No abstract

Patient selection for PI3K-targeted solid cancer treatment was based on the PIK3CA/PTEN mutational status. However, it is increasingly clear that this is not a good predictor of the response of breast cancer cells to the anti-proliferative effect of PI3K inhibitors, indicating that isoform(s) other than p110α may modulate cancer cells sensitivity to PI3K inhibition. Surprisingly, we found that although no mutations in the p110δ subunit have been detected thus far in breast cancer, the expression of p110δ becomes gradually elevated during human breast cancer progression from grade I to grade III. Moreover, pharmacological inactivation of p110δ in mice abrogated the formation of tumours and the recruitment of macrophages to tumour sites and strongly affected the survival, proliferation and apoptosis of grafted tumour cells. Pharmacological inactivation of p110δ in mice with defective macrophages or in mice with normal macrophages but grafted with p110δ-lacking tumours suppressed only partly tumour growth, indicating a requisite role of p110δ in both macrophages and cancer cells in tumour progression. Adoptive transfer of δD910A/D910A macrophages into mice with defected macrophages suppressed tumour growth, eliminated the recruitment of macrophages to tumour sites and prevented metastasis compared with mice that received WT macrophages further establishing that inactivation of p110δ in macrophage prevents tumour progression. Our work provides the first in vivo evidence for a critical role of p110δ in cancer cells and macrophages during solid tumour growth and may pave the way for the use of p110δ inhibitors in breast cancer treatment.

No abstract

Gliomas are common and lethal tumors of the central nervous system (CNS). Genetic alterations, inflammatory and angiogenic processes have been identified throughout tumor progression; however, treatment still remains palliative for most cases. Biological research on parameters influencing cell survival, invasion and tumor heterogeneity identified several cytokines interfering in CNS inflammation, oxidative stress and malignant transformation, including TNF-superfamily (TNFSF) members. In this report we performed a meta-analysis of public gene-array data on the expression of a group of TNFSF ligands (BAFF, APRIL, TWEAK) and their receptors (BAFF-R, TACI, BCMA, Fn14) in gliomas. In addition, we investigated by immunohistochemistry (IHC) the tumor cells' expression of these ligands and receptors in a series of 56 gliomas of different grade. We show that in IHC, BAFF and APRIL as well as their cognate receptors (BCMA, TACI) and Fn14 expression correlate with tumor grade. This result was not evidenced in micro-arrays meta-analysis. Finally, we detected for the first time Fn14, BAFF, BCMA and TACI in glioma-related vascular endothelium. Our data, combined with our previous report in glioma cell lines, suggest a role for these receptors and ligands in glioma biology and advance these molecules as potential markers for the classification of these tumors to the proliferative, angiogenic or stem-like molecular subtype.