Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis

Abstract

Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived HO triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Moreover, increased reactive oxygen species (ROS) production in myeloid cells initiates tumor growth in various organs also in the absence of a carcinogen challenge in a paracrine manner. Our data identify an intricate crosstalk between myeloid cell-derived ROS molecules, oxidative DNA damage, and tumor necrosis factor α-mediated signaling to orchestrate a tumor-promoting microenvironment causing invasive cancer.

Deletion of Runx1 in osteoclasts impairs murine fracture healing through progressive woven bone loss and delayed cartilage remodeling

“…The low bone mass observed in LysM ‐ Cre ; Runx1 F/F mice arises through increased osteoclastic bone resorption rather changes bone formation; thus, it is likely that the alterations in healing are independent of pre‐existing differences in the bone. The newly available inducible LysM ‐ CreER T2 mouse would not only allow for postnatal deletion of Runx1 that would circumvent this issue but would also permit the recombination of Runx1 at various stages of fracture repair (e.g., cartilage remodeling vs woven bone remodeling) . Finally, we were unable to confirm accelerated osteoclastogenesis in the context of Runx1 cKO in vitro as our fracture model involves the insertion of an intramedullary pin that ablates the bone marrow.…”

TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages

“…Inflammation is a well‐known process in many infectious and noninfectious diseases 34‐36 . Mitochondrial dysfunction and amplified ROS production are key events in inflammatory diseases and are responsible for the association between chronic inflammation and increased tumor incidence 37,38 . Abnormal ROS production promotes inflammation and inflammatory programmed cell death 16,22 .…”

Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme

“…Cancer cell proliferation is a hallmark of cancer, and deregulated cell proliferation is a prerequisite for neoplastic cell transformation. Production of ROS and nitrogen intermediates by TAMs and TANs/MDSCs promotes tumor initiation through their contribution to genetic instability in preneoplastic cells (Canli et al, 2017). Innate myeloid cells also produce proinflammatory cytokines and growth factors, such as IL-6, IL-11, IL-1β, and EGF, which play an important role in both the initiation and progression of tumorigenesis, especially in inflammation-induced cancer (Greten and Grivennikov, 2019).…”