Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition

Abstract

Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30–50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1flox/flox mouse model of GEM grade I neurofibroma. In mice aged 1–4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7–9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy.

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

“…De-Nardo et al (21) noted that the leukocyte composition of established tumors, in which immunosuppressive M2-like TAMs likely predominated over M1 macrophages. Prada et al (22) and Wang et al (23) suggested that incipient tumors, which may be more immunogenic than established lesions, contained higher proportions of M1-like TAMs, which could initiate adaptive immune responses. In the present study, we analyzed the expression of PLD4 in 109 colon cancer specimens during different clinical and pathological grades by IHC.…”

Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

“…Analysis of initial data suggests that the macrophages in NF1 tissues are not principally synthetic macrophages (Prada et al 2013), but additional studies are required. Macrophages at an early stage of NF1 are protective against NF1 development, while at late stages macrophages contribute to the severity of neurofibromas (Prada et al 2013). It is currently unclear whether there is a corresponding phenotypic switch from inflammatory M1 macrophages to synthetic M2 macrophages in NF1.…”

“…It is currently unclear whether there is a corresponding phenotypic switch from inflammatory M1 macrophages to synthetic M2 macrophages in NF1. Interactions between inflammatory cells and connective tissue cells leading to proliferative and fibrotic consequences are likely, but still only partially understood (Staser et al 2010;Prada et al 2013). Increased release of TGF-β in particular from mast cells and/or macrophages is suspected as being a driving force in the development of both gingival overgrowth and neurofibromas (Saito et al 1996;Tipton and Dabbous 1998;Ling et al 2005;Yang et al 2006).…”

The biology of cutaneous neurofibromas

“…Although infiltration of macrophages correlates with tumor progression, their exact role in neurofibroma tumorigenesis is not well-understood. 17 Finally, fibroblasts are nonepithelial, noninflammatory, and nonvascular cells of the connective tissue responsible for ECM deposition and reorganization. 18 Upon skin injury, the normal wound repair process includes inflammation followed by fibroblast proliferation, re-epithelization, and ECM remodeling.…”