Role of Vascular Endothelial Growth Factor C in Resected Stage I of Non-small Cell Lung Cancer and New Drugs Investigation for Anti-migration of Lung Cancer Cell
肺癌 ； C型血管內皮成長因子 ； 新藥開發 ； lung cancer ； vascular endothelial growth factor C ； new drugs investigation
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Early stage of Non-small-cell lung cancer (NSCLC) can be treated by surgical resection and had relative better prognosis. But only 20% was stage I disease, and early recurrence may influence the prognosis. When NSCLC makes progress to late stage, the high metastatic ability leads to high mortality rate. Our study focused on the role of VEGF-C in predicting early recurrence of stage I resected NSCLC patients and investigate new compound, dihydroaustrasulfone alcohol, from murine soft coral and its mechanism in inhibition of cancer cell migration. In chapter 1, we hypothesize that vascular endothelial growth factor C (VEGF-C) plays a key role in predicting early recurrence and poor survival of patients with stage I NSCLC because VEGF-C induce lymphaniogenesis, which mediates tumor cell dissemination and the formation of lymph node metastases. The expression of VEGF-C was immuno-histochemically (IHC) analyzed in tumor samples of primary stage I NSCLC and correlated to early recurrence (< 36 months), disease free survival, and overall survival in all 49 patients. Early recurrence was identified in 16 patients (33%), and the early recurrent rate in strong and weak VEGF-C activity was significantly different (p=0.016). VEGF-C was also an independent risk factor in predicting early recurrence (HR=3.98, p=0.02). Patients with strong VEGF-C staining also had poor 3-year disease-free survival (46% vs. 84%, p=0.008) and overall survival (38% vs. 80%, p=0.007). We concluded that strong VEGF-C IHC staining may be a biomarker for predicting early recurrence and poor prognosis of resected stage I NSCLC. There should be more aggressive adjuvant therapy in this group of patients. In chapter 2, we investigate a new natural marine substrate, Dihydroaustrasulfone alcohol, from soft coral against NSCLC cell line migration and tumor growth in Lewis lung cancer (LLC)-bearing mice and its regulation mechanism. Dihydroaustrasulfone alcohol, which was isolated from marine coral, has shown its antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that dihydroaustrasulfone alcohol provided a concentration-dependent inhibitory effect on the migration and motility of human non-small cell lung carcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results of a zymography assay and Western blot showed that dihydroaustrasulfone alcohol suppressed the activities and protein expression of matrix metalloproteinase (MMP)-2 and MMP-9. Further investigation revealed that dihydroaustrasulfone alcohol suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. Dihydroaustrasulfone alcohol also suppressed the expression of PI3K and the phosphorylation of Akt. Furthermore, dihydroaustrasulfone alcohol markedly inhibited tumor growth in Lewis lung cancer (LLC)-bearing mice. We concluded that dihydroaustrasulfone alcohol is a new pure compound with anti-migration and anti-tumor growth activity in lung cancer and might be applied to clinical treatment in the future.
醫學院 > 臨床醫學研究所博士班