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研究生： 曾緯中
Tseng, Wei-Chung
論文名稱： 血管新生與淋巴新生因子於乳癌小鼠的動態影響
Dynamic Expression of Angiogenic and Lymphangiogenic Factors in Breast Tumor-bearing Mice
指導教授： 蔡美玲
Tsai, Mei-Ling
學位類別： 碩士
Master
系所名稱： 醫學院 - 生理學研究所
Department of Physiology
論文出版年： 2010
畢業學年度： 98
語文別： 英文
論文頁數： 113
中文關鍵詞： 血管新生 、淋巴管新生 、癌細胞轉移 、免疫細胞 、細胞骨架
外文關鍵詞： angiogenesis, lymphangiogenesis, metastasis, immune cells, cytoskeleton
相關次數： 點閱：88  下載：1 
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    • 癌細胞本身之基因改變及宿主本身之發炎反應均有助於惡性腫瘤遠端轉移及癌細胞的生長。發炎反應藉由血管內皮生細胞長因子A所誘發的血管新生及血管內皮生細胞長因子C所誘發的淋巴管新生促進惡性腫瘤轉移。為進一步了解宿主本身之發炎反應如何影響腫瘤細胞在特定遠端器官之轉移，本研究使用皮下注射癌細胞所誘發乳癌生長小鼠模式探討受腫瘤細胞活化之免疫細胞對於遠端轉移器官血管新生及淋巴管新生的影響。結果顯示，在原位癌處巨噬細胞標誌（F4/80）隨腫瘤大小增加而上升。血管內皮生細胞長因子A、血管內皮生細胞長因子受體2、血管內皮黏著分子、血管內皮生細胞長因子C、血管內皮生細胞長因子受體3及淋巴管内皮透明質酸受體1的表現量均隨時間增加而上升。在檢驗肝、脾與肺臟等遠端器官後，在五週之腫瘤小鼠中三種器官均增大，而肺部血管內皮黏著分子表現量較肝、脾臟低且在肺臟在外觀及組織切片中發現有許多轉移癌。與正常的小鼠比較後，腫瘤鼠其肺臟肺泡沖洗液中淋巴球的比例隨著時間增加而上升，但巨噬細胞的比例及總細胞數則無改變。肺臟中，腫瘤鼠F4/80表現量僅在第五週上升，血管新生相關因子（如血管內皮生細胞長因子A、血管內皮生細胞長因子受體2）及淋巴管新生相關因子（如血管內皮生細胞長因子Ｃ、血管內皮生細胞長因子受體3及淋巴管内皮透明質酸受體1）表現量在第三週沒有改變，顯示血管新生與淋巴新生在第三週並未在肺臟中出現。地塞米松是一種糖皮質類固醇，可抑制巨噬細胞及第一型T輔助細胞並活化第二型T輔助細胞，接下來使用地塞米松來進一步證明活化的宿主免疫細胞對於遠端轉移器官中血管新生及淋巴管新生的影響。地塞米松降低原生癌處血管內皮生細胞長因子A表現但不影響血管內皮生細胞長因子受體2、血管內皮生細胞長因子C及血管內皮生細胞長因子受體3表現量。在肺臟中，地塞米松則增加血管內皮黏著分子，血管內皮生細胞長因子C及血管內皮生細胞長因子受體3表現，而不改變血管內皮生細胞長因子A、血管內皮生細胞長因子受體2及淋巴管内皮透明質酸受體1的表現量。總論之，地塞米松降低原生癌處血管內皮生細胞長因子A表現量顯示巨噬細胞的活化與原生癌處內皮生細胞長因子A所誘發的血管新生有關。而在肺臟中，地塞米松增加血管內皮黏著分子表現量但巨噬細胞數目不變，顯示在肺臟中可能藉由活化第一型T輔助細胞增加肺微血管通透性並增加癌細胞轉移至肺臟的專一性。定量蛋白質體結果更進一步顯示，在三週腫瘤鼠肺臟中與細胞骨架相關蛋白如細胞黏附蛋白及α輔肌動蛋白均下降，而腫瘤鼠中與蛋白合成相關蛋白及蛋白酶抑制劑胰蛋白酶抑制劑等蛋白均受到抑制，可以進一步解釋在腫瘤鼠肺臟中，細胞與細胞基質的黏附受到破壞、蛋白質生合成以及蛋白酶抑制劑受到抑制的結果將導致肺臟嚴重轉移並導致肺臟的結構崩解。

    The secondary growth of metastasized tumors in the distal sites depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment in hosts. Because inflammation is associated with VEGFA-induced angiogenesis and VEGFC-induced lymphangiogenesis, the purpose of our study was to explore if the activation of immune cells by implanted tumor cells facilitated organ-specific growth of metastasized tumors through both VEGFA-mediated angiogenesis and VEGFC-mediated lymphangiogenesis. The subcutaneously-transplantated breast tumor bearing mice was used as our experimental model. As our data indicated, F4/80 (a macrophage marker) in the primary tumors was increased with the increases in tumor size, VEGFA, VEGFR2, VE-cadherine, VEGFC, VEGFR3 and LYVE-1. Of internal organs examined, three major organs, including spleen, liver, and lung, became enlarged. Among these three organs, lungs contained the greatest number of tumor nodules and expressed the lowest level of VE-cadherin. When compared with the lung of control mice, that of tumor-bearing mice showed a time-dependent increase in tumor size and the ratios of lymphocytes and neutrophils in the bronchoalveolar fluid (BALF) and the decreased expression of VE-cadherin without changing total cell number and total protein in BALF. No significant changes in the expression of angiogenesis-related factors (VEGFA, VEGFR2) and lymphangiogenesis-related factors (VEGFC, VEGFR3 and LYVE-1) in wk 3 were followed by the increased expression of F4/80 in wk 5, suggesting that the angiogenesis and lymphangiogenesis did not occur at wk 3. Dex, a glucocorticoid analogue, which inactivates macrophages, neutrophils and Th1 lymphocytes, was used to examine whether activated immune cells were involved in angiogenesis and lymphangiogenesis during metastasis. At primary sites, dex decreased VEGFA with no effect on VE-cadherin. In distal lung, dex increased VE-cadherin, VEGFC and VEGFR3 with no effects on VEGFA, VEGFR2 and LYVE-1. In conclusion, the decreased expression of VEGFA by dex at primary sites suggests that the activation of macrophages may be involved in VEGFA-induced angiogenesis in primary tumor metastasis. The reversal effect of dex on the decreased expression of VE-cadherin in lungs where macrophages were not increased may indicate the activation of Th1 cells in lungs which may contribute the decreased integrity of pulmonary capillaries and lung-specific growth of metastasized tumors. In our quantitative proteomics data, the cytoskeleton proteins such as vinculin and α-actinin were decreased, the proteases inhibitors such as α1 antitrypsin, contrapsin and A3K as well as protein synthesis related proteins were also decreased in lung in 3 week tumor bearing mice, further revealing that the destruction of cell-cell and cell-ECM adhesion and decreased in the expression protease inhibitors and the protein synthesis may result in serious lung metastasis and lung structure damage.

    Abstract I 中文摘要 IV Index VII Table contents XII Figure contents XIII Abbreviation XX Chapter I. Introduction 1 I. Current studies of breast cancer 1 1. Epidemiological studies of breast cancer 1 2. Animal studies in breast cancer research 2 II. The processes of tumor metastasis 4 1. Tumorigenesis: from cell transformation to metastasis 4 2. Tumor microenvironment during metastasis 5 3. Contribution of chronic inflammation to the shift of tumor microenvironment 6 III. Cellular mechanism of inflammation on tumor metastasis 6 1. Cellular mechanism of inflammation 6 2. Comparison of innate and adaptive immunity in inflammatory responses 8 3. Positive correlation between tumor metastasis and the status of inflammation 9 4. Studies of both innate immunity and adaptive immunity on tumor metastasis 10 IV. Contribution of inflammation to angiogenesis and lymphangiogenesis 12 1. Definition of angiogenesis and lymphangiogenesis 12 2. The effects of chronic inflammation on both angiogenesis and lymphangiogenesis 14 Chapter II. The purpose of this study 16 Chapter III. Materials and Methods 17 1. Animals 17 2. Cell lines and cell culture 17 3. Establishment of breast tumor bearing mice 18 4. In vivo image 19 5. Glucorticoid treatment protocol 20 6. Analysis of cellular components in bronchoalveolar lavage fluid (BALF) 22 7. H&E staining 22 8. Preparation of tumor and lung tissue homogenate 23 9. Western blot analysis 24 10. In-gel protein digestion 24 11. Dimethyl Labeling 25 12. Mass spectrometry and protein identification 26 13. Quantitative analysis of dimethyl labeled peptides 28 14. Data analysis and statistical evaluation 28 Chapter IV. Results 29 Aim 1. To examine time-dependent effects of 4T1 transplantation on tumor growth, inflammation, angiogenesis and lymphangiogenesis at primary tumor sites 29 1. Tumor formation at primary tumor sites 29 2. Expression of angiogenesis factors at primary tumor sites 30 3. Expression of lymphangiogenesis factors at primary tumor sites 30 Aim 2. To examine organ-specific metastasis of disseminated tumors 31 1. Gross analysis of tumor nodules in lung, liver and spleen 31 2. Expression of VE-cadherin in lung, spleen and liver 32 3. The expression of F4/80 inflammation responses occurred in lung and spleen 32 4. The time-dependent increases of tumor area in lung 33 Aim 3. To examine time-dependent effects of transplanted tumor cells on the shift of inflammatory cells in lung 33 1. The inflammatory response in lung 34 2. Expression of angiogenesis factors (VEGFA and VEGFR2) in lung 35 3. Expression of lymphangiogenesis factors (VEGFC and VEGFR3) in lung 35 Aim 4. To examine the effect of dex on the expression of angiogenesis- and lymphangiogenesis- related molecules in tumor tissues 36 1. The effect of dex on tumor development in primary tumor tissues 36 2. The effect of dex on tumor development at distal sites 37 Aim 5. To use the quantitative proteomics to reveal the protein differences in the lung in tumor bearing mice by stable diemthyl labeling coupled with 1D-GelLC MS/MS 38 1. Quantitative analysis of proteins in lung in tumor bearing mice 38 2. Hypothesis 39 Aim 6. Hypothesis-driven study 40 Chapter V. Discussion 42 1. The vascular response and lymphatic response at the primary site 42 2. Organ-specific metastasis of invasive tumors 45 3. Vascular response and lymphatic response to tumor cells in lungs 46 4. Proteomics reveal another factors involved in lung metastasis 47 5. Novel findings in this study 50 Chapter VI. Reference 51 Chapter VII. Tables 59 Chapter VIII. Figures 80 Chapter IX. Appendix 111 Curriculim Vitae 113

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