卵巢癌复发率高一直困扰医学界。美国得克萨斯大学研究人员新近发现了休眠的卵巢癌细胞在人体内的存活机制。这项研究有望帮助人们找到治疗卵巢癌的新途径。
据最新一期美国《临床检查杂志》月刊报道，一些卵巢癌患者切除肿瘤两三年之后，体内再次出现肿瘤，其主要原因是体内休眠的卵巢癌细胞在作祟。这些卵巢癌细胞休眠时不进行细胞分裂，不易被发现，然而一旦重新生长，肿瘤就会再次出现。
研究人员介绍说，一种名为ARHI的基因是卵巢癌细胞自体吞噬机制能否启动的关键，决定着细胞是否会依靠自噬机制“自我灭亡”。在以该基因为重点的研究中，他们发现在移植了卵巢癌细胞的实验鼠体内有几种蛋白质存活因子导致ARHI基因表达异常，从而使细胞自噬机制无法正常启动。在通过阻止上述蛋白质存活因子发挥作用使ARHI基因表达恢复到正常水平后，细胞自噬机制又能完全启动，最终使卵巢癌细胞在数天内死亡。
研究人员表示，自噬机制无法正常启动导致卵巢癌细胞得以休眠并等待合适时机重新分裂。如果能阻止上述蛋白质存活因子发挥作用，自噬机制就会消灭休眠的卵巢癌细胞，从而治愈卵巢癌。（生物谷Bioon.com）
生物谷推荐原始出处：
J. Clin. Invest. 118(12): 3917-3929 (2008). doi:10.1172/JCI35512.
The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells
Zhen Lu1, Robert Z. Luo1, Yiling Lu2, Xuhui Zhang1, Qinghua Yu2, Shilpi Khare1, Seiji Kondo3, Yasuko Kondo3, Yinhua Yu1, Gordon B. Mills2, Warren S.-L. Liao1,4 and Robert C. Bast, Jr.1
1Department of Experimental Therapeutics,
2Department of Molecular Therapeutics,
3Department of Neurosurgery, and
4Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
The role of autophagy in oncogenesis remains ambiguous, and mechanisms that induce autophagy and regulate its outcome in human cancers are poorly understood. The maternally imprinted Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI; also known as DIRAS3) is downregulated in more than 60% of ovarian cancers, and here we show that re-expression of ARHI in multiple human ovarian cancer cell lines induces autophagy by blocking PI3K signaling and inhibiting mammalian target of rapamycin (mTOR), upregulating ATG4, and colocalizing with cleaved microtubule-associated protein light chain 3 (LC3) in autophagosomes. Furthermore, ARHI is required for spontaneous and rapamycin-induced autophagy in normal and malignant cells. Although ARHI re-expression led to autophagic cell death when SKOv3 ovarian cancer cells were grown in culture, it enabled the cells to remain dormant when they were grown in mice as xenografts. When ARHI levels were reduced in dormant cells, xenografts grew rapidly. However, inhibition of ARHI-induced autophagy with chloroquine dramatically reduced regrowth of xenografted tumors upon reduction of ARHI levels, suggesting that autophagy contributed to the survival of dormant cells. Further analysis revealed that autophagic cell death was reduced when cultured human ovarian cancer cells in which ARHI had been re-expressed were treated with growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix proteins found in xenografts. Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.
