臺灣博碩士論文加值系統

為建立小鼠模式而將犬傳染性花柳性腫瘤（canine transmissible venereal tumor, CTVT）接種於免疫缺陷（NOD/SCID）小鼠（小鼠CTVT腫瘤簡稱為XCTVT）。 XCTVT 具有與CTVT相同之細胞學與組織學特性，亦表現出CTVT 之特異性基因片段LINE-c-myc。然而，將此小鼠CTVT腫瘤再次接種回犬隻後（以下簡稱為MCTVT），發現MCTVT的生長特性已有改變，它較CTVT 具有更快的生長速度、較多的mitotic figures、更大的腫瘤體積、及不易進入腫瘤消退期的特性。為了深入探討MCTVT 腫瘤轉趨惡性化的原因，我們使用Affymetrix microarray 分析MCTVT 與CTVT 腫瘤之基因表現狀況。兩倍分析的結果顯示，有136個基因在MCTVT表現量大幅上升，37個基因在MCTVT表現量大幅下降。其中許多基因與重要的生理調控因子，腫瘤發生因子，及免疫調節因子均有關。選擇在MCTVT表現量上升的30個基因，以即時定量聚合酶連鎖反應（Real-time RT-PCR）進行基因表現量的確認，發現有三個基因的表現量確實在MCTVT顯著的上升。此三基因分別為基質金屬蛋白酶-1（matrix metalloproteinase 1，MMP1）、載脂蛋白C1 （ApolipoproteinC-I，APOC1）及尿氨酸-3-單氧酶（kynurenine 3-monooxygenase，KMO）。為了解此三個基因與腫瘤惡性的相關性，我們進一步在犬乳房腫瘤以即時定量聚合酶連鎖反應測試表現量，最後發現KMO在良性腫瘤的表現量極低，然而在惡性腫瘤此基因表現量則顯著上升。此外在腫瘤發生轉移時會更顯著性的升高。更重要的是，當KMO上升時病犬的存活時間會大幅度縮短。本研究首次發現犬KMO表現量與腫瘤的惡性具正相關性，並與預後有關。因此本酵素可能成為一個診斷腫瘤惡性及轉移的標誌。

A xenograft NOD/SCID mouse model bearing canine transmissible venereal tumor (CTVT) (designated XCTVT) was created in this study. In addition to confirmation of the morphological similarities of the CTVT and XCTVT cells, insertion of the specific long interspersed nuclear element (LINE) gene fragment in the 5’ end of the c-myc gene characteristic of CTVT cells was also confirmed in XCTVT. However, when inoculated back into dogs (designated MCTVT), MCTVT exhibited much more aggressive growth and a much higher metastatic frequency than common CTVT. The goal of this research was to explore the differences in gene expression between dog and mouse CTVT and determine the genes involved in the aggressive growth. The differential gene expressions of the two tumors were analyzed using Affymetrix, and in total, 136 genes were identified as being significantly up-regulated and 37 significantly down-regulated in MCTVT in comparison with CTVT by hierarchical analysis and filtering of the differentially-expressed genes by the 2-fold method. Many of these genes are involved in activities such as malignant candidate genes, important biological processes, tumor development and immune modulation, as has been reported previously. Three genes (APOC1, MMP1 and KMO) were highly up-regulated as confirmed by real-time RT-PCR and were tested in 35 spontaneous canine mammary gland tumors (MGT). The real-time RT-PCR results indicated that KMO and MMP1 discriminated malignant from benign MGT, and in addition, KMO gene expression was significantly higher in stages 4 and 5 malignant MGT than MGT of lower stages. The results of KMO mRNA level and IDO mRNA/protein data indicated that KMO up-regulation was independent of IDO. Over-expression of KMO was also found to be associated with poor prognosis in MGT dogs. In conclusion, KMO expression may have the potential to be used as a biological indicator to differentiate degrees of malignancy.

Contents
審查書 I
致謝 II
中文摘要 IV
Abstract VI
Chapter 1. Background and Literature Review 1
1. 1 CANINE TRANSMISSIBLE VENEREAL TUMOR 1
1. 2 MICROARRAY 6
1. 2. 1 Microarrays in human oncology 7
1. 2. 2 Microarrays in dog oncology 8
1. 3 MAMMARY GLAND TUMOR, MGT 9
1. 3. 1 Incidence 10
1. 3. 2 Histological Classification 10
1. 3. 3 Clinical staging 11
1. 3. 4 Prognosis factors 11
1. 4 KYNURENINE PATHWAY 15
1. 4. 1 The physiological and pathological role of the kynurenine pathway in the nervous system. 17
1. 4. 2 The physiological and pathological role of the kynurenine pathway in the immune system 19
1. 4. 3 Activities in malignancy 21
1. 4. 4 Kynurenine 3-monooxygenase 23
Chapter 2. Introduction 25
Chapter 3. Materials and methods 28
3. 1 EXPERIMENTAL ANIMALS AND CTVT MODELS 28
3. 1. 2 CTVT 28
3. 1. 2 Xenographic (X) CTVT 29
3. 1. 3 MCTVT 29
3. 2 TUMOR SAMPLE COLLECTION AND PREPARATION 30
3. 4 RNA EXTRACTION 31
3. 7 WESTERN IMMUNOBLOTTING 35
3. 8 STATISTICAL ANALYSIS 35
Chapter 4. Results 36
4. 1 CHARACTERIZATION OF THE XCTVT AND MCTVT 36
4. 2 COMPARISON OF THE GENE EXPRESSION PATTERNS OF MCTVT AND CTVT 37
4. 3 SELECTION OF MALIGNANT SIGNATURE CANDIDATE GENES BY COMPARISON OF GENE EXPRESSION IN PROGRESSION-PHASE MCTVT AND CTVT 37
4. 4 VERIFICATION OF THE MALIGNANT SIGNATURE CANDIDATE GENES IN CLINICAL CANINE PATIENTS 38
4. 5 COMPARISON OF INDOLEAMINE-2,3-DIOXYGENASE (IDO) EXPRESSION IN CTVT, MCTVT AND MGT 39
5. Discussion 40
Table 47
TABLE 1. CORRELATION BETWEEN OVER-EXPRESSION OF TRYPTOPHAN METABOLITES IN TUMORS AND PATIENT PROGNOSIS. 47
TABLE 2. HISTOLOGIC CLASSIFICATION OF CANINE MAMMARY TUMORS. 48
TABLE 3. CANINE MAMMARY TUMOR STAGING SYSTEM. 49
TABLE. 4 SEQUENCE OF PRIMERS USED IN REAL-TIME RT-PCR. 50
TABLE. 5 THE 136 UP-REGULATED GENES (≥2-FOLD) IN MCTVT IN COMPARISON WITH CTVT. 52
TABLE. 6 THE 37 DOWN-REGULATED GENES (≥2-FOLD) IN MCTVT IN COMPARISON WITH CTVT. 57
TABLE. 7 THE BIOLOGICAL PROCESSES IN WHICH THE 173 DIFFERENTIALLY-EXPRESSED GENES ARE INVOLVED. 59
TABLE. 8 ASSOCIATION BETWEEN PATIENT CHARACTERISTICS, CLINICOPATHOLOGICAL FEATURES AND MRNA EXPRESSION LEVELS OF MALIGNANT CANDIDATE GENES OBTAINED BY REAL-TIME RT-PCR. 63
Figure 64
FIG. 1 THE CYTOLOGY OF XCTVT, MCTVT AND CTVT. 64
FIG. 2. HISTOPATHOLOGY OF CTVT, XCTVT AND MCTVT. 66
FIG. 3. TUMOR MITOTIC FIGURES IN CTVT, XCTVT AND MCTVT. 70
FIG. 4. GEL ELECTROPHORESIS OF THE PCR PRODUCTS USING DIAGNOSTIC PRIMERS FOR DETECTING LINE/C-MYC INSERTION SPECIFIC TO CTVT. 71
FIG. 5. TUMOR GROWTH CURVES OF CTVT AND MCTVT. 72
FIG. 6. GENE EXPRESSION PROFILES OF CTVT AND MCTVT BY PCA MAPPING. 73
FIG. 7. GENE EXPRESSION PROFILES OF CTVT AND MCTVT BY HIERARCHICAL CLUSTERING. 74
FIG. 8. VALIDATION OF AFFYMETRIX DATA BY REAL-TIME PCR. 75
FIG. 9. SELECTION OF CANDIDATE GENES FOR MALIGNANCY. 76
FIG. 10. REAL-TIME PCR RESULTS OF MMP1 AND KMO IN BENIGN AND MALIGNANT MGT TISSUE. 77
FIG. 11. REAL-TIME PCR RESULTS FOR APOC1 AND KMO IN CANINE MGT TISSUE AT STAGES I/II/III AND STAGES IV/V. 79
FIG. 12. CORRELATION OF KMO EXPRESSION AND SURVIVAL RATE (KAPLAN-MEIER SURVIVAL CURVE) IN DOGS SUFFERING FROM MALIGNANT MGT. 81
FIG. 13. COMPARISON OF IDO EXPRESSION BETWEEN CTVT AND MCTVT. 82
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