Debnath Jayanta, Mills Kenna R, Collins Nicole L, Reginato Mauricio J, Muthuswamy Senthil K, Brugge Joan S
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2002 Oct 4;111(1):29-40. doi: 10.1016/s0092-8674(02)01001-2.
We have utilized in vitro three-dimensional epithelial cell cultures to analyze the role of apoptosis in the formation and maintenance of a hollow glandular architecture. Lumen formation is associated with the selective apoptosis of centrally located cells; this apoptosis follows apicobasal polarization and precedes proliferative suppression during acinar development. Notably, either inhibiting apoptosis (by exogenously expressing antiapoptotic Bcl family proteins) or enhancing proliferation (via Cyclin D1 or HPV E7 overexpression) does not result in luminal filling, suggesting glandular architecture is resistant to such isolated oncogenic insults. However, the lumen is filled when oncogenes that enhance proliferation are coexpressed with those that inhibit apoptosis, or when ErbB2, which induces both activities, is activated by homodimerization. Hence, apoptosis can counteract increased proliferation to maintain luminal space, suggesting that tumor cells must restrain apoptosis to populate the lumen.
我们利用体外三维上皮细胞培养来分析细胞凋亡在中空腺性结构形成和维持中的作用。管腔形成与位于中央的细胞的选择性凋亡相关；这种凋亡发生在顶-基极化之后，腺泡发育过程中增殖抑制之前。值得注意的是，抑制细胞凋亡（通过外源性表达抗凋亡Bcl家族蛋白）或增强增殖（通过细胞周期蛋白D1或人乳头瘤病毒E7过表达）均不会导致管腔填充，这表明腺性结构对这种孤立的致癌性损伤具有抗性。然而，当增强增殖的癌基因与抑制细胞凋亡的癌基因共表达时，或者当诱导这两种活性的ErbB2通过同二聚化被激活时，管腔会被填充。因此，细胞凋亡可以抵消增殖增加以维持管腔空间，这表明肿瘤细胞必须抑制细胞凋亡才能填充管腔。
