博碩士論文 etd-0823112-163353 詳細資訊


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姓名 蔡函恩 (Han-en Tsai) 電子郵件信箱 E-mail 資料不公開
畢業系所 生物醫學研究所(Institute of Biomedical Sciences)
畢業學位 博士(Ph.D.) 畢業時期 101學年第1學期
論文名稱(中) POMC壓力荷爾蒙對於治療轉移性癌症的潛力與作用機制   
論文名稱(英) The Therapeutic Potential and Mechanism of POMC stress Hormone for Metastatic Cancer
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    摘要(中) 儘管歷年來在開發新型標靶藥物上有了不少進展,轉移性癌症仍舊佔了全球多數的癌症死亡率之首,並且對現今的治療方式有著強烈的抵抗性。癌症轉移(Metastasis)的生成是藉由血管新生,細胞外滲,躲避免疫監視,附著及在不同器官中複製擴張等多重步驟所組成的現象。若想有效的控制癌轉移則需要能進行全身性(systemic)的療法。過去的研究指出:具有促進發炎及細胞存活等特性nuclear factor kappa B (NFκB)因子,在腫瘤細胞中的癌轉移過程扮演著重要的作用,並被公認為一個在控制癌轉移上極好的標靶。前-腦啡-黑色素激素-腎上腺皮質激素 (pro-opiomelanocortin, POMC) 與其所衍生出來的腎上腺皮質激素 (ACTH),α-, β-, and γ-黑色素激素(α-, β-, and γ-MSH),β-腦內啡(β-EP)等眾多神經胜肽均具有能顯著抑制NFκB途徑的功能。除了調控壓力反應及體內能量平衡之外,POMC亦具有調節皮膚色素、發炎反應,及周邊系統免疫等作用。我們最近的研究發現,在周邊利用腺病毒作為載體來表現POMC基因能提升血液循環以及肝臟中POMC蛋白質的表現量,並且能有效的抑制B16F10惡性黑色素瘤(melanoma)生長及延長帶有腫瘤老鼠的生命。更進一步的,我們發現同時使用POMC與順鉑(cisplatin)的治療能提高POMC的延命療效。經由分析後,我們發現POMC能抑制惡性黑色素瘤中NFκB的活性,並且造成黑色素癌細胞凋亡,重新分化及抗血管新生等。此外,我們還發現POMC基因可透過抑制黑色素細胞的「上皮細胞間質轉型」(Epithelial-mesenchymal transition; EMT:即從上皮細胞型態(epithelium)轉變成間葉細胞(mesenchyme)型態的一種特殊過程)。我們也發現POMC抑制黑色素癌細胞生長可能會透過α-MSH與黑皮質素受器-1 (Melanocortin-1 receptor; MC1R)作用的機轉。
     為了探討POMC在其他種類癌症上的應用,我們利用一株不具有MC1R表現的Lewis lung carcinoma (LLC)細胞作為研究標的。我們也發現,POMC基因表現不但可以有效抑制LLC細胞在體外培養狀態下的生長,POMC也可有效地抑制LLC腫瘤在老鼠上的生長。利用組織學的研究也發現POMC基因傳送可有效抑制LLC腫瘤的細胞增生、促進LLC細胞凋亡、並阻斷腫瘤周邊的血管新生。此外,POMC基因傳送會抑制β-catenin的活性及其下游之原致癌基因(proto-oncogenes),如cyclin D1及c-myc的蛋白質表現。這些結果也更進一步證實儘管POMC在沒有MC1R的表現之下,仍可有效的抑制癌症生長,我們也確認POMC可以用來治療不只一種癌症。
     由於POMC及其衍生胜肽已知具有免疫調控的作用,為了探討POMC的抗癌機制與宿主免疫系統之間的關聯,我們利用免疫缺現(SCID)與正常老鼠(C57BL/6)的黑色素癌模式比較之下,POMC基因治療在這兩者之間皆可有效抑制腫瘤生長。然而,我們也發現POMC基因傳送會造成正常老鼠的脾臟萎縮且會減少周邊淋巴球的數目。研究結果顯示POMC的抗癌機制可能與宿主的免疫系統是否正常無關,但也可發現POMC的免疫抑制可能與ACTH/cortisol的生成有極大關聯。為了減少POMC基因治療所造成的副作用,我們合成了一系列帶有不同ACTH區域突變的POMC基因;如在POMC的ACTH第15個及第17個胺基酸位置坐點突變;ACTH(K15/R17A)。相較於POMC原始基因,ACTH(K15/R17A)基因可減少ACTH表現量且可減緩corticosterone在細胞內以及動物體內的合成。此外,ACTH(K15/R17A)基因表現不僅可抑制原位的黑色素癌生長,亦可有效控制轉移性黑色素癌的生成且不具有任何免疫抑制的副作用。總結以上的研究,我們已更詳盡地得知POMC基因對於抑癌的功能及機轉。更甚者,我們也進一步去改善POMC基因治療的副作用已做為未來在癌症治療上的應用。
    摘要(英) Despite the development of novel target therapy drugs in recent years, metastatic cancer remains refractory to current cancer therapies and accounts for the majority of cancer mortalities worldwide. Metastasis consists of multiple steps including angiogenesis, extravasion, escape from immune surveillance, adhesion, and clonal expansion in different organs that a systemic therapy is required for effective control of metastasis. The pro-inflammatory nuclear factor kappa B (NFκB) pathway plays an important role during each of these metastatic events and constitutes an excellent target for metastasis control. Stress hormone pro-opiomelanocortin (POMC) and its derived neuropeptides including corticotrophin (ACTH), α-, β-, and γ-melanocyte–stimulating hormone (α-, β-, and γ-MSH), β-endorphin are potent inhibitors of NFκB pathway. Other than the central regulation of stress response and energy homeostasis, POMC also regulates the skin pigmentation, inflammatory processes, and immune reactions in the peripheral system. Since adenovirus–mediated POMC gene delivery leads to hepatic POMC expression, it seems plausible that POMC gene therapy may elicit systemic production of anti-inflammatory POMC-derived peptides and hold promises for control of primary and metastatic cancers. In B16-F10 melanoma models, POMC gene delivery elevated the circulating ACTH levels for more than 8 weeks and suppressed the growth of established melanoma, thereby prolonging the life span of tumor-bearing mice. Moreover, combination of POMC therapy with cisplatin further enhances the survival outcome. Subsequent analysis reveals that POMC gene therapy inhibits the growth and metastasis of melanoma through apoptosis, angiogenesis inhibition, and modulation of epithelial-mesenchymal transition. Besides, α-MSH/melanortin-1 receptor (MC-1R) pathway is involved in the POMC-mediated melanoma suppression.
    To investigate whether POMC therapy could be applied to other types of tumor, we evaluated the therapeutic efficacy of POMC gene therapy in Lewis lung carcinoma (LLC) cells which lack MC-1R. Interestingly, POMC gene delivery effectively inhibited the proliferation and colony formation of LLC cells in vitro and the growth of established LLC in mice. Histological analysis indicated that POMC gene delivery attenuated LLC through proliferation inhibition, apoptosis induction, and angiogenesis blockade. Moreover, POMC gene delivery perturbed β-catenin signaling by reducing protein levels of β-catenin and its downstream proto-oncogenes, including cyclin D1 and c-myc. These results support the existence of an MC-1R-independent pathway for POMC gene therapy and expand the therapeutic spectrum of POMC therapy for multiple types of cancer.
    To elucidate the role of host immunity in anti-neoplastic mechanism underlying POMC therapy, we compared the treatment efficacy of POMC gene therapy for B16-F10 melanoma between severe combined immune-deficient (SCID) and immune-competent C57BL/6 mice, and found similar extent of tumor suppression in both strains of mice. In addition, POMC gene therapy reduced the spleen weight and the number of circulating lymphocytes in B6 mice. These findings suggest that POMC therapy was not dependent on host immunity, yet instead induced immune suppression of animals through ACTH/cortisol production. To minimize such side effect of POMC therapy, we generated a series of adenovirus vectors encoding POMC with mutations in ACTH domain (ACTH-K15A/R17A), which fails to stimulate cortisol synthesis in vitro and in vivo. Gene delivery of ACTH (K15A/R17A) remained capable of suppressing the primary and metastatic melanoma, but had no effect on immune functions in mice. In conclusion, we have characterized the anti-neoplastic function and mechanism of POMC therapy for cancer. Furthermore, we have developed improved POMC gene vectors to minimize its adverse effect for future cancer therapy.
    關鍵字(中)
  • 黑色素癌
  • 基因治療
  • 癌症轉移
  • 前-腦啡-黑色素激素-腎上腺皮質激素
  • 免疫調控
  • 關鍵字(英)
  • Gene Therapy
  • Immune system
  • POMC
  • Metastasis
  • Melanoma
  • Epithelial-mesenchymal transition
  • 論文目次 Abstract in Chinese I
    Abstract in English III
    Index VI
    Figure Index XI Index XV
    Abbreviations XVI
    Contents 1
    Chapter 1. General Introducion .1
    1.1 Proopiomelanocortin (POMC) 2
    1.2 Melanocortin receptors (MCRs) 4
    1.3 Melanoma and metastasis 7
    1.4 Melanoma an animal models 10
    1.5 POMC and Melanoma 11
    1.6 Specific Aims 13
    Chapter 2. The Anti-metastatic Potential of POMC Gene Transfer in Melanoma .14
    2.1 Introduction 15
    2.2 Materials and Methods .17
    2.3 Results 20
    Adenovirus-mediated POMC overexpression in B16-F10 melanoma cells 20
    POMC gene delivery potently inhibited the lung metastasis of melanoma in vivo 20
    POMC gene delivery inhibited the neovascularization and colonization of B16-F10 cells in lung 21
    2.4 Discussions .23
    2.5 Figures and Legends 25
    Chapter 3. The underlying mechanism of POMC-mediated metastatic melanoma inhibition .30
    3.1 Introduction 31
    3.2 Materials and Methods 34
    3.3 Results 40
    POMC gene delivery effectively attenuated the motility ability and the invasive capability of melanoma cells in vitro 41
    POMC gene delivery inhibited the expression of Rho family proteins in B16-F10 melanoma cells and metastatic foci .41
    POMC gene delivery reversed epithelial-mesenchymal transition of melanoma through up-regulation of E-cadherin and down-regulation of vimentin and α-SMA 42
    POMC gene delivery elicited HDGF downregulation in B16-F10 cells and metastatic melanoma 42
    Exogenous HDGF supply partially attenuated the POMC-induced invasiveness suppression and EMT change in melanoma cells 43
    Mimicking POMC gene delivery by POMC-derived peptides induces feature on inhibition of invasion and reduced EMT change in melanoma cells 44
    3.4 Discussions 45
    3.5 Figures and Legends .49
    Chapter 4. Role of Melanocortin Receptor-1 (MC1R) expression in POMC-mediated Tumor Suppression 59
    4.1 Abstract 60
    4.2 Introduction 61
    4.3 Materials and Methods 63
    4.4 Results 70
    Defective MC-1R expression and signaling in mouse LLC cells .70
    POMC gene delivery inhibited the malignant behaviors in LLC cells .70
    Systemic POMC gene delivery attenuates tumor growth in mice bearing established LLC 71
    Systemic POMC gene delivery attenuates tumor progression and inhibits β-catenin pathway in tumor tissue of LLC 72
    Systemic POMC gene delivery inhibits blood vessel formation in LLC tumor tissue 73
    4.5 Discussions 74
    4.6 Figures and Legends 77
    Chapter 5. Role of host immunity in POMC over-expresssion in vivo 89
    5.1 Introduction 90
    5.2 Materials and Methods .93
    5.3 Results 96
    Systemic POMC expression elevated plasma ACTH level in C57BL/6 mice...96
    Systemic POMC expression caused depletion of host immune system in C57BL/6 mice .96
    Systemic POMC expression caused depletion of splenocytes in C57BL/6 mice 96
    Systemic of POMC expression is caused depletion of peripherial lymphocytes in C57BL/6 mice 97
    Host immunity is not required for of POMC induced tumor suppression in melanoma 98
    5.4 Discussions 99
    5.5 Figures and Legends 102
    Chapter 6. Generate a POMC mutant to diminish the side-effect of POMC gene therapy in vitro and in vivo 109
    6.1 Introduction 110
    6.2 Materials and Methods 115
    6.3 Results 120
    Adenovirus effectively transduced POMC and ACTH (K15A/R17A) expression in B16-F10 cells 120
    ACTH (K15A/R17A) gene delivery preserved the anti-invasive and anti-tumor potential of POMC in melanoma cells .121
    ACTH (K15A/R17A) gene delivery does not induced the steroidogenic activity in C57BL/6 mice. 121
    ACTH (K15A/R17A) gene delivery reduced POMC-mediated immune suppression in C57BL/6 mice. 122
    Systemic ACTH (K15A/R17A) expression attenuated the growth of established melanoma and metastatic melanoma in C57BL/6 mice 123
    6.4 Discussions 125
    6.5 Figures and Legends 129
    General Conclusions .139
    Appendix 145
    References 157
    Publications 171
    Conference Presentations 173
    Publication Manuscripts 175
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    口試委員
  • 洪文俊 - 召集委員
  • 張榮賢 - 委員
  • 郭柏麟 - 委員
  • 鄭光宏 - 委員
  • 戴明泓 - 指導教授
  • 口試日期 2012-08-06 繳交日期 2012-08-23

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