Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

David N Brindley, Xiaoyun Tang, Guanmin Meng, Matthew G K Benesch, David N Brindley, Xiaoyun Tang, Guanmin Meng, Matthew G K Benesch

Abstract

Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.

Keywords: adiponectin; chemokines; chemotherapy; cytokines; fibrosis; macrophages; radiotherapy; tumor microenvironment.

Conflict of interest statement

D.N.B. is a member of the Scientific Advisory Board for iOnctura and the other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of lysophosphatidate (LPA) signaling pathway. Extracellular LPA is produced from the enzymatic action of autotaxin (ATX) on lysophosphatidylcholine (LPC). LPA is degraded by lipid phosphate phosphatases (LPP)1–3 into inactive monoacylglycerol (MAG). LPA signals through at least six known G-protein coupled receptors (with three sub-units) to mediate its downstream cellular effects, which are dependents on the coupling and/or subunit type.
Figure 2
Figure 2
Breast cancer cells are poor producers of autotaxin (ATX) compared to adjacent adipose tissue tumor-associated fibroblasts. (A) Human breast cancer cells express little ATX compared to other neuroblastoma, melanoma, glioma, thyroid, and liver cancer cells. Results are means ± SEM. Numbers in parentheses indicates the number of cell lines. Results taken from cBioPortal (www.cbiportal.org) [63,64] and are reproduced from Reference [29] with permission. (B) ATX mRNA expression in 176 human breast tumors and 10 normal breast tissue specimens. Box plots show minimum, mean, and maximum values, 25th, 50th, and 75th percentiles (box), and 1st and 99th percentiles. Results are expressed relative to the mean of the breast tumor results, which were given the value of 1. * p < 0.001. Adapted from Reference [67]. (C) ATX, mRNA, and activity levels are significantly lower in tumors compared to adjacent fat pads in orthotopic syngeneic and immunocompetent mouse models (4T1/BALB/C, E0771/C57BL/6) * p < 0.05 by a paired t-test. Results are expressed relative to the mean of the breast tumor results, which were given the value of 1. Includes results adapted from Reference [14]. (D) Relative ATX mRNA and activity levels in patient-matched Hs578T breast cancer cells and Hs578Bst stromal cells. Results are means ± SEM from three independent experiments. * p < 0.05 vs. Hs578T breast cancer cells. Adapted from Reference [67]. (E) ATX expression in mouse 4T1 tumors comes predominantly from cancer-associated fibroblasts. Whole 4T1 tumors were enzymatically digested and sorted by flow cytometry for cancer cells (epithelial cells) using EPCAM (epithelial cell adhesion molecule), leukocytes using CD-45, endothelial cells using CD-31, and cancer-associated fibroblasts using platelet-derived growth factor alpha (PDGFα). ATX mRNA levels are expressed relative to those in the whole tumor. Results are means ± SEM from three independent experiments for whole tumor and cancer cells, and means ± range for two independent experiments for leukocytes, endothelial cells, and fibroblasts.
Figure 3
Figure 3
ATX is induced in tumor-associated compared to normal breast adipose tissue. (A) ATX immunohistochemical staining is increased in human tumor stroma compared to adjacent breast stroma. * p < 0.001 by paired t-test. Staining intensity was quantified by ImageJ [(NIH), Bethesda, MD, USA] and the results were adapted from Reference [67]. (B) ATX mRNA and activity levels are higher in tumor-bearing mammary fat pads compared to unaffected contralateral fat pads in a 4T1 orthotopic, synergistic, and immunocompetent BALB/C mouse model. ATX staining and mRNA levels are expressed relative to the breast stroma and contralateral fat pad, respectively. * p < 0.05 by paired t-test. Results adapted from Reference [14].
Figure 4
Figure 4
Overview of ATX/LPA signaling within the breast tumor microenvironment. Breast cancer cells produce virtually no ATX relative to tumor stroma and surrounding adipose tissue. Instead, as cancer cells grow, they establish an inflammatory milieu where inflammatory mediators (IM) (red arrows) stimulate both tumor stroma cells, including tumor-associated fibroblasts, and adjacent adipose tissue to increase ATX production. The tumor also recruits other circulating cells including macrophages to further increase inflammatory signaling and promote a pro-survival and pro-growth environment. Increased ATX enzymatic activity increases tumor LPA concentrations (green arrows), which, thereby, initiates a vicious cycle that further fuels tumor growth and ultimately metastasis.
Figure 5
Figure 5
ATX signaling protects cancers cells from cytotoxic effects of radiotherapy and chemotherapy. Lysophosphatidate (LPA) signaling stabilizes Nrf2 expression via PI3K-mediated survival pathways [115]. Nrf2 facilitates expression of proteins involved in DNA repair and antioxidant pathways as well as increases expression of multidrug-resistant transporters on the cancer cell surface for export of drug and oxidized molecules from the cell [29]. Combined, these mechanisms contribute to cancer cell survival and resistance to cancer therapy.

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