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研究生：	吳銘斌 Wu, Ming-Ping
論文名稱：	第一型血小板活化素在子宮頸癌化過程中扮演抑制腫瘤血管新生及基質反應角色之探討 The roles of thrombospondin-1 in tumor angiogenesis and stroma reaction during cervical carcinogenesis
指導教授：	周振陽 Chou, Cheng-Yang 吳梨華 Wu, Li-Wha
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	163
中文關鍵詞：	基質反應、基底膜、活化型纖維母細胞、肌纖維母細胞、纖維母細胞、子宮頸癌、惡性腫瘤、血管新生作用、第一型血小板活化素、α-平滑肌肌動蛋白
外文關鍵詞：	myofibroblasts, fibroblasts, desmin, cervical neoplasms, α-smooth muscle actin, angiogenesis, activated fibroblasts, stromal reaction, thrombospondin-1
相關次數：	點閱：119 下載：1
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血管新生表現型的出現(血管新生作用開關)，是子宮頸癌化過程是必須的步驟。而血管新生作用開關是由血管新生活化因子與抑制因子兩者相互抗衡的所調控。第一型血小板活化素(thrombospondin, TSP-1)是一種內生性血管新生抑制因子，具有多處大分子特殊結構(domains)及多個受體(receptor)。首先，我們探討在子宮頸鱗狀細胞癌化過程中，第一型血小板活化素的表現與人體子宮頸鱗狀細胞癌及其癌前病變之子宮頸檢體中，在時間與空間上的關聯性；以及其與腫瘤血管新生表現型的關聯性。我們的結果顯示：第一型血小板活化素主要表現於正常子宮頸基底上皮細胞層，如柵欄(我們命名為“第一型血小板活化素柵欄”)一般阻止血管新生的出現。當子宮頸上皮細胞由低階鱗狀上皮內病變(LSIL)進入至高階鱗狀上皮內病變(HSIL)時，此柵欄發生崩解，與血管新生表現型的出現是同時發生的。由這樣的結果我們推測，第一型血小板活化素扮演抑制血管新生作用的調控角色。血管新生作用開始於子宮頸癌化過程中的早期，與增殖異常的上皮組織中發生第一型血小板活化素的下調節有相關。
基質作用(stroma reaction)是指腫瘤癌化過程中，基質由本來抑制轉為幫助上皮細胞成長，形成適合腫瘤成長環境的反應。因為，第一型血小板活化素除了已知抑制血管新生的角色外，同時也扮演著影響其他基質細胞(如纖維母細胞等)的生理作用的角色。所以，我們假設第一型血小板活化素可以經由抑制基質反應，進而達到抑制腫瘤成長。可能的作用機轉是經由抑制纖維母細胞的活性(移動性、侵襲性等生物特性)、以及抑制基質標記表現量。在本研究中我們探討：一：在臨床子宮頸癌及其癌前病變檢體中，檢視第一型血小板活化素的表現量與基質標記表現量之相關性；二：藉由免疫不全鼠(SCID mice)的異體腫瘤移植實驗，探討第一型血小板活化素經由抑制血管新生，以及基質反應而達到抗腫瘤成長的能力；三：探討第一型血小板活化素經由抑制肌纖維母細胞(活化型纖維母細胞)的移動力、侵襲力，達到抑制基質反應的能力。實驗結果顯示：一、在臨床病人檢體的免疫組織化學染色中發現，第一型血小板活化素表現量消失，會同時合併兩種基質標記α-SMA與 desmin過度表現。顯示在子宮頸癌化過程中，第一型血小板活化素與腫瘤基質反應有關連性。二、經由轉染第一型血小板活化素進入子宮頸癌細胞株(SiHa)，建立第一型血小板活化素過度表現的子宮頸癌細胞株(SiHa-TSP-1)。在體外模式中，具有抑制血管新生作用的生理功能。同時在免疫不全鼠的異體腫瘤移植實驗中，第一型血小板活化素過度表現可以經由降低腫瘤血管生長以及減少基質標記α-SMA與desmin的表現，達到抑制腫瘤生長的作用。三、經由轉染建立第一型血小板活化素過度表現的纖維母細胞株(NIH3T3-TSP-1)或是外加純化的第一型血小板活化素至纖維母細胞株(NIH3T3)中，發現第一型血小板活化素並不會直接影響纖維母細胞株(NIH3T3)之α-SMA與desmin蛋白質的表現量。在乙型變型性成長因子(transforming growth factor β, TGF-β)處理的情況下(乙型變型性成長因子，會增加纖維母細胞的活化作用及其細胞分化及α-SMA與 desmin過度表現)，第一型血小板活化素也沒有抑制作用。相對地，第一型血小板活化素會明顯抑制乙型變型性成長因子處理纖維母細胞株(NIH3T3)後所增加纖維細胞移動力，並抑制金屬蛋白酶-2 (MMP-2)的活性及侵襲癌細胞群的能力。至於作用的細胞種類，不論是經由轉染至子宮頸癌細胞株中(SiHa-TSP-1)或是直接外加純化的第一型血小板活化素至子宮頸癌細胞株中時，對NIH3T3細胞株的侵襲癌細胞群的能力沒有影響。相對地，經由轉染至纖維母細胞株(NIH3T3-TSP-1)或是外加純化的第一型血小板活化素至纖維母細胞株(NIH3T3)中，對NIH3T3細胞株的侵襲癌細胞群的能力皆有影響。
綜合這些結果，我們發現第一型血小板活化素具有抑制基質反應功能的新角色。第一型血小板活化素會抑制免疫不全鼠異體移植腫瘤形成模式中基質標記的表現，與臨床病人子宮頸病變檢體基質標記的表現相符合。第一型血小板活化素經由抑制肌纖維母細胞(非宮頸癌細胞)移動力及侵襲能力，達到抑制基質反應並可能回復腫瘤基質反應到正常狀態。在未來，藉由控制腫瘤基質微環境，可能可以提高治療癌症的有效能力。

The acquisition of an angiogenic phenotype (angiogenic switch) is essential for cervical carcinogenesis. The angiogenic switch is balanced by the angiogenic activators and inhibitors. Thrombospondin-1 (TSP-1) is an endogenous angiogenic inhibitor with multiple functional domains and interacting receptors. Our study was firstly aimed to examine the spatial and temporal relationship of TSP-1 expression in patients with squamous cell carcinoma of uterine cervix and its precursor lesions, and to correlate its expression with tumor angiogenesis. Our results indicate the disruption of TSP-1 fence (the expression of TSP-1 in basal epithelia) and the switch to angiogenic phenotype occurred concordantly during the transition from low grade squamous intraepithelial lesion (LSIL) into high grade squamous intraepithelial lesion (HSIL). This concordance suggests that TSP-1 play a role in the regulation of angiogenic switch during cervical carcinogenesis. We conclude that the onset of angiogenesis is an early event in cervical carcinogenesis due, in part, to the down-regulation of TSP-1 by the dysplastic epithelium.
Stroma reaction (also called stromagenesis) is a host reaction of stroma cells that, when induced in cancer, produces a progressive and permissive mesenchymal microenvironment, thereby supporting tumor progress. In addition to the well-known angiogenesis inhibitor, TSP-1 has been shown to exert different biological functions on various stromal cell types, e.g. fibroblasts. Therefore, we hypothesized that TSP-1 may play a role in stroma reaction, characterized by fibroblast activation. We firstly tried to elucidate the correlation between the TSP-1 expression and the overexpression of stroma markers in human cervical lesions; secondly, we tried to elucidate whether TSP-1 can exhibit its anti-tumor effects through the angio-inhibitory effects and the ability to inhibit tumor stroma reaction in SCID mice xenotransplant model; thirdly, we tried to elucidate whether TSP-1 can change the stroma reaction by inhibiting the migration and invasive ability of myofibroblast (activated fibroblasts) from invading tumor cell cluster. Our results revealed: First, immunohistochemistry staining of human clinical specimens showed the disappearance of TSP-1 coincided with the emergence of the overexpression of two stromal markers, α-SMA and desmin, in a stepwise pattern. Second, transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited anti-angiogenic activity in vitro, and resulted in reduced tumor growth in SCID mice, which was accompanied by a decrease in tumor vascularization and lower expressions of α-SMA and desmin than those in the vector controls. Third, transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of α-SMA and desmin which was increased by transforming growth factor β (TGF-β), a potent fibroblast activation and transdifferentiation factor, but significantly inhibited matrix metalloprotease-2 (MMP-2) activity. The increased migration ability and the invasive ability into tumor cluster of TGF-β-treated-NIH3T3 cells were dose-dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells.
Together, these data demonstrate that TSP-1 possesses a novel role to reduce the expression of stromal markers in both human clinical specimens, and an in vivo tumor model. The inhibitory ability of TSP-1 to reverse stroma reaction could be partly attributed to the blockage of myofibroblasts from invading cancer. By targeting the tumor-stroma microenvironment, treatment effectiveness could be increased.

Thesis Contents 
中文摘要	1
Abstract	3
致謝Acknowledgement	5
Thesis Contents	9
Table list	14
Figure list	15
Abbreviations	16
Chapter 1 Background	17
1 TUMOR ANGIOGENESIS OVERVIEW.	17
1.1 Tumor growth is angiogenesis dependent.	17
1.2 Angiogenic activators and inhibitors are produced by tumor and host cells, respectively	18
1.3 Angiogenic switch depends on the balance of angiogenic activators and inhibitors	18
1.4 The angiogenic process relies on a complex tumor-host interaction	20
2 ANGIOGENESIS IN CERVICAL CARCINOGENESIS	21
2.1 Angiogenesis plays an important role in cervical carcinogenesis.	21
2.2 Timing of angiogenic switch in cervical carcinogenesis	22
3 THROMBOSPODIN (TSP)	23
3.1 Gene function of thrombospondin 1 (TSP-1)	23
3.2 TSP-1 is a matricellular protein with multiple receptors and diverse functions	25
3.3 TSP-1 and clinical cancer prognosis	28
4 MATRIX METALLOPROTEASES (MMPS) AND TUMOR PROGRESSION	28
4.1 MMPs in angiogenesis and tumor progression	28
4.2 TSP-1 can modulate the matrix degradation by changing the MMPs	30
5 STROMA REACTION AND FIBROBLAST ACTIVATION DURING CARCINOGENESIS	31
5.1 The invasion process of cancer cells is associated with stroma reaction	31
5.2 Stroma reaction is characterized by the fibroblast activation	33
Chapter 2 Materials and Methods	36
1 MATERIALS AND METHODS IN CHAPTER 3	36
1.1 Sample selections	36
1.2 Immunohistochemical (IHC) staining	36
1.3 Microvessel density (MVD) in different cervical lesions	37
1.4 TSP-1 expression in different cervical lesions	37
1.5 Statistical analysis	38
2 MATERIAL AND METHODS IN CHAPTER 4	38
2.1 Sample selections	38
2.2 Immunohistochemical staining and scoring system	39
2.3 Cell cultures and transfection	40
2.4 Immunoblotting	41
2.5 Matrigel angiogenesis assay	41
2.6 Animal models	41
2.7 Fibroblast activation	42
2.8 Cell migration assay and MMPs zymography	42
2.9 Matrigel multi-cellular co-culture invasion assay of activated fibroblasts	43
2.10 Statistical analysis	43
Chapter 3 TSP-1 acts as a fence to inhibit angiogenesis that occurs during cervical carcinogenesis	45
1 SUMMARY	45
2 INTRODUCTION	47
3 RESULTS	48
3.1 MVD during cervical carcinogenesis	48
3.2 TSP-1 expression during cervical carcinogenesis	49
3.3 Association of MVD and TSP-1	49
4 DISCUSSION	51
Chapter 4 A novel role of TSP-1 in cervical carcinogenesis: Inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer	55
1 SUMMARY	55
2 INTRODUCTION	57
3 SPECIFIC AIMS AND STRATEGIES:	59
4 RESULTS	63
4.1 The downregulation of TSP-1 coincides with the upregulation of stroma markers during cervical carcinogenesis	63
4.2 TSP-1 inhibits angiogenesis, tumor development and SCC-induced stromal reaction in vivo	63
4.3 TSP-1 does not downregulate α-SMA and desmin expression but inhibits MMP-2 activity	64
4.4 TSP-1 inhibits the migration of untreated and TGF-β treated NIH3T3 cells	65
4.5 TSP-1 inhibits activated fibroblasts from invading tumor cell cluster	66
5 DISCUSSION	68
Chapter 5 Discussion	73
1 HOW DOES TSP-1 REGULATE ANGIOGENESIS IN CERVICAL NEOPLASM	73
1.1 The roles of angiogenic activators in cervical neoplasm	73
1.2 TSP-1 may play a comparative role to VEGF	73
1.3 TSP-1 specifically induces endothelial cell apoptosis	75
1.4 TSP-1 acts as “an angiogenic fence” during cervical carcinogenesis	76
1.5 TSP-1 may influence angiogenesis by changing the ECM	77
1.6 Do TSP-1 or other angiogenic inhibitors play a physiologic gatekeeper role in cancer prevention	78
2 MVD AND OTHER MODALITIES IN EVALUATION OF ANGIOGENESIS STATUS	79
2.1 The usefulness of MVD in assessing angiogenesis	79
2.2 MVD used as a prognostic indicator in cervical neoplasm	80
2.3 MVD may not be an indicator of anti-angiogenic treatment efficacy	81
2.4 Other models for angiogenesis study	82
3 ANTI-ANGIOGENIC THERAPY OFFERS A PARADIGM SHIFT FOR ANTI-CANCER THERAPY	85
3.1 Tumor vasculature as a therapeutic target	85
3.2 Low-dose ‘metronic’ chemotherapy is anti-angiogenic	87
3.3 TSP-1 plays the angio-inhibitory roles via a mediator of the low-dose metronomic chemotherapy, in addition to direct endothelial targeting	88
4 HOST STROMA IS AN ACTIVE PARTICIPANT DURING TUMOR PROGRESSION	89
4.1 Myofibroblasts in host stroma stimulate cancer invasion	89
4.2 Myofibroblasts themselves are invasive	90
5 FACTORS ACTING ON FIBROBLAST TRANS-DIFFERENTIATION AND ACTIVATION	92
5.1 Factors that enhance fibroblasts activation and transdifferentiation	92
5.2 Factors that inhibit fibroblasts activation and transdifferentiation	95
Chapter 6 Conclusion and implications	98
1 TUMOR ANGIOGENESIS CAN BE USED AS A THERAPEUTIC TARGET	98
2 STROMA REACTION CAN BE USED AS A THERAPEUTIC TARGET	99
3 CONCLUSION	100
Tables	129
Figures	133
Appendix- supplementary articles and manuscripts	146
S.1 (Review) Angiogenesis, thrombospondin-1, and cervical carcinogenesis	146
S.2 Tumor/normal counterpart microvessel density ratio has a better correlation with clinicopathologic parameters in endometrial carcinoma than tumor microvessel density alone	147
S.3 TSP-1/ApoE and CD47/ApoE doubly null mice are protected from neointima formation in response to carotid injury but not from atherosclerosis	149
S.4 Her2/neu overexpression is correlated with TSP-1-related angiogenesis and TSP-1-unrelated lymphangiogenesis in breast cancer	151
Publications during 2000-2008	153
I. TSP-1 IN TUMOR ANGIOGENESIS AND STROMA REACTION	153
II. UROGYNECOLOGY AND MINIMALLY INVASIVE GYNECOLOGY	153
III. EDUCATIONAL ARTICLES	155
簡歷	157
Curriculum Vitae	159
                                    

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