肿瘤相关巨噬细胞调节癌干细胞的致瘤性及对抗癌药的敏感性

grape

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Tumor associated macrophages regulate tumorigenicity and anticancer drug sensitivity of cancer stem cells.
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7 V1 g3 l& U$ D9 p) e0 d4 rResearch Announcement, Z+ f# `. V: C" {3 e
Tumor associated macrophages regulate tumorigenicity and anticancer drug sensitivity of cancer stem cells.
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/ s/ ]; D! t& @6 l) ?" d$ {/ g/ jMasahisa Jinushi, MD, PhD
0 |7 l2 U, {# ~) lResearch center for infection-associated cancer, Institute for Genetic Medicine, Hokkaido University
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' w1 o- k( @& M8 _: TResearch background:( {9 M* F0 P& s1 \
Tumor cells contain rare populations termed cancer stem cells that are responsible for rendering tumors to resist various anticancer modalities. Recent studies have been unveiled that indicate tumor-associated macrophages (TAM) play a decisive role in the regulation of tumor progression at tumor microenvironments. However, it remains unclear whether cancer stem cells modify the tumorigenic activities of TAM especially during the course of anticancer treatments. Furthermore, we evaluated the functional role of TAMs in the regulation of tumorigenic activities and anticancer drug responsiveness of cancer stem cells.
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Experimental results:
& R% ?# o& m" P! b, @6 Q9 SWe used MFG-E8 and IL-6 as functional markers for tumor-promoting macrophages because they are highly produced from TAM and play a critical role in triggering anticancer drug resistance and tumorigenesis. We verified in this study that cancer stem cells, but not other tumor subsets, could upregulate MFG-E8 and IL-6 from normal macrophages, providing direct evidence that cancer stem cells are responsible for converting antitumor macrophages into tumor-promoting ones. Furthermore, in vivo adoptive cell transfer model revealed that TAM-derived MFG-E8 is responsible for rendering cancer stem cells to activate and maintain their tumorigenic activities, such as self-renewal capacities and anticancer drug resistance. The pharmacological inhibition of MFG-E8 and IL-6 with neutralizing antibodies significantly reduced tumor burden and increased anticancer drug sensitivities of primary human and murine cancer stem cells. Through screening oncogenic signals responsible for TAM-mediated activation of cancer stem cells, we found that Stat3 and Hedgehog pathways are responsible for enriching and activating cancer stem cells in bulk tumor populations.7 O! w; W% t- t% B8 R* i6 i7 Q

/ ]# a2 [4 w( D6 CSignificance:
0 x. G+ k9 ~  M# t. FWe identified positive feedback mechanisms whereby cancer stem cells conferred macrophages to acquire tumorigenic activities by producing MFG-E8 and IL-6, which trigger tumorigenicity and anticancer drug resistance of cancer stem cells (Figure 1). The molecular targeting of these pathways provides the new therapeutic strategy to eradicate treatment-difficult tumors across the broad spectrums of different genetic and epigenetic alterations.+ [0 P& i- Y: Q9 p: q
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Figure1.
; K; W0 e) W5 q: T8 jThe positive feedback loop that cancer stem cells and tumor-associated macrophages activate their tumor-supporting capacities via each other
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0 K. Y7 o9 Q3 O$ o- l3 j& tHP link: http://www.igm.hokudai.ac.jp/vec/
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4 G( d7 L0 J8 e9 B% ?8 p  BFor the full article, please visit the following link on the Proceedings National Academy of Sciences of United States of America website.
& I5 S  V. h4 T( I8 q  b) ?http://www.pnas.org/content/earl ... c-9614-cf38f1721030]
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For Enquiries:6 \; M4 p9 _( W3 F% H6 K7 ]+ e
Masahisa Jinushi, MD, PhD2 g$ _5 j  I+ m' s
TEL: 011-706-6073 FAX: 011-706-6071 E-mail: jinushi@igm.hokudai.ac.jp
5 \# n( U/ b$ t  y6 A5 g4 VHomepage： http://www.igm.hokudai.ac.jp/vec/( c# P- u$ ^/ Z8 X

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丁子

这篇文章是什么时候刊出的？

jiays

July 11, 2011,

embryonic12

谁有原文？

viv2005

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饶冠华

我勒个去~~看看

embryonic12

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3 e$ e1 @5 u" P2 A1 a谢谢！
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期刊：Nature Reviews Drug Discovery 8, 724-732 (September 2009) | doi:10.1038/nrd29746 ]; x; l; Y, f8 @8 V- C
标题：Protein methyltransferases as a target class for drug discovery5 a3 H' j  s7 W' e

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viv2005

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embryonic12

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感谢！

linzi214

谢谢