進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-0204201411504100
論文名稱(中文) 發展第一型血小板活化素短髮夾核醣核酸作為抗腫瘤劑
論文名稱(英文) Development of Thrombospondin 1 shRNA as anti-cancer agent
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 翁子洋
研究生(英文) Tzu-Yang Weng
學號 S58981395
學位類別 博士
語文別 中文
論文頁數 76頁
口試委員 指導教授-賴明德
召集委員-吳昭良
口試委員-蕭璦莉
口試委員-林以行
口試委員-林季千
口試委員-戴明泓
中文關鍵字 第一型血小板活化素  樹突狀細胞  癌症免疫治療  DNA疫苗 
英文關鍵字 Thrombospondin-1  Dendritic cells  Cancer immunotherapy  DNA vaccine 
學科別分類
中文摘要 一般認為,經由表現第一型血小板活化素(Thrombospondin-1, TSP-1)可以抑制血管新生進而阻止腫瘤生長;然而對於第一型血小板活化素在樹突狀細胞 (dendritic cells,DCs)中的表現是否可以影響腫瘤進長,目前還是十分不清楚。所以我們假設抑制樹突狀細胞內第一型血小板活化素表現後,可以產生較好的免疫反應對抗癌細胞生長。本篇論文將針對三個特定方向做探討: 第一、我們將了解利用基因槍遞送第一型血小板活化素shRNA質體於腫瘤小鼠腹部後是否具有療效。第二、探討第一型血小板活化素 shRNA所誘發的抗癌效果之免疫機轉。第三、瞭解第一型血小板活化素shRNA於DNA疫苗做的應用,並搭配Neu DNA疫苗進行試驗。我們發現利用基因槍遞送第一型血小板活化素 shRNA成功誘發抗腫瘤免疫反應。為了排除shRNA有可能的副作用,利用3個不同片段之TSP-1 shRNA進行實驗也顯示具有相同治療效果。我們也觀察到腫瘤浸潤之CD4+ 與CD8+ T細胞也在遞送第一型血小板活化素 shRNA後大量的增加。利用real-time PCR偵測後也發現基因槍遞送第一型血小板活化素 shRNA後淋巴結的IL-12與IFN-γ表現量上升。自給予TSP-1 shRNA的小鼠取出之淋巴細胞具有專一性毒殺腫瘤細胞的能力,而此毒殺效果在剃除CD8+ T細胞後就消失了。將CD11c+-TSP-1缺乏的骨髓分化樹突狀細胞打入小鼠背部腫瘤側後觀察結果也發現可以延緩腫瘤生長。CD11c+、TSP-1缺乏的骨髓分化樹突狀細胞所誘發的抗腫瘤效果在剔除CD8+ T細胞後就失去效果。在NOD-SCID這種缺乏後天免疫細胞的小鼠中遞送第一型血小板活化素shRNA並沒有治療效果。而TSP家族中另一成員第二型血小板活化的shRNA也不能延腫瘤小鼠壽命。第一型血小板活化素shRNA如同一免疫治療佐劑,可有效增強Neu DNA疫苗的療效。綜合以上結論,我們發現利用shRNA抑制樹突狀細胞中第一型血小板活化素的表現,可以誘發細胞性免疫反應抑制腫瘤生長,延長小鼠壽命;與抑制TSP-1於腫瘤中的表現後造成促進腫瘤生長的現象不同。
英文摘要 Induction of thrombospondin 1 (TSP-1) is generally assumed to suppress tumors by inhibiting angiogenesis; however, it is less clear how the TSP-1 in dendritic cells (DCs) influences tumor progression. We hypothesized that silencing TSP-1 expression in DCs via skin administration of TSP-1 shRNA (short hairpin RNA) plasmid may produce antitumor effects by inducing immune responses. In this study, we investigated three specific aims: First, we evaluated whether down-regulating the expression of TSP-1 in DCs may enhance antitumor response. Second, the possible immunological mechanisms of antitumor response induced by TSP-1 shRNA were explored. Third, to investigate the application of TSP-1 shRNA in anti-cancer therapy, TSP-1 shRNA was combined with neu DNA vaccine. In this study, we found that skin administration of TSP-1 shRNA produced anticancer therapeutic effects. The therapeutic effects were not likely due to off-target effect since three TSP-1 shRNA targeting different sites showed therapeutic effects. Tumor-infiltrating CD4+ and CD8+ T cells were increased after administration of TSP-1 shRNA. The expression of interleukin-12 (IL-12) and interferon-γ (IFN-γ) in the lymph nodes was enhanced by injection of TSP-1 shRNA. Lymphocytes from the mice injected with TSP-1 shRNA selectively killed the tumor cells, and the cytotoxicity of lymphocytes was abolished by the depletion of CD8+ T cells. Injection of CD11c+ TSP-1-knockout (TSP-1-KO) bone marrow-derived dendritic cells (BMDCs) delayed tumor growth in tumor-bearing mice. Similarly, anti-tumor activity induced by TSP-1-KO BMDCs was abrogated by the depletion of CD8+ T cells. TSP-1 shRNA did not exhibit antitumor activity in MBT-2-tumor bearing NOD-SCID mice. In contrast, the administration of shRNA targeting TSP-2, another TSP family member, did not extend the survival of tumor-bearing mice. Finally, TSP-1 shRNA functioned as an immunotherapeutic adjuvant to augment the therapeutic efficacy of Neu-DNA vaccination. Together, our results implicate that the downregulation of TSP-1 in DCs produces an effective anti-tumor response that is opposite to the pro-tumor effects by silencing of the TSP-1 within tumor cells.
論文目次 TABLE OF CONTENT
Abstract (Chinese) 1
Abstract (English) 3
Acknowledgement 5
Content 6
1. Introduction 10
1.1 Dendritic cells 10
1.2 Antitumor DNA vaccine 12
1.3 Augmenting the therapeutic effects of DNA vaccine 13
1.4 Thrombospondin 1 and cancer 14
1.5 Thrombospondin 1 in immunity 16
2. Rationale and Hypothesis 17
3. Materials and Methods 18
3.2 Martials 18
3.2.1 Antibodies and Recombinant proteins 18
3.2.2 Primers and shRNA targeting sequences 19
3.2.3 Reagents 20
3.2.4 Kits 21
3.2.5 Equipment 21
3.3 Methods 22
3.3.1 Cell lines and transfection 22
3.3.2 Plasmid construction preparation of DNA vaccine 22
3.3.3 Animals 23
3.3.4 Measurement of the therapeutic efficacy on established tumors 23
3.3.5 Immunohistochemistry 24
3.3.6 Induction of CTLs and measurement of CTL activity assay in vitro 25
3.3.7 Depletion of CD8+ T cells in vivo 26
3.3.8 Generation of BMDCs and isolation of CD11c+ cells 26
3.3.9 Adoptive transfer of BMDCs into tumor-bearing mice 26
3.3.10 Real-time PCR 27
3.3.11 Flow cytometry analysis of lymphocytes 27
3.3.12 Statistical analyses 28
4. Results 29
4.1 Down-regulation of TSP-1 in vitro and in vivo by using TSP-1 shRNA 29
4.2 Skin administration of TSP-1 shRNA exhibits therapeutic efficacy 29
4.3 Anti-tumor therapeutic effects of TSP-1 shRNA are not due to off-target effects 30
4.4 Skin administration of TSP-1 shRNA does not influence tumor angiogenesis 31
4.5 Silencing TSP-1 in DCs promotes cellular immunity 32
4.6 Down-regulation of TSP-1 in DCs induces cytotoxic cellular immunity 32
4.7 Cellular immunity is required for TSP-1 shRNA induced anti-tumor response 33
4.8 TSP-1-deficient DCs exhibit anti-tumor effects 34
4.9 TSP-1-deficient DCs produce cellular immune response 34
4.10 Thrombospondin-2 shRNA does not exhibit anti-cancer effects 35
4.11 Only TSP-1 shRNA produces effective antitumor immunity 36
4.12 TSP-1 shRNA enhances the antitumor therapeutic efficacy of Neu DNA vaccine 37
4.13 Immunological mechanism of cyto-Neu_shTSP-1 induced antitumor response 37
5. Discussion 39
6. Conclusion 44
7. References 45
參考文獻 Adams, J.C., and Lawler, J. (2004). The thrombospondins. Int J Biochem Cell Biol 36, 961-968.
Akbari, O., DeKruyff, R.H., and Umetsu, D.T. (2001). Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2, 725-731.
Alarcon, J.B., Waine, G.W., and McManus, D.P. (1999). DNA vaccines: technology and application as anti-parasite and anti-microbial agents. Adv Parasitol 42, 343-410.
Allan, R.S., Waithman, J., Bedoui, S., Jones, C.M., Villadangos, J.A., Zhan, Y., Lew, A.M., Shortman, K., Heath, W.R., and Carbone, F.R. (2006). Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153-162.
Allavena, P., Piemonti, L., Longoni, D., Bernasconi, S., Stoppacciaro, A., Ruco, L., and Mantovani, A. (1998). IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol 28, 359-369.
Bocci, G., Francia, G., Man, S., Lawler, J., and Kerbel, R.S. (2003). Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100, 12917-12922.
Cavallo, F., Offringa, R., van der Burg, S.H., Forni, G., and Melief, C.J. (2006). Vaccination for treatment and prevention of cancer in animal models. Adv Immunol 90, 175-213.
Chen, H., Herndon, M.E., and Lawler, J. (2000). The cell biology of thrombospondin-1. Matrix Biol 19, 597-614.
Cheng, W.F., Hung, C.F., Chai, C.Y., Hsu, K.F., He, L., Ling, M., and Wu, T.C. (2001). Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J Clin Invest 108, 669-678.
Condon, C., Watkins, S.C., Celluzzi, C.M., Thompson, K., and Falo, L.D., Jr. (1996). DNA-based immunization by in vivo transfection of dendritic cells. Nat Med 2, 1122-1128.
Dameron, K.M., Volpert, O.V., Tainsky, M.A., and Bouck, N. (1994). Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265, 1582-1584.
Demeure, C.E., Tanaka, H., Mateo, V., Rubio, M., Delespesse, G., and Sarfati, M. (2000). CD47 engagement inhibits cytokine production and maturation of human dendritic cells. J Immunol 164, 2193-2199.
Doyen, V., Rubio, M., Braun, D., Nakajima, T., Abe, J., Saito, H., Delespesse, G., and Sarfati, M. (2003). Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 198, 1277-1283.
Drutman, S.B., and Trombetta, E.S. (2010). Dendritic cells continue to capture and present antigens after maturation in vivo. J Immunol 185, 2140-2146.
Ebbinghaus, S., Hussain, M., Tannir, N., Gordon, M., Desai, A.A., Knight, R.A., Humerickhouse, R.A., Qian, J., Gordon, G.B., and Figlin, R. (2007). Phase 2 study of ABT-510 in patients with previously untreated advanced renal cell carcinoma. Clin Cancer Res 13, 6689-6695.
Faunce, D.E., Terajewicz, A., and Stein-Streilein, J. (2004). Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis. J Immunol 172, 1991-1995.
Feltquate, D.M., Heaney, S., Webster, R.G., and Robinson, H.L. (1997). Different T helper cell types and antibody isotypes generated by saline and gene gun DNA immunization. J Immunol 158, 2278-2284.
Ferrone, C.R., Perales, M.A., Goldberg, S.M., Somberg, C.J., Hirschhorn-Cymerman, D., Gregor, P.D., Turk, M.J., Ramirez-Montagut, T., Gold, J.S., Houghton, A.N., et al. (2006). Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains. Clin Cancer Res 12, 5511-5519.
Futagami, Y., Sugita, S., Vega, J., Ishida, K., Takase, H., Maruyama, K., Aburatani, H., and Mochizuki, M. (2007). Role of thrombospondin-1 in T cell response to ocular pigment epithelial cells. J Immunol 178, 6994-7005.
Garg, S., Oran, A., Wajchman, J., Sasaki, S., Maris, C.H., Kapp, J.A., and Jacob, J. (2003). Genetic tagging shows increased frequency and longevity of antigen-presenting, skin-derived dendritic cells in vivo. Nat Immunol 4, 907-912.
Grimbert, P., Bouguermouh, S., Baba, N., Nakajima, T., Allakhverdi, Z., Braun, D., Saito, H., Rubio, M., Delespesse, G., and Sarfati, M. (2006). Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation. J Immunol 177, 3534-3541.
Gurunathan, S., Wu, C.Y., Freidag, B.L., and Seder, R.A. (2000). DNA vaccines: a key for inducing long-term cellular immunity. Curr Opin Immunol 12, 442-447.
Herber, D.L., Cao, W., Nefedova, Y., Novitskiy, S.V., Nagaraj, S., Tyurin, V.A., Corzo, A., Cho, H.I., Celis, E., Lennox, B., et al. (2010). Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 16, 880-886.
Hodi, F.S., O'Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363, 711-723.
Hsieh, C.Y., Chen, C.A., Huang, C.Y., Chang, M.C., Lee, C.N., Su, Y.N., and Cheng, W.F. (2007). IL-6-encoding tumor antigen generates potent cancer immunotherapy through antigen processing and anti-apoptotic pathways. Mol Ther 15, 1890-1897.
Huang, T.T., Yen, M.C., Lin, C.C., Weng, T.Y., Chen, Y.L., Lin, C.M., and Lai, M.D. (2011). Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer. Cancer sci 102, 2214-2220.
Inaba, K., Inaba, M., Romani, N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu, S., and Steinman, R.M. (1992). Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176, 1693-1702.
Iruela-Arispe, M.L., Bornstein, P., and Sage, H. (1991). Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc Natl Acad Sci U S A 88, 5026-5030.
Kantoff, P.W., Higano, C.S., Shore, N.D., Berger, E.R., Small, E.J., Penson, D.F., Redfern, C.H., Ferrari, A.C., Dreicer, R., Sims, R.B., et al. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363, 411-422.
Kim, T.W., Hung, C.F., Ling, M., Juang, J., He, L., Hardwick, J.M., Kumar, S., and Wu, T.C. (2003). Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J Clin Invest 112, 109-117.
Kim, T.W., Lee, J.H., He, L., Boyd, D.A., Hardwick, J.M., Hung, C.F., and Wu, T.C. (2005). Modification of professional antigen-presenting cells with small interfering RNA in vivo to enhance cancer vaccine potency. Cancer Res 65, 309-316.
Lai, M.D., Yen, M.C., Lin, C.M., Tu, C.F., Wang, C.C., Lin, P.S., Yang, H.J., and Lin, C.C. (2009). The effects of DNA formulation and administration route on cancer therapeutic efficacy with xenogenic EGFR DNA vaccine in a lung cancer animal model. Genet Vaccines Ther 7, 2.
Lamy, L., Foussat, A., Brown, E.J., Bornstein, P., Ticchioni, M., and Bernard, A. (2007). Interactions between CD47 and thrombospondin reduce inflammation. J Immunol 178, 5930-5939.
Letterio, J.J., and Roberts, A.B. (1998). Regulation of immune responses by TGF-beta. Annu Rev Immunol 16, 137-161.
Lin, C.C., Chou, C.W., Shiau, A.L., Tu, C.F., Ko, T.M., Chen, Y.L., Yang, B.C., Tao, M.H., and Lai, M.D. (2004). Therapeutic HER2/Neu DNA vaccine inhibits mouse tumor naturally overexpressing endogenous neu. Mol Ther 10, 290-301.
Lin, C.C., Yen, M.C., Lin, C.M., Huang, S.S., Yang, H.J., Chow, N.H., and Lai, M.D. (2008). Delivery of noncarrier naked DNA vaccine into the skin by supersonic flow induces a polarized T helper type 1 immune response to cancer. J Gene Med 10, 679-689.
Liu, C., Lou, Y., Lizee, G., Qin, H., Liu, S., Rabinovich, B., Kim, G.J., Wang, Y.H., Ye, Y., Sikora, A.G., et al. (2008). Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 118, 1165-1175.
Lu, T.J., Lai, W.Y., Huang, C.Y., Hsieh, W.J., Yu, J.S., Hsieh, Y.J., Chang, W.T., Leu, T.H., Chang, W.C., Chuang, W.J., et al. (2006). Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem 281, 38405-38417.
Macklin, M.D., McCabe, D., McGregor, M.W., Neumann, V., Meyer, T., Callan, R., Hinshaw, V.S., and Swain, W.F. (1998). Immunization of pigs with a particle-mediated DNA vaccine to influenza A virus protects against challenge with homologous virus. J Virol 72, 1491-1496.
Makala, L.H. (2012). The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infection. J Biomed Sci 19, 5.
Markovic, S.N., Suman, V.J., Rao, R.A., Ingle, J.N., Kaur, J.S., Erickson, L.A., Pitot, H.C., Croghan, G.A., McWilliams, R.R., Merchan, J., et al. (2007). A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma. Am J Clin Oncol 30, 303-309.
Marteau, F., Gonzalez, N.S., Communi, D., Goldman, M., and Boeynaems, J.M. (2005). Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells. Blood 106, 3860-3866.
Martin-Manso, G., Galli, S., Ridnour, L.A., Tsokos, M., Wink, D.A., and Roberts, D.D. (2008). Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer res 68, 7090-7099.
Matsuki, K., Tanabe, A., Hongo, A., Sugawara, F., Sakaguchi, K., Takahashi, N., Sato, N., and Sahara, H. (2012). Anti-angiogenesis effect of 3'-sulfoquinovosyl-1'-monoacylglycerol via upregulation of thrombospondin 1. Cancer sci 103, 1546-1552.
Melief, C.J. (2008). Cancer immunotherapy by dendritic cells. Immunity 29, 372-383.
Merad, M., Sathe, P., Helft, J., Miller, J., and Mortha, A. (2013). The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31, 563-604.
Mittal, R., Gonzalez-Gomez, I., and Prasadarao, N.V. (2010). Escherichia coli K1 promotes the ligation of CD47 with thrombospondin-1 to prevent the maturation of dendritic cells in the pathogenesis of neonatal meningitis. J Immunol 185, 2998-3006.
Munn, D.H., Sharma, M.D., Hou, D., Baban, B., Lee, J.R., Antonia, S.J., Messina, J.L., Chandler, P., Koni, P.A., and Mellor, A.L. (2004). Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114, 280-290.
Murphy-Ullrich, J.E., and Poczatek, M. (2000). Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev 11, 59-69.
Narizhneva, N.V., Razorenova, O.V., Podrez, E.A., Chen, J., Chandrasekharan, U.M., DiCorleto, P.E., Plow, E.F., Topol, E.J., and Byzova, T.V. (2005). Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 19, 1158-1160.
Norell, H., Poschke, I., Charo, J., Wei, W.Z., Erskine, C., Piechocki, M.P., Knutson, K.L., Bergh, J., Lidbrink, E., and Kiessling, R. (2010). Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med 8, 53.
Olerud, J., Johansson, M., Lawler, J., Welsh, N., and Carlsson, P.O. (2008). Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets. Diabetes 57, 1870-1877.
Opitz, C.A., Litzenburger, U.M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203.
Ou, X., Cai, S., Liu, P., Zeng, J., He, Y., Wu, X., and Du, J. (2008). Enhancement of dendritic cell-tumor fusion vaccine potency by indoleamine-pyrrole 2,3-dioxygenase inhibitor, 1-MT. J Cancer Res Clin Oncol 134, 525-533.
Palucka, K., and Banchereau, J. (2013). Dendritic-cell-based therapeutic cancer vaccines. Immunity 39, 38-48.
Porgador, A., Irvine, K.R., Iwasaki, A., Barber, B.H., Restifo, N.P., and Germain, R.N. (1998). Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med 188, 1075-1082.
Provinciali, M., Barucca, A., Pierpaoli, E., Orlando, F., Pierpaoli, S., and Smorlesi, A. (2012). In vivo electroporation restores the low effectiveness of DNA vaccination against HER-2/neu in aging. Cancer Immuno Immunother : CII 61, 363-371.
Punekar, S., Zak, S., Kalter, V.G., Dobransky, L., Punekar, I., Lawler, J.W., and Gutierrez, L.S. (2008). Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease. Pathobiology 75, 9-21.
Quaratino, S., Duddy, L.P., and Londei, M. (2000). Fully competent dendritic cells as inducers of T cell anergy in autoimmunity. Proc Natl Acad Sci U S A 97, 10911-10916.
Reizis, B., Bunin, A., Ghosh, H.S., Lewis, K.L., and Sisirak, V. (2011). Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 29, 163-183.
Rice, J., Ottensmeier, C.H., and Stevenson, F.K. (2008). DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8, 108-120.
Rutella, S., Bonanno, G., Pierelli, L., Mariotti, A., Capoluongo, E., Contemi, A.M., Ameglio, F., Curti, A., De Ritis, D.G., Voso, M.T., et al. (2004). Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha. Eur J Immunol 34, 1291-1302.
Rutella, S., Danese, S., and Leone, G. (2006). Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108, 1435-1440.
Sato, K., Yamashita, N., Baba, M., and Matsuyama, T. (2003). Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18, 367-379.
Schneeberger, A., Wagner, C., Zemann, A., Luhrs, P., Kutil, R., Goos, M., Stingl, G., and Wagner, S.N. (2004). CpG motifs are efficient adjuvants for DNA cancer vaccines. J Invest Dermatol 123, 371-379.
Schultz-Cherry, S., and Murphy-Ullrich, J.E. (1993). Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol 122, 923-932.
Shen, L., Evel-Kabler, K., Strube, R., and Chen, S.Y. (2004). Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nature biotechnol 22, 1546-1553.
Snyder, L.A., Goletz, T.J., Gunn, G.R., Shi, F.F., Harris, M.C., Cochlin, K., McCauley, C., McCarthy, S.G., Branigan, P.J., and Knight, D.M. (2006). A MUC1/IL-18 DNA vaccine induces anti-tumor immunity and increased survival in MUC1 transgenic mice. Vaccine 24, 3340-3352.
Tabib, A., Krispin, A., Trahtemberg, U., Verbovetski, I., Lebendiker, M., Danieli, T., and Mevorach, D. (2009). Thrombospondin-1-N-terminal domain induces a phagocytic state and thrombospondin-1-C-terminal domain induces a tolerizing phenotype in dendritic cells. PLoS One 4, e6840.
Teja Colluru, V., Johnson, L.E., Olson, B.M., and McNeel, D.G. (2013). Preclinical and clinical development of DNA vaccines for prostate cancer. Urologic oncology.
Trimble, C., Lin, C.T., Hung, C.F., Pai, S., Juang, J., He, L., Gillison, M., Pardoll, D., Wu, L., and Wu, T.C. (2003). Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe. Vaccine 21, 4036-4042.
Ulmer, J.B., Donnelly, J.J., Parker, S.E., Rhodes, G.H., Felgner, P.L., Dwarki, V.J., Gromkowski, S.H., Deck, R.R., DeWitt, C.M., Friedman, A., et al. (1993). Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745-1749.
Weber, J., Boswell, W., Smith, J., Hersh, E., Snively, J., Diaz, M., Miles, S., Liu, X., Obrocea, M., Qiu, Z., et al. (2008). Phase 1 trial of intranodal injection of a Melan-A/MART-1 DNA plasmid vaccine in patients with stage IV melanoma. J Immunother 31, 215-223.
Willingham, S.B., Volkmer, J.P., Gentles, A.J., Sahoo, D., Dalerba, P., Mitra, S.S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J.D., et al. (2012). The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109, 6662-6667.
Yamazaki, S., Iyoda, T., Tarbell, K., Olson, K., Velinzon, K., Inaba, K., and Steinman, R.M. (2003). Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198, 235-247.
Yen, M.C., Lin, C.C., Chen, Y.L., Huang, S.S., Yang, H.J., Chang, C.P., Lei, H.Y., and Lai, M.D. (2009). A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA. Clin Cancer Res 15, 641-649.
Young, G.D., and Murphy-Ullrich, J.E. (2004). The tryptophan-rich motifs of the thrombospondin type 1 repeats bind VLAL motifs in the latent transforming growth factor-beta complex. J Biol Chem 279, 47633-47642.
Zhang, X., Galardi, E., Duquette, M., Lawler, J., and Parangi, S. (2005). Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model. Clin Cancer Res 11, 5622-5630.
Zhang, X., and Lawler, J. (2007). Thrombospondin-based antiangiogenic therapy. Microvasc Res 74, 90-99.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2019-04-07起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw