肺癌細胞於纖維化基態下之抗藥性機轉研究

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Lung cancer is the leading cause of cancer mortality in the world, including Taiwan. The poor prognosis of lung cancer is contributed to the cancer behavior and market reduction of life quality in lung cancer patients. Recent literatures point out that chronic inflammation results in tissue fibrosis and increased tissue rigidity. Lung cancer formation has been thought to be highly associated to lung fibrosis. It is well known that chronic lung inflammation, such as interstitial lung disease and chronic obstructive pulmonary, may lead to the fibrotic change of lung, and fibrosis increases the rigidity of extracellular matrix at lung parenchyma. However, limited reference to demonstrate how extracellular matrix stiffness affects the biophysical response in lung tissue cells to trigger a tumorigenesis or how extracellular matrix stiffness alters the characteristics of lung cancer cells, i.e., growth rate, metastatic ability and drug resistance. In our previous study, we also proved the concept of cancer metastasis and poor prognosis influenced by the expression of EGFR and c-Met. It is known that epithelial growth factor receptor (EGFR) and hepatocyte growth factor (c-Met) are strongly associated with growth and metastasis of pulmonary adenocarcinoma, while integrin is the molecule delivering the interaction between cell and matrix. To investigate the biophysical effect on pulmonary adenocarcinoma cells response to change on extracellular rigidity is critical to explore why a patient with lung cancer combined with lung fibrosis reveals a poor prognosis. According to the literatures, the rigidity of physiological lung parenchyma is 0.15-0.2 kPa, while fibrotic lung makes the rigidity up to 7-25 kPa. Even though, in most of in vitro cancer researches, cancer cells are cultured on a plastic flask or on a glass disc to investigate the cancer behavior and molecular mechanism before the experiments performed. The rigidity of plastic flask is around 106 kPa, 5 x 106 folds of which of physiological lung parenchyma. It is hard to tell the biophysical effect on lung cancer cells in responsible for the lung fibrosis in such a supra-physiological environment. The underlying mechanism is not clear so far. The aim of this study is to investigate the role of matrix stiffness during lung fibrosis on cancer drug resistance. In this study, culture dish with 0.2, 2 or 25 kPa will be used for the culture of A549 cells, the cell line from pulmonary adenocarcinoma. We will compare the effect of matrix stiffness of physiological (0.2 kPa), fibrotic change (2 kPa) and severe fibrosis (25 kPa) lung parenchyma on cell proliferation and epithelial-mesenchymal transition on A549 cells. In addition, we will identify the putative key mechanoreceptor responsible for rigid matrix, and drug sensitivity targeted on the mechanoreceptor-mediated signals will be measured. The originality of the study is high as no similar studies have been reported in the literature. The valuable research achievement of this study for cancer medicine is that to provide a new therapeutic strategy for patients of pulmonary adenocarcinoma combined with lung fibrosis through a biophysical angle.
StatusFinished
Effective start/end date1/1/1812/31/18

Keywords

  • adenocarcinoma
  • biophysical effect
  • drug resistance
  • lung cancer
  • matrix rigidity