大腸直腸癌的發生在台灣近年來有急遽之上升，但是其五年存活率在這三十年來則未見有大幅度之進步。手術切除是處理大腸直腸癌之基本原則，但是術後是否要搭配化療治療，在第二期之大腸直腸癌之病人而言，目前仍是莫衷一是。主要原因就是因為現在真正被證實有預估預後好壞之獨立因子，最重要的依據是癌症期數。倘若如果可以找出更多其他有效之預後因子，加以利用評估手術後之病人，以選擇適合接受化療或放射治療之病例，應可增加大腸直腸癌病人之存活率。
C反應蛋白是由肝細胞在對發炎時進行反應所製造出來的急性相蛋白，在過去曾有人報告它是一種癌症預後預測因子。而在本研究中發現有三分之一大腸直腸癌病人其C反應蛋白質會明顯上升，而且和腫瘤大小、淋巴結或肝轉移有明顯相關。有較高之C反應蛋白之病人，其預後較差。但是它卻不是可預測病人存活率之預後因子。而C反應蛋白之產生係經由細胞激素介白質-1、介白質-6及腫瘤壞死因子之調控。因此本研究另外對大腸直腸癌病人常見之不同細胞激素加以研究，發現大腸直腸癌病人之介白質-6及介白質-8確實是比正常人高。而介白質-6及介白質-2升高之程度又和腫瘤進展之期數有相關性。但只有介白質-6之高低和病人之存活率有所相關。所以我們再針對血清介白質-6之產生與大腸直腸癌之病人之相關性做一分析研究，結果是血清中介白質-6之高低的確調控著CRP之產生，而較高之介白質-6也和腫瘤大小、肝臟轉移和腫瘤發生之期別有著顯著之關連性，但利用多變數回歸分析法則發現血清中之介白質-6本身卻非有效判斷預後之獨立因子。但因血清中介白質-6有可能由身體其他之單核球、上皮細胞、吞噬細胞、纖維母細胞所產生，分析起來較複雜。而由癌上皮組織中產生之介白質-6或許更能表示癌症本身之介白質-6之角色，因此我們再以免疫組織染色之方式檢測癌組織內介白質-6之表現程度，結果發現癌組織內介白質-6和病人術前癌胚抗原高低有關，另外與腫瘤分期及血管受癌之侵襲有關。經過統計後，介白質-6在組織中之表現可以被認定是一有效之預後因子。為探討為何癌組織中介白質-6對大腸直腸癌之表現扮演著何種角色。我們利用大腸癌細胞株(SW480)做細胞黏連，菌落形成、趨化性及侵襲性等之實驗。發現介白質-6對細胞之增生影響不大，但對細胞之菌落形成、黏連性、趨化性及侵襲性具有促進之能力。但是當介白質-6之量太高時，反而會抑制癌侵襲之能力，表示介白質-6若在體內作用時應有自動迴饋抑制癌細胞之功能。至於細胞激素在體內促進大腸直腸癌之進展事實上也和血管新生作用有關，介白質-6與血管內皮細胞生長因子之關係十分密切。但另一調控血管新生作用因子，血管生成素-1，2(Ang-1,2)也十分重要。根據我們的研究，發現腫瘤有無過度表現Ang和預後有關。Ang-1,2之過度表現均會引導微小血管密度值上升。而Ang-2和淋巴結轉移、靜脈癌侵襲、術前高CEA有關。但只有Ang-2表現與否和病人之存活有關，而且也是一有效之預後預後因子。
經由以上之研究我們可以找出大腸直腸癌之有效預後預測因子是癌組織內介白質-6及血管生成素-2，其他如血清內C反應蛋白及介白質-6之表現則未如預期無法擔任有效之預後因子，而介白質-6會促進癌細胞之菌落形成、黏連性、趨化性及侵襲性，且具有一迴饋抑制之機轉。這因子在因此大腸直腸癌之進展扮演了一重要角色，而影響了存活率。未來可能應可以利用介白質-6之特性來有效治療及追蹤大腸直腸癌之病人。

Colorectal carcinoma (CRC) represents a disease with a high incidence and mortality in Traiwan. There is no doubt that the only for cure is in patients who are candidates for radical resection of primary tumors and isolated metastatic disease. However, the long-term survival after surgical intervention has remained unchanged during the past 30 years. At present, anatomical TNM staging system of CRC is regarded as the most important prognostic factor to predict the survival of CRC. Systemic chemotherapy for CRC is routinely given to the patients in stage III or IV of CRC to decrease the recurrent rate and metastasis. However, in the case of stage II of CRC, considerable controversy exists regarding the relative benefit of treament. Some analyses had suggested that adjuvant chemotherapy was helpful; others had not. The conflicting results are in part related to the result of residual occult viable tumor cells whose bulk is below the threshold of detection of current radiological, laboratory or pathological intervention, which have metastasized prior to primary tumor resection. To identify the patients with high risk of recurrence and metastasis needs another independent prognostic factors except staging classification. New biological or molecular factors, which affect the long-term survival of patients of CRC, are classified as probable prognostic factors. Long-term survival might be improved by evaluating these factors to select proper cases for further chemotherapy.
C-reactive protein (CRP) is synthesized in hepatocyte. It belongs to the family of acute-phase protein, the concentration of which changes in response to inflammatory process. The serum level of CRP is frequently elevated in cancer patients and was found to be an indicator of the malignant potential of tumor as well as a predictor of the prognosis. In our study, one-third of patients had increased CRP levels and this was associated with larger tumor size, lymph node or liver metastasis and advanced cancerous stage. High CRP levels were related to the poor survival of CRC. However, multivariate analysis indicated that CRP was not an independent prognostic to predict survival. The changes of CRP are upregulated by cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF). So we investigated whether cytokines play a role in the development or progression of CRC. In this study, we demonstrated that levels of IL-6 and IL-8 were significantly higher in patients than in controls. The serum concentrations of IL-2 and IL-6 were correlated with cancerous staging. Only the levels of IL-6 were found to be associated with patient survival. In addition, high levels of IL-6 (＞12pg/ml) were correlated with large tumor size, elevated serum CRP levels and liver metastases. Although serum IL-6 correlated with survive, it still was not an independent prognostic indicator. Because serum IL-6 is produced by several kinds of cells, such as monocytes, macrophages, fibroblast and tumor cells, we designed another experiment to evaluate the protein expression in the cancerous cells of CRC. By immunohistochemical examination, the actual role of IL-6 expressed in cancerous tissues could be demonstrated. The results showed tissue expressions of IL-6 associated with higher preoperative CEA level, tumor staging and venous invasion by cancer. Futhermore, tissue expression of IL-6 correlated with the survival of patients with CRC, and could be regarded as independent prognostic factor by multivariate analyses. Thereafter, different concentrations of IL-6 were added to cancerous cell lines to clarify the changes of biological behaviors of CRC. IL-6 did not affect the proliferation of the colon cancer significantly. It increased the abilities of clonogenic growth, adhesion, chemotaxis and invasion in CRC, especially in the dosage of 10~50ng/ml. But IL-6 proceeded to a reciprocal inhibition of these potentials after the dosage increasing to 100ng/ml, which represented an autocrine-like feedback effect. Cytokines could promote tumor angiogenesis and IL-6 had been reported to be associated with the functions of vascular endothelial growth factor. So, angiopoietins (Angs) were also investigated in this thesis. We found both Ang-1 and Ang-2 were associated with increasing of microvascular density. However, only Ang-2 was correlated with lymph node metastasis, venous invasion by cancer and elevation of preoperative CEA levels. The overexpression of Ang-2 was associated with the poor survival of patients with CRC and could be a useful prognostic factor to predict patient survival.
According to our results, tissue expressions of IL-6 and Ang-2 were recognized as independent prognostic factors. Serum CRP and IL-6 were not effective prognostic factors. Elevation of IL-6 could enhance clonogenic growth, adhesion, chemotaxis and invasion abilities of CRC and reciprocal inhibitions were also demonstrated. IL-6 played an important role in the progression of CRC and it could be a useful factor in the treatment and follow-up of the patients with CRC.

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