自吞(損壞的或多餘的細胞材料的降解)是促進還是抑制腫瘤發生長期以來是一個有爭議的問題。最近的證據表明,根據情況的不同二者都可能是正確的。
現在Kevin Ryan等人在一個由Kras突變驅動的胰腺腫瘤的小鼠模型中發現,抑制自吞的結果取決於p53的狀態。如果p53是完好的,關鍵自吞基因的刪除會阻止低等級腫瘤向侵襲性腫瘤的發展。
但在沒有p53的情況下,自吞的失去會加速腫瘤發生,同時伴隨著癌細胞代謝的失控。
這項工作對於以癌症中的自吞為目標的治療思想有重要意義。(生物谷Bioon.com)
生物谷推薦的英文摘要
Nature doi:10.1038/nature12865
p53 status determines the role of autophagy in pancreatic tumour development
Mathias T. Rosenfeldt,Jim O』Prey,Jennifer P. Morton,Colin Nixon,Gillian MacKay,Agata Mrowinska,Amy Au,Taranjit Singh Rai,Liang Zheng,Rachel Ridgway,Peter D. Adams,Kurt I. Anderson,Eyal Gottlieb,Owen J. Sansom& Kevin M. Ryan
Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation1. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease2, 3, 4. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles3, 5, 6, 7, 8, 9, 10, 11, 12. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy’s role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)—the most common mutational event in PDAC13—develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials14, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.