Repeated Fractions of X-Radiation to the Breast Fat Pads of Mice Augment Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle.

Guanmin Meng,Jonathan M Curtis,Frank Wuest,David N Brindley,David Murray,Jennifer Dufour,Todd P W Mcmullen,Xiaoyun Tang,Yuanyuan Zhao,Melinda Wuest

doi:10.3390/cancers11111816

Abstract

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal “image-guided” RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin–lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.

Highlights

Radiotherapy (RT) is a mainstay of cancer treatment, but it sometimes fails to eliminate residual cancer cells and it can produce adverse side effects, such as fibrosis
Inflammation can be a key component of RT, we propose that persistent activation of the autotaxin (ATX)–lysophosphatidate (LPA)-inflammatory cycle becomes maladaptive
We previously showed that a single γ-ray exposure of between 0.25 and 5 Gy to rat and human adipose tissues in vitro activates LPA signaling by increasing the levels of ATX, LPA1 and LPA2 receptors; COX-2; and multiple inflammatory cytokines [58]

Summary

Introduction

Radiotherapy (RT) is a mainstay of cancer treatment, but it sometimes fails to eliminate residual cancer cells and it can produce adverse side effects, such as fibrosis. Cancers 2019, 11, 1816 causes inflammation, which in turn can enhance the immunologic elimination of cancer cells [1,2,3]. Inflammation can be a key component of RT, we propose that persistent activation of the autotaxin (ATX)–lysophosphatidate (LPA)-inflammatory cycle becomes maladaptive. Extracellular LPA is synthesized mainly by ATX and it signals through six G protein-coupled receptors. ATX is secreted in response to inflammation [5,6] to facilitate wound healing [5]. Inflammation resolves when the tissue is repaired and ATX secretion decreases [5]. When inflammation is not resolved, chronic activation of the ATX–LPA-inflammatory cycle becomes maladaptive [7,9] in conditions such as pulmonary fibrosis, cirrhosis, rheumatoid arthritis, inflammatory bowel disease and cancers [10,11]. Many inflammatory conditions are accompanied by fibrosis, and LPA drives fibrosis through LPA1 receptors [12,13,14,15,16,17,18,19,20,21,22,23]

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