Repeated Fractions of X-Radiation to the Breast Fat Pads of Mice Augment Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle
Open Access
- 18 November 2019
- Vol. 11 (11), 1816
- https://doi.org/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.Keywords
Funding Information
- Canadian Cancer Society Research Institute (INNOV15-2)
This publication has 93 references indexed in Scilit:
- Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapyBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Systemic effects of local radiotherapyThe Lancet Oncology, 2009
- Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant ResponseMolecular Cell, 2009
- Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instabilityCarcinogenesis: Integrative Cancer Research, 2009
- Lysophosphatidic Acid 2 Receptor-mediated Supramolecular Complex Formation Regulates Its Antiapoptotic EffectJournal of Biological Chemistry, 2009
- Inhibition of autotaxin production or activity blocks lysophosphatidylcholine‐induced migration of human breast cancer and melanoma cellsMolecular Carcinogenesis, 2009
- Cancer as an overhealing wound: an old hypothesis revisitedNature Reviews Molecular Cell Biology, 2008
- The Lysophosphatidic Acid 2 Receptor Mediates Down-regulation of Siva-1 to Promote Cell SurvivalJournal of Biological Chemistry, 2007
- The role of apoptosis in cancer development and treatment responseNature Reviews Cancer, 2005