Myeloid Cell PI3Kγ and Tumor Inflammation and Progression

The relationship between inflammation and cancer has long been recognized, but the mechanisms of inflammatory cell recruitment to tumors are not well understood. Schmid and colleagues found that CD11b⁺ myeloid cells populated and persistently invaded spontaneous or orthotopic murine and human breast, pancreatic, and lung carcinomas, but not normal tissue. They further found that a range of inflammatory factors derived from both tumor and inflammatory cells present in the tumor microenvironment activated G-protein–coupled receptors (GPCR), receptor tyrosine kinases (RTKs), and Toll-like/interleukin (IL)-1 receptors (TLR/IL1R) on the surface of Gr1⁺CD11b⁺ myeloid cells. Current dogma is that only GPCRs activate the PI3-kinase p110γ isoform. Here, it was found that p110γ was also activated by RTKs and TLR/IL1Rs, albeit by different mechanisms, and that once activated, p110γ promotes activation of integrin α₄β₁, causing myeloid cell invasion into tumors, thus identifying a common pathway linking these receptors. These findings reveal an important therapeutic target as specific inhibitors of p110γ suppressed spontaneous tumor growth by inhibiting inflammation, growth, and metastasis of implanted and spontaneous tumors.

Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011;19:715–27.

Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.