly 100% of familial ccRCC (in VHL disease) are VHL mutant. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation, and this solid tumor contains a substantial number of infiltrated immune cells. This suggests that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory
microenvironment.
Monocyte-derived tissue effector cells, macrophages, are a crucial player in linking inflammation and cancer formation. Macrophage infiltration in the inflammatory microenvironment has been observed in previous studies of ccRCC models containing VHL mutations. However, the mechanism by which VHL loss-of-function cells activate macrophages during ccRCC formation has remained unclear.
In this study, we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to tumor-associated inflammation and ccRCC formation.
The study demonstrated that the VHL-deficient kidney epithelial cells, representing the early stage of cancer initiation, secreted IL-6 to induce macrophage infiltration and subsequent polarization toward the pro-tumorigenic tumor-associated macrophage (TAM) phenotype both in vitro and in vivo. In the reciprocal action, the induced macrophages promote tumor development by secreting CCL18 and TGF-β1 to induce epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Blockade of the IL-6 significantly inhibited macrophage extravasation and polarization, and reduced the inflammatory and proliferative phenotypes of the Vhlh conditional kidney knockout mouse. On the other hand, blockade of the macrophage secreted CCL18 and TGF-β inhibited the EMT-like phenotype in the VHL-deficient cells.
Specially, knocking down the expression of CCL18 in macrophages reduces tumor growth and cell metastasis in the xenograft model. The findings identified specific factors involved in a reciprocal mechanism that established the crosstalk between the tumor cells and the immune
components such as macrophages in the microenvironment. These results suggest an avenue for early detection and treatment of ccRCC.

關鍵字(中)

★ 腎透明細胞癌

關鍵字(英)

★ VHL
★ Macrophage
★ ccRCC

論文目次

Abstract------------------------------------------------------------------------------------------------------i
中文摘要---------------------------------------------------------------------------------------------------iii
誌謝辭 – ACKNOWLEDGEMENT------------------------------------------------------------------- iv
Table of contents -------------------------------------------------------------------------------------------v
List of Figures ------------------------------------------------------------------------------------------- viii
List of Tables -----------------------------------------------------------------------------------------------x
Abbreviations ---------------------------------------------------------------------------------------------- xi
Chapter 1. Literature review---------------------------------------------------------------------------1
1.1. Cancer and tumor microenvironment ..................................................................................1
1.1.1. Introduction to cancer------------------------------------------------------------------------------1
1.1.2. Tumor microenvironment -------------------------------------------------------------------------2
1.1.3. Tumor-promoting inflammation------------------------------------------------------------------3
1.1.4. Epithelial-to-mesenchymal transition and metastasis -----------------------------------------3
1.2. Renal cell carcinoma ...........................................................................................................4
1.2.1. Introduction to renal cell carcinoma -------------------------------------------------------------4
1.2.2. Clear-cell renal cell carcinoma (ccRCC) and the relation to kidney inflammation -------5
1.2.2. VHL tumor suppressor gene-----------------------------------------------------------------------5
1.2.4. Study of ccRCC: status and future directions --------------------------------------------------6
1.3. Macrophages and the tumor-associated inflammation ........................................................6
1.3.1. Introduction to macrophages----------------------------------------------------------------------7
1.3.2. TAMs and their function --------------------------------------------------------------------------8
1.4. Cytokines.............................................................................................................................8
1.5. Significance and purpose.....................................................................................................9
Chapter 2. Materials and methods------------------------------------------------------------------ 14
2.1. Mouse model and human kidney samples.........................................................................14
2.2. Cell lines and culture condition .........................................................................................14
2.3. Macrophage differentiation ...............................................................................................15
2.4. Short-hairpin RNA and lentiviral vector transduction for gene knockdown.....................15
2.5. Macrophage extravasation assay .......................................................................................16
2.6. Crystal violet assay............................................................................................................16
2.7. Flow cytometry analysis....................................................................................................17
2.8. Total RNA sequencing ......................................................................................................18
2.9. Cytokine array ...................................................................................................................18
2.10. ELISA..............................................................................................................................18
2.11. Realtime PCR validation .................................................................................................19
2.12. Immunohistochemistry (IHC) and immunofluorescence (IF) .........................................19
2.13. Cell circularity analysis ...................................................................................................19
2.14. Kidney tubule cell invasion assay ...................................................................................19
2.15. Western blotting ..............................................................................................................20
2.16. Inhibition of cytokine/chemokine and pSTAT3 activities in vitro..................................20
2.17. Xenograft experiments ....................................................................................................20
2.17.1. 786-O mixed with THP-1---------------------------------------------------------------------- 20
2.17.2. 786-O mixed with primary human CD14+ monocytes------------------------------------ 21
2.18. Statistical analysis............................................................................................................21
Chapter 3. Increase of interstitial macrophages in human ccRCC samples and mouse
kidney containing Vhlh mutant tubule cells ------------------------------------------------------ 22
3.1. Introduction and objective.................................................................................................22
3.2. Results ...............................................................................................................................22
3.2.1. Conditional Vhlh KO mouse is a good model for studying the early tumorigenic event
-------------------------------------------------------------------------------------------------------------- 22
3.2.2. Macrophages are abnormally increased in VHL/Vhlh-deficient kidney samples-------- 23
3.3. Discussion..........................................................................................................................23
Chapter 4. VHL/Vhlh-deficient kidney cells induce macrophage infiltration and
polarization toward the M2 phenotype ------------------------------------------------------------ 27
4.1. Introduction and objective.................................................................................................27
4.2. Result.................................................................................................................................28
4.2.1. VHL/Vhlh-deficient kidney tubule cells directly induce macrophage extravasation---- 28
4.2.2. VHL/Vhlh-deficient kidney tubule cells induce macrophage polarization toward protumorigenic phenotype ---------------------------------------------------------------------------------- 29
4.2.3. Tissue resident macrophages do not contribute to increased macrophage number in Vhlh
mutant kidney--------------------------------------------------------------------------------------------- 31
4.3. Discussion ------------------------------------------------------------------------------------------- 31
Chapter 5. VHL/Vhlh-deficient kidney cells secrete increased levels of IL-6 -------------- 44
5.1. Introduction and objective.................................................................................................44
5.2. Results ...............................................................................................................................44
5.3. Discussion..........................................................................................................................46
Chapter 6. IL-6 secreted from VHL/Vhlh-deficient kidney tubule cells mediates
macrophage activation and promotes pre-ccRCC phenotypes ------------------------------- 56
6.1. Introduction and objective.................................................................................................56
6.2. Results ...............................................................................................................................56
6.2.1. IL-6 secreted from VHL/Vhlh-deficient kidney tubule cells mediates macrophage
activation -------------------------------------------------------------------------------------------------- 56
6.2.2. Blockade of IL-6 signaling rescues the inflammatory and hyperplastic phenotypes of Vhlh
KO kidney------------------------------------------------------------------------------------------------- 57
6.3. Discussion..........................................................................................................................58
Chapter 7. IL-6 signaling-activated macrophages are critical for development of Vhlhdeficient phenotypes------------------------------------------------------------------------------------ 65
7.1. Introduction and objective.................................................................................................65
7.2. Results ...............................................................................................................................65
7.2.1. IL-6 signaling-activated macrophages are critical for development of Vhlh-deficient
phenotypes ------------------------------------------------------------------------------------------------ 65
7.2.2. T cell population increase in Vhlh deficient kidney is dependent on IL-6 signaling --- 66
7.3. Discussion..........................................................................................................................66
Chapter 8. IL-6 signaling-activated macrophages promote mesenchymal phenotypes of
the kidney tubule cells --------------------------------------------------------------------------------- 71
8.1. Introduction and objective.................................................................................................71
8.2. Results ...............................................................................................................................71
8.2.1. The activated macrophages promote EMT phenotypes in VHL/Vhlh deficient kidney
tubule cells. ----------------------------------------------------------------------------------------------- 71
8.2.2. Gene expression program in the activated macrophages shows specific EMT-stimulating
capacity ---------------------------------------------------------------------------------------------------- 72
8.2.3. Blockade of CCL18 and TGF-β1 reduces EMT capacity of co-cultured HK-2 cells--- 73
8.2.4. CCL18 and TGF-β1 production by THP-1 macrophages are mediated by IL-6 signaling
-------------------------------------------------------------------------------------------------------------- 74
8.3. Discussion..........................................................................................................................74
Chapter 9. CCL18-expressing macrophages promote tumor growth and metastasis of
ccRCC cells in vivo ------------------------------------------------------------------------------------- 83
9.1. Introduction and objective.................................................................................................83
9.2. Results ...............................................................................................................................83
9.2.1. TAMs are important for metastasis of ccRCC ----------------------------------------------- 83
9.2.2. CCL18-expressing macrophages promote ccRCC tumor growth and metastasis------- 84
9.3. Discussion..........................................................................................................................85
Chapter 10. Conclusions and prospectives -------------------------------------------------------- 95
10.1. Conclusion and discussion...............................................................................................95
10.2. Prospectives.....................................................................................................................96
REFERENCES------------------------------------------------------------------------------------------ 99
Publication list------------------------------------------------------------------------------------------118

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指導教授

徐沺(Tien Hsu)

審核日期

2022-7-25

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