Abstract
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.