Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology

Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression.

HIRSCH, Emilio;
2011

Abstract

Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology
19
715
727
http://dx.doi.org/10.1016/j.ccr.2011.04.016
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WWK-5333YD3-1-1&_cdi=7133&_user=525216&_pii=S1535610811001607&_origin=&_coverDate=06%2F14%2F2011&_sk=999809993&view=c&wchp=dGLbVzz-zSkzk&md5=6257c11e8ca65338bc06101d75235fdd&ie=/sdarticle.pdf
Cancer; inflammation; PI3K
Schmid MC; Avraamides CJ; Dippold HC; Franco I; Foubert P; Ellies LG; Acevedo LM; Manglicmot JR; Song X; Wrasidlo W; Blair SL; Ginsberg MH; Cheresh DA; Hirsch E; Field SJ; Varner JA
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/91736
Citazioni
  • ???jsp.display-item.citation.pmc??? 164
  • Scopus 291
  • ???jsp.display-item.citation.isi??? 279
social impact