Sell Stewart
Wadsworth Center and Ordway Research Institute, New York State Dept. of Health, Empire State Plaza, Albany, NY 12201, USA.
Curr Gene Ther. 2006 Oct;6(5):579-91. doi: 10.2174/156652306778520674.
To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.
为了达到最大疗效，癌症治疗必须针对癌症的静止干细胞和增殖细胞。正常组织和癌组织的细胞群体均由静止干细胞、增殖的过渡扩增细胞、终末分化细胞和死亡（凋亡）细胞组成。正常组织更新与癌症生长之间的差异在于，癌群体中的一些过渡扩增细胞不会成熟为终末分化细胞，而是继续增殖且不会死亡（成熟停滞）。因此，癌细胞数量增加，而正常组织的细胞群体保持相对恒定。传统的放射治疗和化学疗法会杀死癌症中活跃增殖的过渡扩增细胞。使用特定的激活靶向抑制剂进行分化治疗，可有效诱导增殖的过渡扩增癌细胞分化。然而，即使增殖的癌细胞被完全抑制或消除，癌症干细胞仍可能恢复过渡扩增群体，从而使临床缓解通常是暂时的。本文提出的假设是，成功的癌症治疗必须针对癌症的静止干细胞和增殖细胞。如果使用基因疗法抑制特定的干细胞信号，同时通过传统的放射治疗或化学疗法攻击增殖细胞，这或许是可行的。随着使用特异性抑制性RNA方法的进展，这种联合治疗现在或许可行，但将抑制作用特异性地传递给癌症干细胞的关键问题仍有待解决。
