Connective Tissue Growth Factor and Its Role in Colorectal Cancer

• Main Authors: Been-Ren Lin, 林本仁
• Other Authors: 郭明良
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/01347343821859577232

博士 === 國立臺灣大學 === 毒理學研究所 === 94 === Colorectal cancer is the third leading cause of cancer death in men and women in Taiwan and the second cause in the United States. The major cause of cancer death in patients with colorectal cancer is local recurrence and distal metastasis after curative surgical treatment, intensive chemotherapy and/or radiotherapy. So, it is important for these patients to find the possible risk factors and underlying molecular mechanism of local recurrence and metastasis. Over the last decade, a new family of structurally related proteins has been described that comprises cysteine-rich 61(CYR61; CCN1), connective tissue growth factor (CTGF; CCN2), nephroblastoma over- expressed (NOV; CCN3), Wnt-induced secreted protein-1 (WISP-1; CCN4), WISP -2 (CCN5), and WISP-3 (CCN6). Collectively, CCN proteins appear to be important regulators of diverse cellular functions including cell cycle progression, division, chemotaxis, differentiation, apoptosis and adhesion and angiogenesis. Because I am a clinical surgeon, the research direction would focus on the clinical meanings and the underlying possible mechanism between CTGF and the major causes of cancer death in patients with CRC ----- distal metastasis and peritoneal seeding. In our data, Stages II and III CRC patients whose tumors displayed high CTGF expression in the immunohistochemical staining had a significantly higher overall survival and a disease-free advantage over CRC patients with a low CTGF expression (P < 0.001). In in vitro invasion assays, alterations in the CTGF level in CRC cell lines modulated their invasive ability with an inverse correlation. In addition, a reduction in the CTGF level of CT-26 cells after stable transfection with antisense CTGF resulted in increased liver metastasis in BALB/c mice. The activity of β-catenin/Tcf signaling pathway in these CTGF-transfected cells was strongly attenuated at the level of transcription. Besides, peritoneal dissemination is an important metastatic mode of intra-abdominal cancers such as gastric, colorectal, and ovarian cancer. At initial diagnosis of colorectal cancer, the peritoneal surface is involved by tumor in 10 to 15% patients. Next to the liver, peritoneal surfaces are the most common sites for cancer recurrence (25% to 35%) after so-called curative resection of colorectal cancer. Because this mode of metastasis severely affects the prognosis of cancer patients (median survival 5-6 months), colorectal peritoneal carcinomatosis has previously been considered a pre-terminal condition suitable for palliative treatment. The steps of peritoneal metastasis include detaching from the primary tumor mass, surviving in the abdominal fluid (ascites) and then adhering to the peritoneum, proliferating in the seeding sites. In order to understand whether CTGF is involved in anoikis and adhesion regulation, we analyzed that several colorectal cancer cell lines which expressed different levels of CTGF undergo apoptosis in anoikis condition and own adhesion ability. In chapter 3, we demonstrated that highly CTGF expressed cells showed increased sensitivity to anoikis and reduced adhesion capacity in vitro. We further demonstrated that CTGF inhibited in vivo tumor growth and peritoneal seeding by animal models. In summary, these studies provide evidences for the tumor metastasis suppressing effect of CTGF in the colorectal adenocarcinoma. Herein, as an invasion blocker, anoikis promoter and adhesion inhibitor that specifically targets cancer cells, CTGF has a unique potential for colorectal adenocarcinoma treatment.