Do-Youn Park

BACKGROUND: Previous studies have shown that TIMP-2 overexpression is a useful therapeutic tool for inhibiting tumor growth and invasion in animals. However, it has not been reported whether genetic manipulation for TIMP-2 overexpression can induce an inhibitory effect on spontaneous metastasis from the primary tumor site to other organs such as lungs or lymph nodes in an animal model. METHODS: The present studies describe the effects of retrovirus-mediated TIMP-2 gene transfer into human breast cancer cell lines on the in vitro invasion of the tumor cells or the in vivo growth in nude mouse. Here we also used retroviral-mediated TIMP-2 overexpression by intratumoral injection for suppression of metastasis in human breast carcinoma established in the mammary fat pad of nude mice. RESULTS: As expected, overexpression of TIMP-2 inhibited matrix metalloprotenase (MMP) activity and invasion of the tumor cells. Also, the growth rate of tumors grafted with the breast cancer cells transduced with the retrovirus vector encoding TIMP-2 cDNA was significantly slower than the growth rate of tumors grafted with the breast cancer cells transduced with a control retrovirus vector. Furthermore, single intratumoral injection of the TIMP-2 retrovirus-producing cells into human breast tumor tissue established in mammary fat pads of nude mice showed a dramatic decrease in size and number of lung metastatic tumors. CONCLUSIONS: Retrovirus-mediated TIMP-2 gene transfer into human breast cancer cells is able to down-regulate invasion and show that tumor-derived angiogenesis is reduced. In this model, retroviral-mediated transduction of TIMP-2 cDNA into a limited population of human tumor cells inhibits tumor growth and prevents distant pulmonary metastasis. These results indicate that it may not be necessary to deliver and express these genes in every single tumor cell as long as the level of expression in a limited number of transduced cells is sufficient to prevent the excessive breakdown of the extracellular matrix.

Purpose: The purpose of this study is to identify useful clinicopathologic factors for the prediction of lymph node metastasis in submucosally invasive colorectal carcinoma. Methods: A total of fifty-four cases of colorectal carcinomas with submucosal invasion were included. The patients underwent curative resection with en bloc lymph node dissection. Clinical features such as age, gender, tumor size and tumor location were reviewed. Histopathologic examinations for tumor growth type, differentiation, depth of tumor invasion, lymphovascular invasion, neural invasion, tumor budding and peritumoral inflammation were performed. The expression of E-cadherin, β-catenin, Smad4, p53 and Ki-67 were examined by immunohistochemistry. The correlation between the clinicopathologic factors and lymph node metastasis was evaluated. Results: From the 54 patients with submucosally invasivecolorectal carcinoma, lymph node metastasis was identified in 13 cases (24.1%). The incidence of lymph node metastasis was significantly higher in cases positive for lymphovascular invasion (55.6% vs. 17.8%, P=0.028) and positive for tumor budding (47.4% vs. 11.45%, P=0.006). Cases negative for Smad4 had a higher tendency for incidence of lymph node metastasis (28.6% vs. 15.8%, P=0.341). Other clinicopathologic and immunohistochemical features were irrelevant to the lymph node status. In multivariate analysis, only tumor budding was an independent predictor of lymph node metastasis (P=0.051). Conclusion: Lymphovascular invasion and tumor budding were predictive factors of lymph node metastasis in submucosally invasive colorectal carcinoma. The incidence of lymph node metastasis of submucosally invasive colorectal carcinoma was not low. Careful selection for avoiding surgery in submuocally invasive colorectal carcinoma should be considered.