| Summary: | 碩士 === 國立陽明大學 === 臨床醫學研究所 === 100 === Antiangiogenesis has been demonstrated as an efficient therapy for reducing tumor size in colon cancers, but because of recurrence even with continuous therapy it remains only palliative. We showed that tumor cells expressing CD133, a marker for colon tumor initiating or stem cells (TICs), were enriched after antiangiogenic therapy in several mouse models and survived under antiangiogenesis conditions in vitro, whereas CD133- cells underwent apoptosis. CD133+ tumor cells preferentially activated the p38MAPK-MAPKAPK2-Hsp27 pathway via suppression of PP2A to inhibit caspase 9 and 3 cleavage. In addition, inhibition of Hsp27 signaling sensitized CD133+ cells to antiangiogenesis-induced apoptosis. The CD133+ population in colon cancer was resistant to anti-angiogenesis therapy. Moreover, we identified an anti-apoptotic signaling pathway that may offer a new avenue to develop target therapy for colon cancer. Finally, the anti-apoptotic pathway is also activated in tumor stem cells from a variety of solid tumor cells including lung, brain and oral cancer. Thus, activation of PP2A or inactivation of the p38MAPK-MAPKAPK2-Hsp27 pathway may be new strategies for anti-angiogenesis therapy of cancer by reducing their TICs.
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