TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling
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TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. / Becker, Christoph; Fantini, Massimo C; Schramm, Christoph; Lehr, Hans A; Wirtz, Stefan; Nikolaev, Alexei; Burg, Jürgen; Strand, Susanne; Kiesslich, Ralf; Huber, Samuel; Ito, Hiroaki; Nishimoto, Norihiro; Yoshizaki, Kazuyuki; Kishimoto, Tadamitsu; Galle, Peter R; Blessing, Manfred; Rose-John, Stefan; Neurath, Markus F.
In: IMMUNITY, Vol. 21, No. 4, 10.2004, p. 491-501.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling
AU - Becker, Christoph
AU - Fantini, Massimo C
AU - Schramm, Christoph
AU - Lehr, Hans A
AU - Wirtz, Stefan
AU - Nikolaev, Alexei
AU - Burg, Jürgen
AU - Strand, Susanne
AU - Kiesslich, Ralf
AU - Huber, Samuel
AU - Ito, Hiroaki
AU - Nishimoto, Norihiro
AU - Yoshizaki, Kazuyuki
AU - Kishimoto, Tadamitsu
AU - Galle, Peter R
AU - Blessing, Manfred
AU - Rose-John, Stefan
AU - Neurath, Markus F
PY - 2004/10
Y1 - 2004/10
N2 - Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.
AB - Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.
KW - Animals
KW - Blotting, Western
KW - Colonic Neoplasms/immunology
KW - DNA-Binding Proteins/immunology
KW - Disease Models, Animal
KW - Disease Progression
KW - Endoscopy, Digestive System
KW - Enzyme-Linked Immunosorbent Assay
KW - Humans
KW - Immunohistochemistry
KW - Interleukin-6/immunology
KW - Intestinal Mucosa/immunology
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Protein Serine-Threonine Kinases
KW - Receptor, Transforming Growth Factor-beta Type II
KW - Receptors, Interleukin-6/immunology
KW - Receptors, Transforming Growth Factor beta/genetics
KW - Recombinant Fusion Proteins/immunology
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - STAT3 Transcription Factor
KW - Signal Transduction/physiology
KW - T-Lymphocytes/immunology
KW - Trans-Activators/immunology
KW - Transforming Growth Factor beta/genetics
U2 - 10.1016/j.immuni.2004.07.020
DO - 10.1016/j.immuni.2004.07.020
M3 - SCORING: Journal article
C2 - 15485627
VL - 21
SP - 491
EP - 501
JO - IMMUNITY
JF - IMMUNITY
SN - 1074-7613
IS - 4
ER -