The Effect of Hepatocyte Growth Factor and Insulin-like Growth Factor-I on Tumor Metastasis in Lung Cancer Cell Lines

• Main Authors: Li-Wei Lin, 林禮薇
• Other Authors: Yi-Ju Lee
• Format: Others
• Language: zh-TW
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/67398554774530083831

碩士 === 中山醫學大學 === 免疫學研究所 === 91 === Lung cancer is one of the leading causes of death in Taiwan. The high mortality of lung cancer is due to tumor metastasis that makes the treatment difficult. Tumor metastasis is a complex process involving coordination of matrix disintegration, cell detachment, cell-cell junction disassembly, cell migration, and the changes in the expression of integrins and other cell adhesion molecules. Hepatocyte growth factor (HGF) and insulin-like growth factor I (IGF-I) play a critical role in tumor metastasis, probably through their stimulatory effect on cell proliferation, migration, invasion and angiogenesis. Although it has been known that elevated expression of these growth factors and their receptors are associated with poor prognosis, the underlying mechanisms are not fully understood. Besides, there have not been many reports studying the correlation between the deregulation of HGF and its receptor with lung cancer. Thus, we investigated into the role of HGF and IGF-I in lung tumor metastasis. A lung cancer cell line CL1-0 and its sublines CL1-1 and CL1-5 were used in this study since they exhibit different extents of invasiveness. CL1-5 is prone to invade, while CL1-1 shows very low extent of invasiveness. We examined the expression of the HGF receptor Met and IGF-I receptor (IGF-IR), the signaling pathways triggered by HGF and IGF-I, as well as the effect of these growth factors on cell proliferation, matrix metalloproteinase (MMP) activity, survival, cell migration and invasion. Higher level of Met expression was observed in CL1-5, whereas greater extent of IGF-IR expression was detected in CL1-1. Exposure to HGF strongly induced the tyrosine phosphorylation of Met in CL1-5, but there was no ligand-independent activation, suggesting that Met did not harbor activation mutations, and autocrine-loop did not exist in CL1-5. IGF-I-stimulated signaling was distinct in these cell lines. Tyrosine phosphorylation of IGF-IR and IRS-2 was mainly restricted to CL1-1, but phosphorylation of IRS-1 was more pronounced in CL1-5. This was due to the differences in the expression levels of these proteins. Moreover, we found that CL1-1 was highly proliferative, whereas CL1-5 was more refractory to apoptosis induced by disruption of both cell-matrix and cell-cell interactions. Both HGF and IGF-I were potent to promote cell migration, but were ineffective in augmentation of MMP activity. We hope our studies will help for deciphering the mechanisms for tumor metastasis and furthermore, for designing strategies to treat lung cancer.