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Park, Jin-Sung,Kim, Il-Kug,Han, Sangyeul,Park, Intae,Kim, Chan,Bae, Jeomil,Oh, Seung Ja,Lee, Seungjoo,Kim, Jeong Hoon,Woo, Dong-Cheol,He, Yulong,Augustin, Hellmut G.,Kim, Injune,Lee, Doheon,Koh, Gou Y Cell Press 2016 CANCER CELL Vol. No.
<P><B>Summary</B></P> <P>A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ABTAA-induced Tie2 activation and Ang2 inhibition normalize tumor vasculature </LI> <LI> Tumor vessel normalization leads to enhanced blood perfusion and drug delivery </LI> <LI> Tumor vessel normalization lessens hypoxia, acidosis, tumor growth, and metastasis </LI> <LI> Tie2 activation favorably alters the tumor microenvironment and immune infiltration </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Cho, In Ha,Lee, Min Jung,Kim, Dae Hwan,Kim, Bora,Bae, Jeomil,Choi, Kyu Yeong,Kim, Seon-Myung,Huh, Yun Hyun,Lee, Kun Ho,Kim, Chong-Hyun,Song, Woo Keun Springer Basel 2013 Cellular and molecular life sciences Vol.70 No.22
<P>Actin plays a fundamental role in the regulation of spine morphology (both shrinkage and enlargement) upon synaptic activation. In particular, actin depolymerization is crucial for the spine shrinkage in NMDAR-mediated synaptic depression. Here, we define the role of SPIN90 phosphorylation/dephosphorylation in regulating actin depolymerization via modulation of cofilin activity. When neurons were treated with NMDA, SPIN90 was dephosphorylated by STEP61 (striatal-enriched protein tyrosine phosphatase) and translocated from the spines to the dendritic shafts. In addition, phosphorylated SPIN90 bound cofilin and then inhibited cofilin activity, suggesting that SPIN90 dephosphorylation is a prerequisite step for releasing cofilin so that cofilin can adequately sever actin filaments into monomeric form. We found that SPIN90 YE, a phosphomimetic mutant, remained in the spines after NMDAR activation where it bound cofilin, thereby effectively preventing actin depolymerization. This led to inhibition of the activity-dependent redistribution of cortactin and drebrin A, as well as of the morphological changes in the spines that underlie synaptic plasticity. These findings indicate that NMDA-induced SPIN90 dephosphorylation and translocation initiates cofilin-mediated actin dynamics and spine shrinkage within dendritic spines, thereby modulating synaptic activity.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00018-013-1391-4) contains supplementary material, which is available to authorized users.</P>