Tbx3 fosters pancreatic cancer growth by increased angiogenesis and activin/nodal-dependent induction of stemness

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• 作者：Lukas Perkhofer^a ; Karolin Walter^a ; Ivan G. Costa^b ; Maria C. Romero Carrasco^a ; Tim Eiseler^a ; Susanne Hafner^c ; Felicitas Genze^c ; Martin Zenke^d ; Wendy Bergmann^a ; Anett Illing^a ; Meike Hohwieler^a ; Ralf Kö ; hntop^a ; Qiong Lin^d ; Karl-Heinz Holzmann^e ; Thomas Seufferlein^a ; Martin Wagner^a ; Stefan Liebau^f ; Patrick C. Hermann^a ; ^{patrick.hermann@uni-ulm.de" class="auth_mail" title="E-mail the corresponding author} ; Alexander Kleger^a ; ^{alexander.kleger@uni-ulm.de" class="auth_mail" title="E-mail the corresponding author} ; Martin Mü ; ller^a
• 关键词：TBX3 ; Pancreas ; Pancreatic adenocarcinoma ; Development ; Cancer stem cells
• 刊名：Stem Cell Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：17
• 期：2
• 页码：367-378
• 全文大小：1941 K

文摘

Cell fate decisions and pluripotency, but also malignancy depend on networks of key transcriptional regulators. The T-box transcription factor TBX3 has been implicated in the regulation of embryonic stem cell self-renewal and cardiogenesis. We have recently discovered that forced TBX3 expression in embryonic stem cells promotes mesendoderm specification directly by activating key lineage specification factors and indirectly by enhancing paracrine NODAL signalling. Interestingly, aberrant TBX3 expression is associated with breast cancer and melanoma formation. In other cancers, loss of TBX3 expression is associated with a more aggressive phenotype e.g. in gastric and cervical cancer. The precise function of TBX3 in pancreatic ductal adenocarcinoma remains to be determined. In the current study we provide conclusive evidence for TBX3 overexpression in pancreatic cancer samples as compared to healthy tissue. While proliferation remains unaltered, forced TBX3 expression strongly increases migration and invasion, but also angiogenesis in vitro and in vivo. Finally, we describe the TBX3-dependency of cancer stem cells that perpetuate themselves through an autocrine TBX3–ACTIVIN/NODAL signalling loop to sustain stemness. Thus, TBX3 is a new key player among pluripotency-related genes driving cancer formation.