Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

Abstract

We have previously established that adipose tissue adjacent to breast tumors becomes inflamed by tumor-derived cytokines. This stimulates autotaxin (ATX) secretion from adipocytes, whereas breast cancer cells produce insignificant ATX. Lysophosphatidate produced by ATX promotes inflammatory cytokine secretion in a vicious inflammatory cycle, which increases tumor growth and metastasis and decreases response to chemotherapy. We hypothesized that damage to adipose tissue during radiotherapy for breast cancer should promote lysophosphatidic acid (LPA) signaling and further inflammatory signaling, which could potentially protect cancer cells from subsequent fractions of radiation therapy. To test this hypothesis, we exposed rat and human adipose tissue to radiation doses (0.25-5 Gy) that were expected during radiotherapy. This exposure increased mRNA levels for ATX, cyclooxygenase-2, IL-1β, IL-6, IL-10, TNF-α, and LPA and LPA receptors by 1.8- to 5.1-fold after 4 to 48 h. There were also 1.5- to 2.5-fold increases in the secretion of ATX and 14 inflammatory mediators after irradiating at 1 Gy. Inhibition of the radiation-induced activation of NF-κB, cyclooxygenase-2, poly (ADP-ribose) polymerase-1, or ataxia telangiectasia and Rad3-related protein blocked inflammatory responses to γ-radiation. Consequently, collateral damage to adipose tissue during radiotherapy could establish a comprehensive wound-healing response that involves increased signaling by LPA, cyclooxygenase-2, and other inflammatory mediators that could decrease the efficacy of further radiotherapy or chemotherapy.-Meng, G., Tang, X., Yang, Z., Benesch, M. G. K., Marshall, A., Murray, D., Hemmings, D. G., Wuest, F., McMullen, T. P. W., Brindley, D. N. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy.

Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

“…Human adipose tissue samples were obtained with approval of the University of Alberta Health Research Ethics Board (ID Pro00018758), with written informed consent of the participants, as previously described (40). Adipose tissues were cut into small pieces, ;5-10 mg per piece (1-2 mm 3 ) in sterile conditions.…”

“…Centrifuged culture medium from human adipose tissue was analyzed for cytokines and chemokines with the Human Cytokine/Chemokine 65-plex ELISA Discovery Luminex assay (Eve Technologies Corp., Calgary, AB, Canada) (40). Mouse plasma and tissue homogenates were analyzed for cytokines, chemokines, and hormones with Mouse Cytokine/Chemokine 32-plex ELISA and Mouse Metabolic 11-plex arrays (Eve Technologies).…”

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

“…This bi-directional signaling between adipose tissue and breast tumors has been confirmed by other investigators [34,35]. Indeed, adipocytes produce~40% of the body's ATX [36,37] and the breast is rich in adipose tissue.We subsequently showed that exposing cultured human breast adipose tissue to γ-radiation increased the secretion of ATX as well the expression of LPA 1 and LPA 2 receptors downstream of DNA damage [21]. These events activate a feed-forward inflammatory cycle since LPA increases the expression of cyclooxygenase-2 and multiple inflammatory cytokines/chemokines, which in turn promote further ATX secretion [32,38].…”

“…We subsequently showed that exposing cultured human breast adipose tissue to γ-radiation increased the secretion of ATX as well the expression of LPA 1 and LPA 2 receptors downstream of DNA damage [21]. These events activate a feed-forward inflammatory cycle since LPA increases the expression of cyclooxygenase-2 and multiple inflammatory cytokines/chemokines, which in turn promote further ATX secretion [32,38].…”

“…RT-induced fibrosis also contributes to the development of lymphedema, which results in impaired function and decreased quality of life [8].Increased signaling through the autotaxin (ATX)-lysophosphatidate (LPA)-LPA 1 receptor pathway has been widely recognized as a major contributor to various types of fibrotic pathologies, notably of the liver and lungs [9][10][11][12][13][14][15][16][17][18][19][20]. In this pathway, the enzyme ATX generates LPA from lysophosphatidylcholine; LPA in turn activates six G-protein coupled LPA receptors that promote cell survival, proliferation and migration as well as inflammation [21]. Inhibition of ATX and LPA signaling significantly attenuated lung fibrosis in various disease models, including idiopathic pulmonary fibrosis (IPF) and the fibrosis that occurs following exposure to bleomycin (BLM) [19,22,23], a radiomimetic anticancer agent [24].The key role for activation of this pathway in fibrosis was borne out in clinical trials where drugs such as GLPG1690 (an ATX inhibitor) and BMS986020 (an LPA 1 receptor antagonist) attenuated the progression of IPF [25,26].…”