E2f3 in tumor macrophages promotes lung metastasis

Abstract

The Rb-E2F axis is an important pathway involved in cell cycle control that is deregulated in a number of cancers. E2f transcription factors have distinct roles in the control of cell proliferation, cell survival and differentiation in a variety of tissues. We have previously shown that E2fs are important downstream targets of a CSF-1 signaling cascade involved in myeloid development. In cancer, tumor associated macrophages (TAMs) are recruited to the tumor stroma in response to cytokines secreted by tumor cells and are believed to facilitate tumor cell invasion and metastasis. Using the MMTV-Polyoma Middle T antigen (PyMT) mouse model of human ductal carcinoma, we show that the specific ablation of E2f3 in TAMs, but not in tumor epithelial cells, attenuates lung metastasis without affecting primary tumor growth. Histological analysis and gene expression profiling suggests that E2f3 does not impact the proliferation or survival of TAMs, but rather controls a novel gene expression signature associated with cytoskeleton rearrangements, cell migration and adhesion. This E2f3-TAM gene expression signature was sufficient to predict cancer recurrence and overall survival of ER-positive breast cancer patients. Interestingly, we find that E2f3b but not E2f3a levels are elevated in TAMs from PyMT mammary glands relative to controls, suggesting a differential role for these isoforms in metastasis. In summary, these findings identify E2f3 as a key transcription factor in TAMs that influences the tumor microenvironment and tumor cell metastasis.

MicroRNA‑433 reduces cell proliferation and invasion in non‑small cell lung cancer via directly targeting E2F transcription factor 3

“…E2F3 (Fig. 3A) was predicted as a primary target of miR-433 and selected for investigation, to further verify its previously reported contribution to NSCLC formation and progression (26)(27)(28)(29)(30). To confirm this hypothesis, luciferase reporter assays were performed using A549 and H460 cells cotransfected with miR-433 mimics or miR-NC and pMIR-Wt-E2F3-3'-UTR or pMIR-Mut-E2F3-3'-UTR.…”

Human glioblastoma‐associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples

“…By analyzing enriched transcription factor binding sites of the upregulated cell cycle-associated genes we found that E2F family members might be involved in the regulation of these genes. A recent study could show that E2f3 expression in murine lung cancer-associated macrophages is positively correlated with metastasis (Trikha et al, 2015). E2f3 expression did not influence the survival or proliferation of lung cancer-associated macrophages, but it positively influenced cytoskeleton rearrangements, cell migration, and cell adhesion, all of which are features that were also enriched in the upregulated genes in hGAMs.…”

Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

“…7,28 As exosomes are critical mediators in the interaction of cancer cells with TME, we need to explore their role and function in oncogenesis to be able to restrict their cancer-promoting features. The present study shows that miR-23a, which is characteristically expressed and secreted by hypoxic lung cancer cells, is a potent proangiogenic factor through triggering HIF-1α and decreasing tight junction in endothelial cells.…”