黑料网

Abstract

Background: Peritoneal dissemination is characterized by an aggressive clinical course, therapeutic resistance and striking molecular heterogeneity. Cancer stem-like cells (CSCs) closely model this molecular heterogeneity and likely have a key role in tumor recurrence and therapeutic resistance. Emerging evidence indicates that signal transducer and activator of transcription 3 (STAT3) is an important mediator of tumor cell survival, growth and invasion in peritoneal dissemination that correlated with PIM-1 expression. Herein, we generated characterized 12 clones cells populations in gastric tumors with distinct properties that have stem cell-like characteristics to evaluate the translational potential therapeutics by PIM-1 inhibitors. Methods: CSCs were cultured in Doxorubicin resistant condition; condense sphericity and highly expression of stem cells marker (CD133, CD44, DLL4 and LGR5) were determined by soft agar, real-time PCR. Endogenous PIM-1 and STAT3 activity was assessed in human gastric tissue, CSCs and animal xenografts by immunohistochemistry, PET/CT and Western blotting. PIM-1 inhibitors were used to inhibit PIM-1 and STAT3 activity in vitro and in vivo. Results: Both PIM-1 and STAT3 activity was demonstrated to be highly activated in human gastric tissue, molecularly heterogeneous CSCs tumors and CSCs xenografts. PIM-1 inhibitors or PIM-1 siRNA knockdown administration resulted in ontarget STAT3 inhibition and dramatically reduced CSCs survival, soft agar assay and stem cells markers. CSCs animal xenografts maintained high levels of activated PIM-1 and STAT3 activity seen in their parent tumors. Intra-peritoneal PIM-1 inhibitors reduced intra-tumoral PIM-1 and STAT3 activity, stem cells marker and prolonged animal survival. Conclusion: Our study demonstrates the in vitro and in vivo efficacy of on-target PIM-1 and STAT3 inhibition in heterogeneous CSCs that closely emulate the genomic and tumorigenic characteristics of molecular heterogeneity in cancer stem-like cells.

Biography