2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646228摘要:癌症的發生率在最近十年逐年上升,研究數據顯示婦癌的發生是一個值得重視的疾病。根據以往的文獻,類胰島素生長因子都有抑制生物體免疫力的情形,其中包括先天性免疫(innate immunity)及適應性免疫(adaptive immunity)系統。而免疫的降低在臨床上則可能提高腫瘤發生及擴散的機會。近年來類胰島素生長因子與癌症發生及抗藥性的研究已經被證實具有正相關性,然而藉由類胰島素生長因子所調節的包括樹突細胞為媒介的免疫反應並不十分清楚。然而令人憂心的是,許多包括非癌症型的病理現象如肥胖也同樣具有類胰島素生長因子大量表現的情形,而肥胖患者是否會因此較容易罹患癌症則不得而知。因此研究類胰島素生長因子誘發癌症的形成、進展和其免疫調節的機制將有助於我們了解這個疾病和發展,並提供癌症將來可能的治療新策略諸如免疫治療及標靶治療與理論基礎。在先前的研究報告中,類胰島素生長因子會在癌症組織中大量表現,並抑制化療藥物所誘發之細胞凋亡。此外類胰島素生長因子在免疫能力健全的naïve 老鼠中具促進腫瘤生長的能力。樹突細胞的抗原呈現能力在腫瘤免疫學上相當重要,腫瘤現象發生時往往伴隨著抗原呈現能力的低下,使腫瘤細胞不容易被毒殺T 細胞所辨認而引起免疫逃避的反應。在初步的研究成果中,我們證實類胰島素生長因子會抑制骨髓衍生之樹突細胞之成熟化與抗原呈現能力。但類胰島素生長因子是否會影響樹突細胞抗原呈現的能力進一步的促使腫瘤發生則不得而知。因此我們設計了這個三年的計畫並嘗試了解:第一,在以骨髓細胞衍生樹突細胞的研究模式下,類胰島素生長因子如何影響這些樹突細胞的抗原吞噬及呈現能力調節的免疫反應;第二,以類胰島素生長因子過度表現的腫瘤注射後動物模式,研究類胰島素生長因子如何在腫瘤微環境下影響生物體內之樹突細胞抗原吞噬、呈現能力、免疫反應及抗腫瘤活性;第三,探討以骨髓細胞衍生樹突細胞的研究模式,研究類胰島素生長因子影響樹突細胞調節免疫反應之機制及其訊息傳遞路徑的影響。這個計畫的研究結果將能提供完整的瞭解類胰島素生長因子與免疫系統的關連與分子機制,它將會幫助我們在將來設計新的腫瘤免疫治療的新策略。<br> Abstract: The incidence of cancer has increased over the past 10 years and studies have suggested that theprogression of gynecologic malignancies has become a disease that should be respected. Based on previousliterature, insulin-like growth factor (IGF) family proteins have demonstrated the inhibition activity inbiological immune system, including innate and adaptive immunities. Besides, the reduction of immunitymight improve the tumor progression and metastasis rate based on clinical observation. In recent years, IGFsexpression has been suggested to have a positive correlation with cancer incidence and resistance ofchemotherapeutic agents. However, the influence of IGFs on dendritic cell (DCs)-mediated immuneresponse is still unclear. Moreover, in many types of non-cancer pathological phenomena such as obesity,has demonstrated the high IGFs expression as well while whether obese patients are more likely to developcancer is not known yet. Therefore, to investigate how the IGFs increase carcinogenesis, progression andimmunological regulation mechanisms will help us understand this disease and develop new treatmentstrategies that include immunotherapy and targeted therapy for gynecologic malignancies in the future.In previous studies, IGFs could be over-expressed in cancer tissues and suppressedchemotherapy-induced apoptosis. In addition, IGFs could promote tumor growth in naïveimmuno-competent mice. Antigen presenting abilities of dendritic cells in tumor immunology is important.Tumor progression is often accompanied by a low capacity of antigen presentation and the cause of thetumor cells is not easily recognized by antigen-specific cytotoxic T cells, which even causes theimmune-escape responses. Our preliminary data demonstrated that IGFs could inhibit bone marrow-deriveddendritic cell maturation and antigen presenting abilities. How the IGFs affect dendritic cells-mediatedimmunity or further promote tumor still remains unknown.So we proposed this three-year proposal to evaluate the following: First, if IGFs influence on theantigen processing and presenting activities by using ex-vivo bone marrow-derived dendritic cell models?Second, how do the ectopic IGFs-expressing cancer cells, when implanted into animals, regulate the antigenprocessing and presenting activities of dendritic cells-mediated immunity, and promote tumorignesis in ofthe tumor microenvironment? Third, what are the mechanisms and signal transduction pathways of IGFs onDCs-mediated immunity. From the results of this project, we will understand the complete molecularmechanism and the correlation between IGFs and immunity. It will help us to design new strategy of cancerimmunotherapy in the future.Roles of Insulin-Like Growth Factors in Tumor Development---Focus on the Mechanism of Regulating Immunity