作为肿瘤转移的屏障, 细胞与邻近细胞或者细胞外基质(Extracellular matrix, ECM)失去联系后将遭受凋亡, 这种细胞死亡方式称为“失巢凋亡”。正常上皮细胞或不具备转移性质的实体瘤细胞从原位脱落进入血液循环后就会引发失巢凋亡, 失巢凋亡的意义在于防止这些脱落的细胞种植并生长于其他不适宜的地方。而肿瘤细胞, 尤其是一些容易发生远距离转移的恶性肿瘤细胞, 具有极强的抗失巢凋亡特性, 便于转移侵袭。研究发现肿瘤细胞能通过多种方式抵抗失巢凋亡, 比如细胞自分泌生长因子或者由邻近细胞旁分泌, 激活促存活信号通路; 细胞改变整合蛋白的表达模式, 使之能够接收新环境的生存信号; 活性氧(Reactive oxygen species, ROS)通过不依赖配体的方式激活生长因子受体, 从而逃逸凋亡; 上皮间质转化(Epithelial-mesenchymal transition, EMT)激活等。这些方式导致细胞存活信号激活和凋亡途径抑制, 最终使肿瘤细胞抗失巢凋亡, 促进转移。文章综述了当前研究的肿瘤转移的关键机制, 这些策略也将成为肿瘤治疗的重要靶点。
As a barrier to metastasis of cancer, cells that lost contact with the neighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be subjected to apoptosis. This cell death process has been termed “anoikis”. When normal epithelial cells or solid tumor cells without metastatic potential detach from the primary site, and then enter into the circulatory system, the anoikis mechanism will be activated. The significance of anoikis is to prevent the shedding cells from growing and implanting into other inappropriate sites. Tumor cells, especially several malignant cells that is prone to transfer to distant sites, have properties of anti-anoikis, which facilitates metastasis as well as invasion of tumor cells. The studies found that tumor cells can resist anoikis through multiple mechanisms: the pro-survival pathways are activated by cells autocrine growth factors and paracrine factors derived from neighboring cells; cells change the pattern of integrin expression so that they can receive survival signals from new environment; reactive oxygen species (ROS) activates growth factor receptors in a ligand-independent way to avoid apoptosis; and epithelial-mesenchymal transformation(EMT) is activated etc.. All of these mechanisms lead to activation of survival signals and inhibition of apoptotic pathways, and ultimately cause resistance to anoikis as well as metastasis. This paper summarizes the key mechanisms of the current studies on metastasis, which also suggest important targets for cancer therapy.
[1] Grossmann J. Molecular mechanisms of “detachment- induced apoptosis--Anoikis”. Apoptosis, 2002, 7(3): 247-260.
[2] Cohen GM. Caspases: the executioners of apoptosis. Biochem J, 1997, 326(1): 1-16.
[3] Thornberry NA. Caspases: key mediators of apoptosis. Chem Biol, 1998, 5(5): 97-103.
[4] Bouillet P, Strasser A. BH3-only proteins-evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci, 2002, 115(8): 1567-1574.
[5] Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol, 2008, 9(3): 231-241.
[6] Cheng EHYA, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ. BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell, 2001, 8(3): 705-711.
[7] Le Gall M, Chambard JC, Breittmayer JP, Grall D, Pouysségur J, Van Obberghen-Schilling E. The p42/p44 MAP kinase pathway prevents apoptosis induced by anchorage and serum removal. Mol Biol Cell, 2000, 11(3): 1103-1112.
[8] Qi XJ, Wildey GM, Howe PH. Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem, 2006, 281(2): 813-823.
[9] Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer Lett, 2008, 272(2): 177-185.
[10] Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell, 2005, 17(4): 525-535.
[11] Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2002, 2(3): 183-192.
[12] Schmelzle T, Mailleux AA, Overholtzer M, Carroll JS, Solimini NL, Lightcap ES, Veiby OP, Brugge JS. Functional role and oncogene-regulated expression of the BH3- only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci USA, 2007, 104(10): 3787-3792.
[13] Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene, 2003, 22(53): 8590-8607.
[14] Gazaryan IG, Brown AM. Intersection between mitochondrial permeability pores and mitochondrial fusion/fission. Neurochem Res, 2007, 32(4-5): 917-929.
[15] Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature, 2003, 426(6967): 671-676.
[16] Woods NT, Yamaguchi H, Lee FY, Bhalla KN, Wang HG. Anoikis, initiated by Mcl-1 degradation and Bim induction, is deregulated during oncogenesis. Cancer Res, 2007, 67(22): 10744-10752.
[17] Zhong Q, Gao WH, Du FH, Wang XD. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell, 2005, 121(7): 1085-1095.
[18] Bozzo C, Sabbatini M, Tiberio R, Piffanelli V, Santoro C, Cannas M. Activation of caspase-8 triggers anoikis in human neuroblastoma cells. Neurosci Res, 2006, 56(2): 145-153.
[19] Rytomaa M, Martins LM, Downward J. Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr Biol, 1999, 9(18): 1043-1046.
[20] Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med, 2001, 7(1): 94-100.
[21] Valentijn AJ, Gilmore AP. Translocation of full-length Bid to mitochondria during anoikis. J Biol Chem, 2004, 279 (31): 32848-32857.
[22] Ao
