透過調控p53路徑及血管新生控制肺癌細胞生長

Abstract

在世界各地中，肺癌佔造成癌症死亡的首位，因此尋找具有新穎治療機制的抗癌策略成為一件重要的工作。根據文獻報導，腫瘤微環境、致癌基因和腫瘤抑制基因在癌化過程中扮演著重要角色，因此，在肺癌治療上透過控制腫瘤微環境及致癌、抑癌基因的表現或許是可行的辦法。p53是重要的腫瘤抑制基因，作為一個轉錄因子，它可以維持基因組的穩定性、造成細胞週期停滯、細胞凋亡、衰老及自體吞噬。我們也試著從控制腫瘤微環境的角度切入，看能否透過抑制血管新生來減緩腫瘤生長。受腫瘤微環境調控的血管新生，在肺癌的惡化過程中扮演重要角色，也是癌症的標誌之一。透過分析利用H1975、A549、PC9及PC9IR等四株細胞篩選抗癌藥物的數據，我們證實AS7128可以在細胞層次及動物實驗中抑制腫瘤細胞的生長，是個具有潛力的藥物，其機轉是經由抑制微管蛋白聚合與降低和p53抑制物iASPP的交互作用來恢復p53轉錄因子的活性，可以讓細胞週期停在有絲分裂及造成細胞凋亡。我們也發現，將人類臍帶靜脈內皮細胞(HUVEC)和人類肺癌細胞培養在一起後，會透過PI3K/Akt訊息傳遞路徑及COX-2基因表現來增加臍帶靜脈內皮細胞微血管結構的形成，減少細胞凋亡，進而影響微環境以利腫瘤生長；這樣子的培養過程也會改變內皮細胞的基因表現，而這些表現量有差異的基因，也可以用來預測非小細胞肺癌病人的整體存活與無疾病存活。總結來說，透過解析藥物新的作用機轉及阻斷腫瘤微環境對血管內皮細胞的影響，可加強控制腫瘤生長，這些研究希望能提供肺癌病患在治療上的新策略。

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing anti-cancer drugs with novel mechanism becomes an important issue. It has been reported that tumor microenvironment, oncogene and tumor suppressor gene play an important role in lung cancer progression. Thus management of the tumor microenvironment or gene expression could be a practical strategy in lung cancer therapy. p53 is an important tumor suppressor gene which acts as a transcriptional factor to maintain genome stability and induce cell cycle arrest, apoptosis, senescence and autophagy. Angiogenesis which is regulated by tumor microenvironment is a hallmark of cancer and plays a critical role in lung cancer progression. Using the data from a high-throughput screening against H1975, A549, PC9 and PC9IR cell lines, we identified AS7128 as a potential compound to inhibit tumor growth in vitro and in vivo. In addition, AS7128 induced cell cycle M phase arrest and cell apoptosis through microtubule polymerization inhibition and p53 transactivation ability restoration, which by decreasing the interaction with p53 inhibitor, iASPP. Furthermore, we found that after co-culture with lung cancer cells, human umbilical vein endothelial cells (HUVECs) showed increased microvessel tube formation ability and a decreased apoptotic percentage through PI3K/Akt signaling pathway and COX-2 expression, and thus changed the microenvironment to benefit tumor growth. Interaction with cancer cells also altered the gene expression of HUVECs, and these gene signatures could predict overall survival and disease-free survival in non-small cell lung cancer (NSCLC) patients. Taken together, we tried to control tumor growth by discovering drugs and blocking the effect of tumor microenvironment on endothelial cells. These findings provide novel strategies to overcome lung cancer in patients.