血管新生(angiogenesis)不但是腫瘤生長必備的條件，亦是腫瘤變大、侵入周邊、遠處轉移所不可或缺的現象。血管內皮細胞生長因子(VEGF)在血管新生佔有重要角色，亦是固態腫瘤不可或缺的因子。近年來的研究發現血管內皮細胞生長因子在血液惡性疾病上亦有重要角色。本篇研究即針對多種血液惡性疾病病患，收集其周邊血液或骨髓血液細胞做體外培養，收取第三天及第七天的上清液及細胞做血管內皮細胞生長因子活性的測定。其目的在於：1.檢測各種血液惡性疾病的血管內皮細胞生長因子濃度，以期找出它與疾病之預後關係；2.偵測腫瘤細胞在不同的體外生長時間其自我分泌血管內皮細胞生長因子的能力。
結果：本研究計收集75人次檢體進行研究分析。在13例良性疾病中，VEGF值大都不高，顯示沒明顯自我分泌能力。急性淋巴球性白血病之VEGF值無法預估疾病預後，但各案太少(只有七例)。17例惡性淋巴瘤中，第0天VEGF值小於300pg者有較好預後；復發的病例群中有較高的VEGF自我分泌能力，但無統計學上意義。在14例急性骨髓性白血病病患中，第0天VEGF值大於150pg者、第七天VEGF值大於兩倍第三天值者，均顯現不好的預後因子，疾病都未得到良好控制(部分緩解或再發死亡)。在16例慢性骨髓性白血病病患中，血漿VEGF值低者(<300pg)，疾病都在穩定的慢性期；而所有加速期及急性期病患其血漿VEGF值均偏高(>300pg)。血漿VEGF濃度增加者有70%處在疾病惡化階段(>300pg有10例，3例慢性期，7例為加速或急性期)；顯示血漿VEGF濃度增加為不好的預後因子(P=0.010)。慢性期病患其第三天及第七天VEGF值不高，無明顯自我分泌能力；第七天VEGF值明顯增加者大都為急性期病患；顯示VEGF自我分泌能力強者，其疾病大都惡化，是為一不好的疾病預後因子(P=0.248)。
討論：本研究雖是初步的實驗研究，收集的病例多樣，但仍提供了重要的訊息顯示VEGF在血液惡性疾病中亦是扮演重要角色。期望在後續的研究中，能收集單一特定疾病，做治療前、治療後VEGF值的檢測，以期能夠有效的提供疾病的預後評估及做為疾病治療的參考。

Angiogenesis is not only essential for tumor growth but is also implicated in invasion of the cancer cells into the circulation, and growth of dormant micro-metastases into frank metastatic lesions. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis as well as in solid tumors. It also has a role for VEGF in hematopoietic neoplasms; although has not been fully elucidated. This study will examine the VEGF secretary activity of malignant cells in the patients with hematologic malignancies. Supernatants of cell culture after 72 hours & 7th day were analyzed for VEGF value by ELISA method. The purposes of this study are to assay the VEGF activity and its correlation with disease prognosis in various hematological disorders; and to detect the VEGF autocrine activity of tumor cells in sequential culture without any stimulation in vitro.
Results: our research samples were 75 specimens. The VEGF value was low in 13 cases of benign diseases, no obvious auto-secretary activity of those cells. There was no significant correlation between VEGF value and disease status in acute lymphoblastic leukemia; however, the cases were too small to had exact predict value (only 7 cases). In 17 Cases of malignant lymphoma, low D0 VEGF value (<300 pg) had good prognosis; those cases relapsed after treatment had high auto-secretary activity (high VEGF value of 7th culture day) and had bad disease prognosis, but there was no statistic significance. In 14 Cases of acute myelogenous leukemia, high D0 VEGF value (>150 pg) and high VEGF value of 7th culture day both presented bad disease outcome. In 16 cases of chronic myeloid leukemia (CML), low plasma VEGF level (D0<300pg) was all in chronic phase; all cases in accelerated phase (3 cases) and acute blastic crisis (5 cases) presented with high plasma VEGF level (>300pg). Patients with high plasma VEGF level had 70 % (7of 10) in worse disease status (P=0.010). Patients in chronic phase of CML had low VEGF auto-secretary activity and most of the blastic crisis patients were with high VEGF auto-secretary activity and also had bad prognosis. (P=0.248)
Conclusion: although our study is a primary result, study cases are varied, but it still provide important information that VEGF has an important role in hematological malignancies. We will process further research of single and specific disease in the future to analyze the exact correlation of VEGF and hematological diseases.

目錄
中文摘要-----------------------------------------2
英文摘要-----------------------------------------4
文獻回顧-----------------------------------------6
材料與方法-------------------------------------12
實驗結果----------------------------------------18
討論----------------------------------------------21
參考文獻----------------------------------------26
圖-------------------------------------------------30
表-------------------------------------------------40

1. Folkman J: Clinical applications of research on angiogenesis. N Engl J Med, 1995; 333: 1757-1763.
2. Folkman J: What is the evidence that the tumors are angiogenesis - dependent? J Natl Cancer Inst, 1990; 82: 4-6.
3. Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med, 1971; 285: 1182-1186.
4. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996; 86: 353-364.
5. Poon Ronnie TP, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Onco, 2001; 19:1207-25.
6. Weidner N, Semple P, Welch WR, Folkman J: Tumor angiogenesis and metastases: Correlation in invasive breast carcinoma. N Engl J Med, 1991; 324: 1-8.
7. Weidner N: Intratumoral microvessel density as a prognostic factor in cancer. Am J Pathol, 1995; 147: 9-19
8. Vacca A, Ribatti D, Ruco L, Giacchetta F. Nico B. Quondamatteo F. Ria R. Iurlaro M. Dammacco F.: Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas. Br J Cancer, 1999; 79: 965-970.
9. Padro T, Ruiz S, Bieker R, Burger H, Steins M, Kienast J, Buchner T, Berdel WE, Mesters RM: Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood, 2000; 95: 2637-2644.
10. Fujimoto K. Ichimori Y. Kakizoe T. Okajima E. Sakamoto H. Sugimura T. Terada M.: Increased serum levels of basic fibroblast growth factor in patients with renal cell carcinoma. Biochem Biophys Res Commun, 1991; 180: 386-392.
11. Takahashi Y. Bucana CD. Liu W. Yoneda J. Kitadai Y. Cleary KR. Ellis LM: Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: Role of infiltrating cells. J Natl Cancer Inst, 1996; 88: 1146-1151.
12. Houck KA, Leung DW, Rowland AM, Winer J. Ferrara N.: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem, 1992;. 267:26031-26037.
13. Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocrine reviews, 1997; 18: 4-25.
14. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z.: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J, 1999; 13: 9-22.
15. Klagsbrun V, D’Amore PA: Vascular endothelial growth factor and its receptors. Cytokine & growth factor reviews, 1996; 7(3), 259-270.
16. Neufeld G, Cohen T, Gitay-Goren H, Poltorak Z. Tessler S. Sharon R. Gengrinovitch S. Levi BZ.: Similarities and differences between the vascular endothelial growth factor (VEGF) splice variants. Cancer Metastasis Rev, 1996; 15: 153-158.
17. Poltorak Z, Cohen T, Sivan R, Kandelis Y. Spira G. Vlodavsky I. Keshet E. Neufeld G.: VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem, 1997; 272: 7151-7158.
18. Burchardt M. Burchardt T. Chen MW. Shabsigh A. de la Taille A. Buttyan R. Shabsigh R.: Expression of messenger ribonucleic acid splice variants for vascular endothelial growth factor in the penis of adult rats and humans. Biol Reprod, 1999; 60: 398-404.
19. Whittle C, Gillespie K, Harrison R, Mathieson PW, Harper SJ.: Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci (Colch), 1999; 97: 303-312.
20. Aoki Y, Tosato G.: Role of vascular endothelial growth factor/vascular permeability factor in the pathogenesis of Kaposi’s sarcoma-associated herpesvirus-infected primary effusion lymphomas. Blood, 1999; 94: 4247-4254.
21. Veikkola T, Karkkainen M, Lena CW, Alitalo K: Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer res, 2000; 60, 203-212.
22. Gale NW, Yancopoulos GD: Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Gene & development, 1999; 13: 1055-1066.
23. Aiello LP. Pierce EA. Foley ED. Takagi H. Chen H. Riddle L. Ferrara N. King GL. Smith LE: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl. Acad. Sci. USA, 1995; 92:10457-10461.
24. Bellamy WT, Richter L, Frutiger Y, Grogan TM: Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer res, 1999; 59: 728-733.
25. Ribatti D, Vacca RD, Nico B, Fanelli M, Roncali L, and Dammacco F: Angiogenesis spectrum in the stroma of B-cell non-Hodgkin’s lymphomas. An immunohistochemical and ultrastructural study. Eur. J. Haematol, 1996; 56: 45–53.
26. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J: Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol, 1997; 150: 815–821.
27. Vacca, A., Ribatti, D., Roncali, L., Ranieri, G., Serio, G., Silvestris, F., and Dammacco, F. Bone marrow angiogenesis and progression in multiple myeloma. Br. J. Haematol, 1994; 87: 503–508.
28. Maniwa Y, Okada M, Ishii N, Kiyooka K: Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer. Chest,1998; 114: 1668-1675.
29. Aguago A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, Giles F, Estrov Z, Barlogie B, Albitar M: Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood, 1999; 94:3717-3721.