ElevatedARG1expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients

Abstract

Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n D 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p D 0 .032), moist desquamation (p D 0 .027), and CTC grade (p D 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p D 0 .069), moist desquamation (p D 0 .037), and CTC grade (p D 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.

Radiotherapy-Associated Long-term Modification of Expression of the Inflammatory Biomarker Genes ARG1, BCL2L1, and MYC

“…The first gene, ARG1 , catalyzes the hydrolysis of arginine to ornithine and urea and is expressed in macrophages. Interestingly its expression has been found upregulated in vitro , in primary monocytes-derived macrophages obtained from blood samples collected from patients before and after the first delivered 2 Gy radiotherapy dose in breast cancer patients (36). The authors found that the level of ARG1 mRNA significantly correlated with higher grades of radiation-induced acute skin toxicities in early breast cancer patients.…”

Lp-PLA 2 (Lipoprotein-Associated Phospholipase A 2 ) Deficiency Lowers Cholesterol Levels and Protects Against Atherosclerosis in Rabbits

“…34 After differentiation into macrophages, cells were stimulated with LPS (lipopolysaccharide; 100 ng/mL) plus IFN (interferon) γ (50 ng/mL) or vehicle (0.1% BSA) for 48 hours. 35,36 Then, the cellular RNA was collected, and reverse transcribed into cDNA. qPCR was performed to detect the expression of M1 macrophage markers.…”

Transcriptomic analysis of eyelid pigmentation in Hereford cattle

“…2018) and its elevated expression indicates radiation therapy‐induced acute skin toxicities (Jung et al . 2015). Gene FGF23 acts as a proinflammatory cytokine, and its high expression is associated with an increased risk of mortality, probably because of its contribution to decreased host defense response to infection, left ventricular hypertrophy, inflammation and anemia (Courbebaisse & Lanske 2017).…”

“…Gene ARG1 catalyzes the conversion of L-arginine to L-ornithine and urea, is considered an oncogene in hepatocellular carcinoma (You et al 2018) and its elevated expression indicates radiation therapy-induced acute skin toxicities Figure 2 Differential network analysis. Topological differences in gene coexpression networks between pigmented and non-pigmented samples: GO terms pigmentation (GO:0043473), melanosome (GO:0042470) and defense response to bacterium (GO:0042742) (Jung et al 2015). Gene FGF23 acts as a proinflammatory cytokine, and its high expression is associated with an increased risk of mortality, probably because of its contribution to decreased host defense response to infection, left ventricular hypertrophy, inflammation and anemia (Courbebaisse & Lanske 2017).…”