Department of Cancer Biology, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614, USA *Correspondence: [email protected]
(S. Furuta). http://dx.doi.org/10.1016/j.trecan.2017.09.003
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Lysophosphatidate Signaling: The Tumor Microenvironment’s New Nemesis Matthew G.K. Benesch,1,2 Zelei Yang,2 Xiaoyun Tang,2 Guanmin Meng,2 and David N. Brindley2,* Lysophosphatidate (LPA) is emerging as a potent mediator of cancer progression in the tumor microenvironment. Strategies for targeting LPA signaling have recently entered clinical trials for ﬁbrosis. These therapies have potential to improve the efﬁcacies of existing chemotherapies and radiotherapy by attenuating chronic inﬂammation, irrespective of diverse mutations within cancer cells. Overview Cancer research has classically concentrated on cancer cells and their innate characteristics, but this focus is shifting towards the permissibility of host tissues that enable cancer initiation and progression. We focus here on extracellular LPA signaling through its six G protein-coupled receptors as a crucial component of the tumor microenvironment. LPA promotes tumor growth, metastasis, angiogenesis, and immune evasion, and it diminishes the efﬁcacies of radiotherapy and chemotherapy . Most extracellular LPA is produced from plasma lysophosphatidylcholine by the secreted enzyme, autotaxin . LPA signaling is terminated through rapid
degradation of LPA by a family of three lipid phosphate phosphatases (LPPs) (Figure 1A). Knockout of autotaxin is embryonically lethal because LPA signaling is essential for embryonic development. However, postnatal decreases in the expression of autotaxin and changes in expression of the LPPs produce little obvious phenotypic change. Therefore, pharmacological targeting of autotaxin is well tolerated, probably because some LPA can still be produced by phospholipase A type activities.
cancer cells in melanomas, glioblastomas, and thyroid cancers (Figure 1B) . Autotaxin gene copy numbers are ampliﬁed in 10–20% of some cancers . The possibility that other neighboring genes in the locus are also ampliﬁed and contribute to the malignant phenotype is poorly understood and warrants further investigation. Autotaxin mutations are extremely rare . We recently established a novel alternative model of increased autotaxin production in breast cancer where cancer cells produce little autotaxin. Instead, inﬂammatory cytokines and chemokines from breast cancer cells induce autotaxin expression in tumorassociated ﬁbroblasts and adjacent adipose tissue, and this increases breast cancer progression (Figure 1B) [2,4]. Signiﬁcantly, 40% of body autotaxin is produced by adipocytes, and this is increased further by inﬂammation in obesity linked to insulin resistance. Increased autotaxin from adipocytes could provide a possible link between obesity and its contribution to an estimated 20–40% of breast cancers .
A major physiological function of LPA in adults is to facilitate wound healing in response to acute inﬂammation . LPA suppresses autotaxin gene (ENPP2) expression through PI3K signaling, but parallel signaling by inﬂammatory cytokines counteracts this effect to increase autotaxin production (Figure 1A) . LPA increases platelet aggregation and the migration of cells that are needed for tissue repair and angiogenesis . LPAmediated lymphocyte extravasation maintains immune homeostasis and stimulates the conversion of monocytes to macrophages . When tissue repair is achieved, inﬂammation resolves and Upregulation of LPA receptors (LPARs) in autotaxin secretion decreases . multiple cancers is linked to a more invasive phenotype. Elevation of LPAR1 is Maladaptations of LPA Signaling correlated with downregulation of the tumor-suppressor p53 in hepatocellular in Cancers The tissue-remodeling, repair, and immu- carcinomas . LPAR2 is signiﬁcantly nological effects of LPA become expressed in ovarian and colon cancers maladaptive in chronic inﬂammatory dis- where it is closely associated with eases including pulmonary ﬁbrosis, increased levels of multiple pro-angiorheumatoid arthritis, atherosclerosis, genic agonists . Tumors commonly inﬂammatory bowel disease, hepatitis, display decreased LPP1 and LPP3 and cancers (wounds that do not heal) expression, which aggravates the effects . These conditions involve a vicious of increased autotaxin activity and LPAR cycle in which inﬂammatory cytokines expression by decreasing LPA turnover increase autotaxin secretion and LPA . The LPP1 gene (PLPP1) was also production, which in turn stimulates the recently identiﬁed as one of 12 markers expression of cyclooxygenase 2 (COX-2) that predict poor survival for breast canas well as additional inﬂammatory cyto- cer patients . kines and chemokines (Figure 1B) [4,5]. Chronic inﬂammatory conditions such as LPA Signaling in Metastasis and inﬂammatory bowel diseases and hepati- Resistance to Therapy tis predispose to cancer development. The major obstacles to effective cancer Autotaxin can be produced directly by treatment are preventing metastasis and
the loss of efﬁcacy of chemotherapy and radiotherapy [1,6,10]. LPA contributes to metastasis by increasing tumor growth and angiogenesis, as well as by acting as a potent motility factor. LPA is implicated in epithelial-to-mesenchymal (EMT) transitions that facilitate cancer cell spread beyond the primary tumor . The subsequent mesenchymal-to-epithelial (MET) transition facilitates seeding of cancer cells at distant sites. During these transitions, cancer cells must evade the immune system during extravasation and survive at distant sites long enough to establish secondary tumors. LPA facilitates this in part by inhibiting CD8+ T cell activation, and this could suppress adaptive immunity . Furthermore, the LPA reservoir in platelets promotes the survival of circulating cancer cells and subsequent bone metastases . In addition, multiple myeloma (MM) cells stimulate mesenchymal stroma cells (MSCs) at sites of metastases to produce autotaxin . Interestingly, differential LPA signaling through LPAR1 and LPAR3 transduces opposing signals to determine the fate of MSCs. Silencing LPAR3 in MSCs leads to cellular senescence-related phenotypes, transdifferentiation into tumorassociated ﬁbroblasts, and tumor-related angiogenesis in response to stimulation by MM cells. By contrast, MSCs in which LPAR1 signaling was impaired were refractory to cellular senescence and transdifferentiation into tumor-associated ﬁbroblasts, and had reduced MM-promoting abilities . Overall, how LPA signaling in stroma cells promotes metastases provides an active area of investigation. Increased LPA signaling contributes to the loss of therapeutic efﬁcacy of doxorubicin, paclitaxel, tamoxifen, cisplatin, and ionizing radiation [1,5,10,14,15]. This can be explained partly by LPA-induced increases in the expression of the transcription factor, Nrf-2, which promotes the synthesis of antioxidant proteins and multidrug-resistance transporters. This protects cancer cells against
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O P O O−
O O P OH O−
C Adipose ssue/ tumor stroma
PI3K MDRTs NF-κB Nrf-2
COX-2 DNA damage
Anoxidants Oxidave damage
Figure 1. Overview of Autotaxin (ATX)–Lysophosphatidate (LPA)–Lipid Phosphate Phosphatase (LPP) Signaling. (A) Most extracellular LPA is produced by the enzyme ATX from plasma lysophosphatidylcholine (LPC). LPA then signals through its six G protein-coupled receptors (LPARs). LPA is degraded by lipid phosphate phosphatases (LPPs) to form inactive monoacylgylcerol (MAG), terminating the signal. ATX protein production is negatively regulated by LPA through phosphatidylinositol-3-kinase (PI3K) signaling. Cytokines and chemokines, C, produced in response to tissue injury signal through their own receptors to upregulate ATX expression and overcome the inhibition by LPA. When tissue repair is complete, the inﬂammatory signal is terminated and ATX levels fall. ATX production is maintained in chronic inﬂammation. (B) ATX is produced directly by cancer cells in melanomas, glioblastomas, and thyroid tumors (blue arrows). ATX in breast cancer is secreted by adjacent adipose tissue and the tumor stroma (orange arrows), which produces LPA for signaling through cancer cell LPARs. This establishes a vicious cycle because LPA stimulates production of inﬂammatory cytokines and cyclooxygenase-2 (COX-2). Nuclear factor k light-chain enhancer of activated B cells (NF-kB) is activated in response DNA damage produced by radiotherapy, further increasing the concentrations of inﬂammatory mediators and ATX. Chemotherapy-induced oxidative damage can be mitigated by LPA signaling through PI3K, which increases nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) levels. This stimulates the production of antioxidant proteins and multidrug-resistance transporters (MDRTs) to attenuate oxidative damage and increase the efﬂux of chemotherapeutic drugs and toxic oxidation products from cancer cells.
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Table 1. Drugs Targeting Autotaxin/LPA Signaling Currently in Clinical Trialsa
LPA monoclonal antibody
In addition, multiple clinical trials are testing the use of tetracyclines for improving cancer treatments. This could involve an attenuation of LPA signaling by stabilizing LPP activity in addition to decreasing inﬂammation or matrix metalloproteinase activity. Abbreviation: IPF, idiopathic pulmonary ﬁbrosis.
oxidative damage and against the accu- more inﬂammatory cytokines/chemomulation of cytotoxic drugs and toxic oxi- kines in thyroid tumors or in adipose tisdation products (Figure 1B) . sue adjacent to breast tumors . Inhibiting LPA signaling decreases the Radiation-induced cell damage and production of antioxidant enzymes and death also involves the production of the expression of multidrug-resistance reactive oxygen species, and this could transporters, which otherwise could proalso be attenuated by LPA-induced tect cancer cells from different chemostabilization of Nrf-2. We showed that therapies (Figure 1B) . Inhibiting LPA irradiation of human breast adipose tis- signaling also provides a strategy for sue, such as would occur during multiple increasing the sensitivity of tumors to rounds of radiotherapy for breast cancer, radiotherapy [5,10]. stimulates an inﬂammatory response which involves increases in the expres- Finally, increasing the rate of LPA turnover sion of autotaxin, LPAR1, and LPAR2. by increasing the abnormally low expresThis response results from DNA damage sion of LPP1 and LPP3 in cancer cells and activation of NF-kB and COX-2 decreases tumor growth and metastasis (Figure 1B) . This inﬂammation-medi- in mouse models of breast, thyroid, and ated increase in LPA signaling could ovarian cancer . Tetracyclines stabilize diminish the efﬁcacy of subsequent LPP protein expression at the cell surface, rounds of radiation treatment and contrib- thereby increasing overall LPA degradaute to radiation-induced ﬁbrosis, espe- tion in a mouse breast cancer model . cially through activation of LPAR1 . This decreases NF-kB activation and inﬂammation in addition to the expected Targeting the Autotaxin–LPA–LPP inhibition of matrix metalloproteinase activities. The decreased LPA signaling Axis in Cancer Although targeting LPA signaling appears limits tumor macrophage inﬁltration and to be an attractive approach for cancer angiogenesis. Overall, these changes treatment, it is unlikely that this will be decrease breast tumor inﬂammation effective as a monotherapy. However, and tumor growth in preclinical models several modalities are in clinical trials to . treat chronic inﬂammatory diseases and these demonstrate therapeutic efﬁcacy Concluding Remarks (Table 1). The ability to block maladaptive The information that has been reviewed responses to chronic inﬂammation could has necessarily been restricted to publibe exploited as an adjuvant to improve cations appearing mainly in the past 3 existing cancer therapies. In support, years. The background to previous semiwork in mice shows that inhibiting auto- nal work can be obtained from these taxin activity reduces tumor growth partly citations. It is concluded from the recent by decreasing the concentrations of 16 or literature that maladaptive signaling
through the autotaxin–LPA–inﬂammatory axis is important in promoting tumor growth and metastasis. Chemotherapies and radiotherapy damage cells, thus eliciting an inﬂammatory response in addition to that created by the tumor. There is accumulating evidence that LPA-associated inﬂammation can contribute to cancer cell evasion of surveillance by the immune system. Consequently, various strategies for blocking signaling through the autotaxin–LPA–inﬂammatory axis (Table 1) could show promise as adjuvant treatments for improving the efﬁcacy of existing chemotherapies, radiotherapy, and possibly immunotherapies. These treatments might also slow the progression of chronic inﬂammatory diseases to cancer. Blocking LPA signaling could also decrease some side effects of therapy such as radiation-induced ﬁbrosis. The role of adipose tissue in producing autotaxin in response to inﬂammation produced by tumors is also emerging as an important promoter of breast cancer progression. In addition, autotaxin production by the omentum could facilitate basement membrane invasion and metastasis of multiple aggressive abdominal cancers including colon, ovarian, and pancreatic cancers. A signiﬁcant advantage of targeting LPA signaling is that blocking pro-survival crosstalk between various cell populations in the tumor microenvironment impedes cancer cells from recovering from chemotherapy and radiotherapy damage. This could have potential for improving the efﬁcacy of most current cancer therapies. Hence,
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these treatments could be effective for a variety of tumors, and independently of speciﬁc mutations. Acknowledgments The work was supported by the Canadian Cancer Society Research Institute, the Canadian Breast Cancer Foundation, and the Women and Children’s Health Care Institute. D.N.B. has received consultancy payments and/or research funds from Ono Pharmaceuticals Ltd (Osaka, Japan) and Galapagos NV (Mechelen, Belgium). 1
Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, A1B 3V6, Canada 2 Signal Transduction Research Group, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada *Correspondence: [email protected]
(D.N. Brindley). http://dx.doi.org/10.1016/j.trecan.2017.09.004
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