Abstract
Activator protein (AP) -1 is a transcription factor, plays important role in cell differentiation, proliferation and apoptosis. Analysis of tumor cells grown on ex vivo 4D lung cancer model shows increase in components of AP-1, c-Fos and c-Jun in circulating tumor cells (CTC) compared to primary tumor. Our aim was to determine whether the AP-1 inhibitor SR11302 reduces metastatic lesion formation in the 4D model. Human lung cancer cell lines A549, H1299, and H460 were grown in the 4D model and treated with SR11302 (1 μM). We compared the number of cells in the metastatic site upon SR11302 treatment and number of viable CTCs isolated from the 4D model with parental cells treated/untreated with SR11302 on a petri dish. There were significantly fewer tumor cells per high-power field on metastatic site in 4D model seeded with H460 (p = 0.009), A549 (p = 0.01), or H1299 (p = 0.02) cells treated with SR11302. Furthermore, the CTCs from SR11302 treated 4D models, seeded with H460 (p = 0.04), A549 (p = 0.008), or H1299 (p = 0.01) cells had significantly fewer viable tumor cells after 4 days in culture than the respective untreated control. However, the SR11302 had no impact on the viability of parental H460 (p = 0.87), A549 (p = 0.93), or H1299 (p = 0.25) cells grown on a petri dish (2D). SR11302 reduces metastatic lesion formation in the ex vivo 4D lung cancer model due to the presence of an independent yet common pathway among three cell lines. The ex vivo 4D model may provide a tool to better understand the complex process of metastasis.
Highlights
Lung cancer is the leading cause of cancer-related death in the United States [1]
Our gene expression analysis of c-Jun and c-Fos in the primary tumor, circulating tumor cells (CTC), and metastatic lesions of an ex vivo 4D model seeded with A549, H1299, and H460 cells showed a significant over-expression in CTCs compared to the primary tumor (Fig. 1)
Our results demonstrated that SR11302, an AP1 inhibitor reduces tumor metastasis in the 4D model by affecting the viability of CTCs without impact on primary tumor growth
Summary
Lung cancer is the leading cause of cancer-related death in the United States [1]. The predominant cause of lung cancerrelated death is organ failure due to metastatic lung cancer to other organs. To better understand lung cancer progression and metastasis, we have developed a four-dimensional (4D) lung cancer ex vivo model, from acellular rat lung, which has intact basement membrane that allows tumor cells to grow in the epithelial space and continuous nutrient flow and perfusion to occur through the vascular space. It is different from the conventional 2D/monolayer cells which are grown on flat and rigid substrates and 3D cell culture [2] where cells grow in an artificial extracellular matrix component in threedimensional fashion, there is absence of vasculature. The gene signature of the primary tumor from the 4D model predicts poor survival in Mishra D.K., Kim M.P
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