| 摘要: | 本計畫符合「免疫與發炎」之重點研究領域，同時也與「癌症發生、成長、與轉移」有關，因為此計畫的焦點在於研究發炎於癌症發生之關聯性。目前主要的癌症療方是針對殺死癌細胞。這樣的策略對延長患者生命有重要貢獻，但經常的結果是癌細胞會產生抗藥性，或是復發成更惡性之腫瘤。最近將癌症視為整個人體系統疾病的新觀念已引發一些新理念，其中一個發現是很多癌症的起始點實際上是組織發炎（即失控的免疫反應）。因此，在一些已經確認發炎與癌症有因果關係的例子，如大腸癌與肝癌，早期控制發炎病變應可以有機會預防癌症發生。一些臨床證據顯示這個觀念是正確的，如長期服用阿斯匹林可以降低大腸癌風險。本實驗室在用小鼠模式研究腎臟癌時也發現類似腎臟病之腎臟組織發炎確實為腎臟癌之前身 。傳統放射線、化療對腎臟癌無效，而且腎臟癌沒有明顯徵狀，不容易早期發現。腎臟病在台灣非常普遍（末期腎臟病人在全人口比率台灣是世界第一），某些型的腎臟癌比率也比世界正常數字高很多。不像其他較普遍癌症，腎臟癌病例持續在增加。我們的研究如果能確認腎臟病與腎臟癌的因果關係，利用消炎藥物即早處理腎臟病應可達到突破性之預防腎臟癌效果。因此本研究計畫要運用細胞學、動物模式、流型病學、及臨床檢體來整體性的探討組織發炎與癌症發生之關係。最近我們以剔除抑癌基因VHL 的策略（VHL 基因突變是80％透明腎細胞癌的病因），開發了一株小鼠模式。此小鼠帶有在特定腎小管細胞中VHL 之剔除，結果產生與人類腎臟病類似之特徵（發炎與纖維化），並導至囊泡與透明癌細胞之發生。這個結果可以支持慢性發炎會致癌的新理念。我們的目標是找出腎臟病的機制，以及腎臟發炎與腎臟癌的關係。這樣的結果可以協助設計用抗發炎的方法來預防或早期治療腎臟癌。我們提出四個特定目標來探討這個課題。 如下： 特定目標一（為國衛院同步提出之院內計畫）：利用腎臟癌小鼠模式解出致癌的發炎過程。（與國衛院特聘研究員兼免疫研究中心主任譚澤華合作。） 特定目標二：解出腎臟發炎及癌組織中「基質肌型纖維母細胞」之特性及功能。我們會從我們的VHL 小鼠及腎臟癌病人檢體分離肌型纖維母細胞，分析其基因體與表基因體之變化，並研究這些變化與致癌功能之關係。（與新竹國泰綜合醫院院長李興中醫師／博士合作。） 特定目標三：利用健保資料庫，以流行病學分析法確定腎臟病與腎臟癌之關係。（與醫師公會全國聯合會研究員，前中國醫藥大學醫院臨床藥劑科主任許婓凱合作。） 特定目標四：解出變型之上皮細胞引發系統性發炎反應的機制。我們提出以下假說：VHL 突變會造成細胞內新陳代謝失調，因而引發長期內質網壓力。無法解決之慢性內質網壓力進而引發發炎訊號傳遞機制活化。（與美國波士頓大學醫學院風濕研究中心主任Maria Trojanowska 合作。） ;This proposal fits with the interest of “Immunity and inflammation,” but also relates to “Cancer development, progression and metastasis,” as the research focuses on the relationship between inflammation and cancer. Most cancer therapies involve targeting cancer cells specifically. Such strategy is valuable in prolonging patients’ lives. However, the strategy often results in drug resistance and recurrence of more aggressive cancer. Recent concept that views cancer as a systemic disease has suggested that tissue inflammation is an early promoter of cancer formation. As such, in many cases when the causal relationship between inflammation and cancer can be established, opportunity exists for cancer prevention during the early stage of inflammatory diseases. Some examples include colon cancer and liver cancer. This notion is supported by preliminary clinical studies; e.g., aspirin has proved effective in lowering the risk of colon cancer. In our study using mouse model, we have obtained promising results that indicate inflammatory kidney disease is the precursor of kidney cancer. Kidney cancer is refractory to conventional therapies and is difficult to diagnose early. For unknown reason, the death rate of kidney cancer continues to rise, contrary to the trends of other cancers. Since kidney disease is highly prevalent in Taiwan and in some parts of the world, we believe our continued studies should present a breakthrough in preventing the deadly and untreatable kidney cancer by using anti-inflammatory therapies. This proposal aims to comprehensively study the link between tissue inflammation and kidney cancer, employing cell biology, animal model, epidemiology, and patient samples. Using a new conditional knockout strategy targeting the tumor suppressor gene VHL (the mutations of which constitute 80% of the clear-cell renal cell carcinoma) in the kidney, we have developed a mouse model that recapitulates features of kidney inflammation and fibrosis (kidney disease), leading to cyst formation and clear cell carcinoma. This result provides support for the important new concept that chronic inflammation is tumorigenic. We aim to elucidate the mechanism of kidney disease and the link between kidney inflammation and kidney cancer, and help design preventive and early treatment strategies for kidney cancer by treating early inflammation. In the current study, we will perform 4 Specific Aims as follows: Specific Aim 1 (proposed separately as a NHRI intramural project): To elucidate the precancerous inflammatory program in the kidney cancer mouse model [in collaboration with Dr. Tse-Hua Tan (), Distinguished Investigator and Director, Immunology Research Center, National Health Research Institutes]. Specific Aim 2: To elucidate the role of stromal myofibroblasts in kidney inflammation and cancer [in collaboration with Dr. Hsin-chung Lee (), Superintendent, Hsin-Chu Cathay General Hospital]. We will analyze the genomic/epigenomic changes in the stromal myofibroblasts in mouse and human as they relate to tumor-promoting functions. Specific Aim 3: To verify the link between kidney disease and kidney cancer by epidemiological analysis of the National Health Insurance Data Base [in collaboration with Fei-kai Syu (), Researcher, Taiwan Medical Association, and Director, Division of Clinical Pharmacy, Department of Pharmacy, China Medical University Hospital]. Specific Aim 4: To elucidate the cellular mechanism that links epithelial cell transformation with induction of inflammation. We will test the hypothesis that the metabolic abnormalities caused by VHL gene mutation can lead to unresolved chronic endoplasmic reticular stress (ER stress), which in turn induces pro-inflammatory signaling pathways (in collaboration with Dr. Maria Trojanowska, Director of Arthritis Center, Boston University School of Medicine). |
