臺灣博碩士論文加值系統

壹、背景

肝癌是一種常見的惡性腫瘤，更是台灣主要致死癌症之一。肝癌是一種富含血管的腫瘤，主要的血流供應來自肝動脈，肝癌具有血管侵犯的特性，它可以經由血液轉移到肝臟或身體的其他部位。目前治療肝癌的方法中，以腫瘤切除及肝臟移植最有可能達成根治的目的，然而肝癌治療後的復發率偏高，嚴重影響肝癌患者的長期預後，因此如何減少肝癌的復發就成為治療上一個重要的課題，要達成這個目的就必須發展能夠預測個別肝癌病患預後的方法。

傳統上我們運用許多臨床病理因素如血管侵犯(VI)、血清中胎兒蛋白濃度、腫瘤大小和數量來預測肝癌病患接受腫瘤切除以後腫瘤復發與存活的狀況，然而這些因素並無法正確預測所有肝癌病患手術後的結果，而且它們無法解釋肝癌生長與轉移的機制；若加入分子生物因素的分析將有助於改善傳統預測方法的不足。

血管新生是許多惡性腫瘤出現、生長、發展及侵犯重要的過程，近年來的研究也顯示肝癌的血管新生在肝癌的轉移與復發扮演重要的角色，臨床上與肝癌血管新生相關的因子或訊息傳導路徑都有可能成為將來診斷或治療肝癌復發的一個重要標的。然而肝癌血管新生是一個複雜的過程，許多參與其中的因子未被發現；而單一血管新生相關因子往往無法適用在所有的肝癌病例。本論文將嘗試解決部分的問題，並為將來肝癌血管新生的研究提供一些新的想法與方向。

許多血管新生促進因子和抗血管新生因子都被證明與調控肝癌的血管新生有關，有一些血管新生相關因子在肝癌組織中可能具有特殊的生物功能和臨床意義，因此它們可能成為肝癌診斷與治療的重要標的。在這些因子中血管內皮生長因子(VEGF)的相關研究最多，VEGF和它的接受體Flt-1在肝癌組織中有高度表現，其表現量和MVD、腫瘤的血管侵犯和轉移有關，也曾有報告指出VEGF的高度表現可能造成腫瘤的早期復發。然而在其他研究中VEGF與肝癌臨床病理表現的關聯性卻不一定存在，甚至有些報告呈現相反的結果，因此我們認為單靠VEGF及其相關訊息傳導路徑並無法完全解釋肝癌的血管新生，不同原因引發的肝癌；發展至不同階段的肝癌可能受到不同血管新生相關因子透過不同的機制來調控其血管新生。除了現在已知的血管新生因子外，可能還有其他因子在肝癌的血管新生過程中扮演重要的角色。

胎盤生長因子(PlGF)是一個dimeric glycoprotein，它的構造與功能都和VEGF相似，除了是胎盤生長過程中重要的血管新生因子，也是成年人體內許多病理性血管新生過程中重要的促進因子，最近的研究發現PGlF促進胃癌、大腸直腸癌、腎癌的血管新生，而且影響這些癌症病患的預後，然而PlGF在肝癌中的表現以及它與肝癌預後的關聯目前並不清楚，因此在本論文中的第一部分，我們以qRT-PCR的方法分析肝癌組織內VEGF家族包括VEGF-A、VEGF-C和PlGF的表現量與肝癌臨床病理背景的關係，並評估個別血管新生促進因子對肝癌切除後復發的影響。

過去的研究證明血管侵犯是造成肝癌切除後早期復發的重要因素，因此許多抗血管新生的藥物都開始被嘗試用來預防肝癌的復發。然而這些藥物的效果目前都還不確定，如果能夠知道肝癌發生血管侵犯的分子標記，將有助於預測病患對這些治療的反應。

基於本論文第一部分研究的發現，我們相信肝癌的血管侵犯絕無法單純的以一個血管新生因子來解釋。近年來微陣列分析的發展提供我們一個很好的研究平台，可以同時分析上萬個基因在肝癌組織中的表現，雖然過去已有許多研究分析不同種類肝癌的基因表現，但是卻鮮有人分析這些基因組合對肝癌預後的影響。本論文中的第二部份就利用這樣的實驗方法來分析有血管侵犯的肝癌和沒有血管侵犯的肝癌組織中基因表現的不同，根據所找到的基因組合去建立一個預測肝癌血管侵犯的方法，希望運用這樣的方法我們可以有效預測另一群與訓練組無關之肝癌病患的腫瘤早期復發。希望這樣的預測方法，將來可以運用來預測肝癌的預後並且引導治療的策略，減少肝癌切除後腫瘤復發的機率並延長病患的存活。

貳、研究方法與材料

本論文的第一部分評估PlGF在肝癌組織中的表現量與病患接受肝癌切除後腫瘤復發的關聯，此研究以qRT-PCR的方法測量71位病患肝癌組織中PlGF、VEGF-A、VEGF-C mRNA的表現量；以ELISA的方法檢測PlGF蛋白質分子在肝癌組織中的濃度；以CD34染色來評估肝癌組織中的微血管密度。然後分析這三個血管新生促進因子與肝癌各種臨床病理特徵的關係；以中位數為分組標準，比較各組之間腫瘤切除後早期復發的情況是否有明顯差異；分析這三個分子的表現量彼此間是否有關聯；並且觀察這幾個血管新生促進因子與肝癌微血管密度的關係。

論文的第二部份以18位接受完整腫瘤切除的肝癌病患作為建立預測模組的訓練組，以cDNA microarray的實驗取得這些病患大量的基因表現資料，然後以腫瘤是否有血管侵犯為條件做分群的分析(supervised clustering analysis)，發現十四個表現量有差異的基因可以成功地將有血管侵犯與沒有血管侵犯的肝癌完全分開。根據這十四個基因，我們以k-Nearest Neighbor(KNN)的方法建立預測模型，並以此模型預測35位測試組病患腫瘤復發的情形。

參、結果

本論文的研究結果發現在肝癌組織中PlGF也是一個重要的血管新生因子，在大於五公分的肝癌組織中，PlGF表現量和MVD成正相關，同時PlGF表現量高的病患腫瘤的復發率也跟著偏高，這樣對腫瘤復發率的影響在AJCC第二期及第三期的腫瘤尤其明顯，這表示PlGF在早期腫瘤的血管新生可能比較不具重要性，但是當腫瘤發展至第二期第三期時，其它血管新生因子的重要性下降，而PlGF可能就成為舉足輕重的血管新生因子，腫瘤組織中是否表現PlGF就成了影響此時期肝癌預後的重要因素。

在本論文第二部份的研究中我們成功地篩選出14個與肝癌血管侵犯有關的基因，以此建立的預測模組也成功地預測了肝癌切除後腫瘤復發的情況，即使在AJCC第一期的肝癌病患，這個預測模組依然有效，也就是肝癌病患接受手術切除後，如果肝癌組織分析預測屬於會發生血管侵犯或高復發率的病患，應當接受手術後的附加治療以減少復發的機會，而預測屬於不會發生血管侵犯或低復發率的病患只要定期追蹤即可，避免附加治療藥物的副作用。不僅如此，所篩選出的基因若經過細胞及動物模型的驗證，了解它們在肝癌產生、發展及轉移中所扮演的角色，也可能成為將來肝癌治療的可能標的。

肆、結論

PlGF在肝癌組織中的表現量與肝癌早期復發有關，但是與其他臨床病理因素及VEGF表現量無關，這意味著PlGF可以作為肝癌術後獨立的預後因子，尤其是在晚期的肝癌，它可能可以用來引導肝癌術後的附加治療。這個研究的發現支持了我們對於不同期別的腫瘤可能有不同血管新生機制的假說。也使我們進一步使用一次可以產生多數基因表現資料的平台來進行後續的研究。

在第二部份的研究中，與肝癌血管侵犯相關的14個基因組合可以比傳統分期方法更準確預測肝癌復發的情形，這代表以多數分子生物標記可以作為預測肝癌復發的參考，讓未來在選擇肝癌術後的附加治療上有所依循，而且它更能提供有關肝癌生長和轉移機制的資訊，這讓我們對肝癌複雜的致病機轉能夠有多一些的了解。

Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. It is a hypervascular tumor mainly supplied by hepatic arteries and characterized by a propensity for vascular invasion. HCC is associated with a high metastatic potential. Early post-operative recurrence is a common phenomenon following resection of HCC. To achieve a better outcome after HCC resection, choosing optimal peri-operative management beneficial for each individual patient is of utmost importance. Of course, this depends on the development of an effective method that can predict clinical outcome for an individual patient.

Conventionally, clinical factors, such as vascular invasion (VI), serum α-FP level (AFP), tumor size and tumor number, are used as the possible predictive factors for clinical outcomes after HCC resection; However, they cannot accurately predict the outcome of all HCC patients. A complementary way is to analyze molecular markers for their prognostic significance with reference to cancer recurrence.

Angiogenesis is now recognized as playing a pivotal role in hepatocarcinogenesis and regarded as one of the marker for invasiveness and metastasis in HCC. Tumor angiogenesis is regulated by a variety of pro- and anti-angiogenic factors. Among them, vascular endothelial growth factor(VEGF) has been studied most extensively and is considered to be the most important proangiogenic factor in HCC. The correlation between VEGF expression and the prognosis of HCC, however, remains unclear. Li et al. (1998) and Ng et al. (2001) both reported that expression of VEGF is related to invasion and metastasis of HCC. Yamaguchi et al. (1998), however, found that VEGF expression was lower in advanced HCC with increased tumor vasculatures. These observations suggest that other angiogenic factors may also contribute to angiogenesis stimulation in HCC.

Placenta growth factor (PlGF) is a dimeric glycoprotein, structurally and functionally related to VEGF. PlGF appears to be crucial for pathological angiogenesis in adults and is not produced by the majority of normal human tissues. A prognostic implication of tumor PlGF expression level independent of conventional pathologic prognosticators has been demonstrated in a variety of cancers. To date, PlGF expression in HCC and any correlation between PlGF and prognosis remains unknown. Therefore, in the first part of this thesis, we evaluated the expression of PlGF in post-operative HCC patients following primary resection of the liver to determine if a correlation between PlGF expression and early postoperative recurrence of HCC existed.

Previous reports provided epidemiological evidence that VI has been involved in early intra-hepatic recurrence after hepatectomy for HCC. Treatments focusing on VI such as anti-angiogenesis of HCC are under development. However, the survival advantages of these regimens are uncertain. Identifying the gene expression patterns in HCC specimens with and without VI might help to predict response to these anti-VI treatments.

VI of HCC has been reported to be associated with molecules of various biological functions. Genome-wide gene expression analysis by microarray offers a systematic approach to unfold comprehensive information about the transcription profile of HCC. Previous studies have used microarrays to address the changes in gene expression of HCC. In the second part of this thesis we aimed at seeking a signature associated with VI from the genome-wide expression profile of HCC as generated from microarray study. With this signature, we tried to predict early recurrence after HCC resection. Hopefully, this will provide information for each individual patient to guide the implementation of adjuvant therapy. Thus, early recurrence after HCC resection can be reduced and survival prolonged.

Materials and methods

Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma

In the first part of this thesis we evaluate the relationship between the expression of PlGF in tumor tissue and clinical outcomes in 71 HCC patients who underwent primary liver resection for HCC at the National Taiwan University Hospital. Tumor PlGF and vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA were analyzed using qRT-PCR. Concentrations of PlGF in tumor tissues were quantified using enzyme linked immunoabsorbant assay, and CD34 was used to evaluation of intratumorous microvessel density. The clinical and pathologic characteristics of the patients in relation to PlGF, VEGF-A and VEGF-C were compared. Overall, cumulative recurrence free survival rates were obtained using the Kaplan–Meier method. The differences in recurrence free survival between the groups were compared using the log-rank test. To evaluate the prognostic influence of PlGF, VEGF-A and VEGF-C in the entire cohort and in subgroups of patients stratified by AJCC stage, the median value in each group was used as the cutoff value for comparison. Pearson Product Moment Correlation was used to show the correlation between PlGF, VEGF levels and degree of vascularization in HCC.

A gene expression profile for vascular invasion can predict the recurrence after resection of hepatocellular carcinoma: A microarray approach

Eighteen patients receiving complete HCC resection were included as a “training group”. Genome-wide gene expression profile was obtained for each tumor using a microarray technique. Datasets were subjected to clustering analysis supervised by the presence or absence of VI to obtain 14 discriminative genes. We then applied those genes to execute pattern recognition using the k-Nearest Neighbor (KNN) classification method, and the best model for this VI gene signature to predict recurrence-free survival in the training group was obtained. The resulting model was then tested in an independent “test group” of 35 patients.

Results

Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma

Our results demonstrated that no significant differences were identified when evaluating PlGF expression according to the clinicopathologic parameters, but PlGF expression levels correlate significantly with the degree of vascularization in advanced HCC. Patients with PlGF expression levels higher than median tended to have early recurrence compared to patients with PlGF expression lower than median (P = .031). In patients with AJCC stage Ⅱ-Ⅲ disease, this difference was even more significant (P =.002). In contrast, VEGF-A and VEGF-C could not predict early recurrence-free survival.

A gene expression profile for vascular invasion can predict the recurrence after resection of hepatocellular carcinoma: A microarray approach

In the second part of this thesis, a 14-gene profile was extracted which could accurately separate ten patients with VI and eight patients without VI in the “training group”. The expression levels of four human malignancy related genes obtained from cDNA microarray were confirmed by qRT-PCR. Significant correlation was found in 3 of them. In the “test group”, significant difference in disease-free survival was found between patients predicted to have and not to have recurrence (P = .02823). In patients with stage_I disease, this model can also predict outcomes (P = .000205).

Conclusions

Since PlGF expression correlated with early recurrence of HCC, and is not correlated with any clinicopathologic parameters or VEGF expression level. PlGF may be an important prognostic indicator in HCC, especially in advanced HCC. Therefor, PlGF may be used as a postoperative prognostic indicator and may guide selection and administration of adjuvant therapy in HCC patients following the surgical resection of HCC. This study provides evidence that various angiogenesis related factors play different roles in the metastasis of HCC with different backgrounds and stages. High throughput technologies, especially -omic technologies may help to unravel many complex mechanisms associated with the tumor biology of different HCCs. Biomarkers developed through these technique will immense potentials in HCC screening, diagnosis, prognosis and therapeutic targets.

For this reason, in the second part of this thesis we showed that using the 14-gene expression profile extracted from microarrays based on the presence of VI can not only discriminate the recurrence free survival of 35 independent patients as a whole but was also helpful in separating AJCC stage_I patients into groups with different disease-free survival. This implies that negative vessel invasion, as revealed by pathology examination, cannot precisely reflect the behavior of an early HCC. The patients classified as VI positive or at high risk of recurrence should be followed up more closely for recurrence, and they may be the subjects who will benefit from the future effective adjuvant treatment now under development. Also, this strategy for stratification of HCC patients after surgical resection might provide an avenue to more rational clinical trials for HCC post-operative adjuvant therapy in the future. Hopefully, this multigene profile will offer further insights into the extremely complex molecular process of cancer recurrence.

一. 中文摘要 1
二. 緒論 5
三. 研究方法與材料 28
四. 結果 39
五. 討論 45
六. 展望 66
七. 論文英文簡述 78
八. 參考文獻 83
九. 圖表 132
十. 附錄 148

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