IL-6 signaling promotes tumor growth in colorectal cancer.
Recent investigations support an important role for TGF-beta in the development of colorectal cancer. However, the molecular consequences of TGF-beta signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-beta in a murine model of colon cancer. Using transgenic mice overexpressing TGF-beta or a dominant negative TGF-beta receptor II under control of the CD2 minigene, we show that TGF-beta signaling in tumor infiltrating T lymphocytes regulates the growth of dysplastic colon epithelial cells, as determined by histology and a novel system for high resolution chromoendoscopy in vivo. 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. Similar to these observations in mice, here we show that human colon cancer tissue expressed only low amounts of membrane bound IL-6R. In contrast, expression and activity of the matrix metalloproteinase TACE were increased. In summary, our data provide novel insights into the role of TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-beta-dependent IL-6 trans-signaling.
Becker
C
C
Lab. of Immunology, I. Medical Clinic, University of Mainz, Mainz, Germany.
Fantini
M C
MC
Wirtz
S
S
Nikolaev
A
A
Lehr
H A
HA
Galle
P R
PR
Rose-John
S
S
Neurath
M F
MF
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018801:CD2 Antigens / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000970:Antineoplastic Agents; D018801:CD2 Antigens; D015850:Interleukin-6; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse