臺灣博碩士論文加值系統

前列腺癌 (Prostate cancer, PCa) 經常發生骨轉移，其轉移時導致的併發症為骨折、骨疼痛和高血鈣症；癌細胞與骨頭之間的聯繫是產生惡性骨轉移最重要的原因，所以有必要進一步地了解癌細胞與骨頭之間聯繫的相關機制，在我們先前的研究中發現Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) 機制有參與前列腺癌與骨頭之間的聯繫，並導致人類前列腺癌細胞的移動能力增加。
本論文中，我們發現 WISP-1 可以增加成骨細胞表現骨型態發生蛋白-2 (Bone morphogenetic protein-2, BMP2)、骨型態發生蛋白-4 (Bone morphogenetic protein-4, BMP4) 和骨橋蛋白 (Osteopontin, OPN)，我們也發現 WISP-1 可以抑制核因子 kappa-B 配體受體致活劑 (Receptor activator of nuclear factor kappa-B ligand, RANKL) 依賴的蝕骨細胞生成；此外，成骨細胞所分泌之 WISP-1 可以促進人類前列腺癌表現 VCAM-1，而癌細胞表現的 VCAM-1 可以有利於其貼附至成骨細胞上；此外， 前列腺癌細胞表現的內皮素-1 (Endothelin-1, ET-1) 亦受成骨細胞所分泌之 WISP-1 所調控，並且其表現的內皮素-1反而能透過絲裂原活化蛋白激酶 (Mitogen-activated protein kinase, MAPK) 路徑來增加成骨細胞表現 integrin α4β1 利用前列腺癌細胞前處理 VCAM-1 抗體亦或是成骨細胞前處理 integrin α4β1 抗體，皆能有效地抑制前列腺癌細胞貼附到成骨細胞上，這個實驗結果表示 integrin α4β1 為一個配體能抓住具有 VCAM-1 表現的前列腺癌細胞。
結論為成骨細胞所分泌之 WISP-1 可以透過 VCAM-1/integrin α4β1 機制來幫助人類前列腺癌細胞貼附到成骨細胞上，顯示成骨細胞所分泌之 WISP-1 具有潛力來做為研發抑制癌細胞與骨頭之間聯繫的目標蛋白。

Bone metastasis is frequent occurred in prostate cancer (PCa), and is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor-bone interaction contributes to human PCa cell motility.
In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited Receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin α4β1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin α4β1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin α4β1 serves as a ligand that captures VCAM-1+ metastatic tumor cells adhering to osteoblasts.
Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin α4β1 system. Osteoblast-derived WISP-1 is a promising target for the prevention and inhibition of PCa-bone interaction.

Contents
中文摘要……………………………………………………………………….………i
Abstract…………...………………………………………………..………………....ii
Contents…………………………………………...……………….……..….………iii
Figure Contents………………….………………………………...….…….………..v
Table Contents………………………....……………………………….…..………..vi
Abbreviations……………..……………………………………………..….……….vii
Chapter 1. Background and literature reviews…………….………...……...……..1
1.1. Background of prostate cancer…………………………………………………2
1.1.1. Causes, risk factors, and prevention of prostate cancer………………...2
1.1.2. Screening, diagnosis and staging of prostate cancer……………………4
1.1.3. Treatment for prostate cancer…………………………...….…………...7
1.2. Prostate cancer bone metastasis………………………………………………16
1.2.1. Cancer metastasis…………………………………………….………..16
1.2.2. The role of prostate cancer osteoblastic metastasis………….….……..16
1.3. Contribution of VCAM-1/integrin α4β1 binding in cancer……….….………22
1.3.1. Background of VCAM-1 and integrin α4β1……………….………….22
1.3.2 .The role of VCAM-1/integrin α4β1 binding system………….……….23
1.4. The role of Wnt-induced secreted protein-1 (WISP-1) in cancer…………….25
1.4.1 Background of WISP-1……………………………………..………….25
1.4.2. WISP-1 is involved in regulating many types of cancers……………..25
1.5. Specific aims…………………………………………………….……………28
Chapter 2. Materials and Methods……………….………...……………………...29
2.1. Materials………………………………………………………………………30
2.2. Cell culture……………………………………………………………………30
2.3. Collection of conditioned medium……………………………………………31
2.4. Transient transfections…………………………………………………..……31
2.5. Western blot analysis…………………………………………………………31
2.6. Immunohistochemistry (IHC)……………………… …………………….….32
2.7. Quantitative real-time polymerase chain reaction (qRT-PCR)………..……...32
2.8. Cell adhesion assay……………………………………………………….…..33
2.9. Osteoclast differentiation………………………………………………….….34
2.10. Measurement of mineralized nodule formation……………………………..34
2.11. Meta-analyses of microarray datasets from The Cancer Genome Atlas
(TCGA) database………………….………………………………..……..….35
2.12. Statistics………………………………………………………………….….35
Chapter 3. Results and Discussions………………….……………………….……36
3.1. WISP-1, a key regulator of bone formation…………………….………….…37
3.2. Prostate cancer cells adherent to osteoblasts via VCAM-1…………………38
3.3. Clinical significance of VCAM-1 expression in patients with prostate
cancer…………………….………………..…………………………………39
3.4. The prostate cancer-osteoblast interaction is regulated via VCAM-1
/integrin α4β1 binding……………………………………………………....39
3.5. ET-1 regulates integrin α4β1 expression in osteoblasts via the MAPK signaling pathway………………………………………….…………………40
3.6. Discussion……………………………………………………………...……..42
Chapter 4. Conclusions…………………….………...……………………………..73
Chapter 5. References…………………..…………..………………………………75
Chapter 6. Publications……………..………….………..……………….…………85
6.1. Journals accepted…………………………………………………………...…86
6.2. Conferences……………………………………………………….….……….88
6.3. Honors…………………………………………………………………...……88


Figure Contents
Appended Figure 1. The situation of prostate gland…………………..……………10
Appended Figure 2. The metastatic cascade……………………………..…………19
Appended Figure 3. VCAM-1 promotes lung colonization of breast cancer………24
Appended Figure 4. Molecular interactions through modular domains of CCN
proteins…………………………………...……………….....27

Figure 1. WISP-1 enhances levels of osteogenic markers and induces bone
formation………………………………………..…………………………45
Figure 2. WISP-1 inhibits RANKL-dependent osteoclastogenesis………………….49
Figure 3. VCAM-1-positive prostate cancer cells adhere to osteoblasts………….…53
Figure 4. The clinical importance of VCAM-1 in prostate cancer patients………....59
Figure 5. Integrin α4β1-positive osteoblasts promote prostate cancer cell adhesion..62
Figure 6. ET-1 promotes integrin α4β1 expression in osteoblasts through the
MAPK pathway…………………………………………………………....66
Figure 7. Schema of osteoblast-derived WISP-1 promotion of PCa cell adhesion to bone……………………………..…………………………………………72
 
Table Contents
Appended Table 1. Prostate cancer age statistics……………………...……………11
Appended Table 2. Inherited gene mutation is associated with prostate cancer…....12
Appended Table 3. Benign causes for changed PSA expression…………….……..13
Appended Table 4. The prostate cancer staging is described by TNM system….…14
Appended Table 5. Acknowledgment of prostate cancer Gleason score……….…..15
Appended Table 6. Vicious cycle in metastatic bone cancer…………………….....20
Appended Table 7. Prostate cancer produces factors to induce bone formation…...21

Table 1. Correlation of VCAM-1 expression with clinicopathological features of prostate cancer…………………………………...…………...……………..60

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