Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy

Silva-Jr, I A da; Chammas, Roger; Lepique, Ana Paula; Jancar, Sônia

doi:10.1038/oncsis.2016.90

Cited by 38 publications

(74 citation statements)

References 34 publications

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“…All these factors have been shown to promote recruitment of monocytes and induction of M2 phenotype at the tumor site . Interestingly, M2 phenotype may also be induced by chemotherapy and by‐products of chemotherapy, such as PAFR ligands (platelet‐activating factor receptor ligands), further promoting tumor cell repopulation and growth . Besides, tumor cell metabolites may also control Mϕ phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 Interestingly, M2 phenotype may also be induced by chemotherapy and by-products of chemotherapy, such as PAFR ligands (platelet-activating factor receptor ligands), further promoting tumor cell repopulation and growth. 12,13 Besides, tumor cell metabolites may also control M phenotype. Selleri and co-workers showed that lactate, secreted by mesenchymal stromal cells, skewed GM-CSF/IL-4 driven dendritic cells maturation from monocytes to M2 M s. 14 In a similar fashion, Colegio and co-workers showed that lactate can promote M2 M phenotype through hypoxia induced factor-1 (HIF-1 ) stabilization.…”

Section: Introductionmentioning

confidence: 99%

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Lactate secreted by cervical cancer cells modulates macrophage phenotype

Stone

Rossetti

Alvarez

et al. 2019

Journal of Leukocyte Biology

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Cervical cancer continues to be a public health problem in developing countries. Previous studies have shown that cervical cancer cells display markers of aerobic glycolysis, indicating that these tumors are likely to secrete lactate. Mostly, lactate is recognized as a molecule capable of suppressing immune responses, through inhibition of T cells, Mϕs, and dendritic cells. We and others have previously shown that Mϕs are frequent cells infiltrating cervical cancers with the ability to inhibit antitumor immune responses and promote tumor growth through angiogenesis. Here, we have tested the hypothesis that lactate, secreted by cervical cancer cells, can modulate Mϕ phenotype. First, we showed higher lactate plasma concentrations in patients with increasing cervical lesion grades, with maximum concentration in the plasma of cancer patients, which supported our hypothesis. We then inhibited lactate production in tumor cell spheroids established from cervical cancer derived cell lines, using the lactate dehydrogenase inhibitor, oxamate, prior to co‐culture with monocytes. Lactate mediated part of the crosstalk between tumor cells and Mϕs, promoting secretion of IL‐1β, IL‐10, IL‐6, and up‐regulation of hypoxia induced factor‐1α expression, and down‐regulation of p65‐NFκB phosphorylation in Mϕs. We also showed that Mϕs from co‐cultures treated with oxamate were better inducers of T cell activation. Of note, experiments performed with inhibition of the monocarboxylate transporters rendered similar results. Our data confirms the hypothesis that lactate, secreted by cervical tumor cells, influences the phenotype of tumor Mϕs, promoting a suppressive phenotype.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lactate secreted by cervical cancer cells modulates macrophage phenotype

Stone

Rossetti

Alvarez

et al. 2019

Journal of Leukocyte Biology

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“…Eicosanoids are derived from arachidonic acid and are pivotal regulators of inflammatory responses (21). Chemotherapy or irradiation stimulates the release of tumor-promoting lipid mediators, including prostaglandins, platelet-activating factor, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and lysophosphatidic acid into the tumor microenvironment (5,19,22,23). Chemotherapy has been recently reported to stimulate the proliferation of ovarian cancer cells through a caspase-3-mediated arachidonic acid pathway (24).…”

mentioning

confidence: 99%

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Gartung

Yang

Sukhatme

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

113

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While chemotherapy remains a mainstay in cancer treatment, growing evidence indicates that it may stimulate tumor growth. Other cancer therapies including radiation, immunotherapy, and stem cell transplantation may also trigger the release of pro‐inflammatory and pro‐tumorigenic cytokines in the tumor stroma. We recently demonstrated that although cancer therapy reduces tumor burden by killing tumor cells, the resulting dead cells, or ‘debris', can promote tumor growth by stimulating the release of cytokines. Chemotherapy fails to generate remission in over 70% of patients with ovarian cancer, is rarely curative, and simultaneously creates tumor cell debris. Thus, cancer therapy is inherently a double‐edged sword and targeting a single cytokine or pathway may not prevent therapy‐induced cancer. Soluble epoxide hydrolase (sEH) inhibitors have been shown to stimulate the resolution of inflammation by promoting the synthesis of pro‐resolving mediators and counter‐regulating pro‐inflammatory cytokines. In this study, tumor cell debris was prepared in vitro by treating either murine or human ovarian tumor cells with first‐line platinum or taxane‐based cytotoxic chemotherapies used for treating ovarian cancer (e.g. cisplatin, carboplatin, or paclitaxel). Chemotherapy‐generated tumor cell debris stimulated ovarian tumor growth in both immunocompetent and immunocompromised hosts. Debris triggered macrophage production of a series of pro‐inflammatory and pro‐angiogenic cytokines. Further, LC‐MS‐MS–based oxylipin profiling of tumor cell debris generated by chemotherapy revealed a pathological release of tumor‐promoting bioactive lipids (‘eicosanoid storm’) including cyclooxygenase (COX)‐derived prostaglandins, lipoxygenase‐derived HETEs, CYP450‐derived DiHOMEs and EpOMEs. We hypothesize that dual COX‐2/sEH inhibition may be a novel modality in suppressing ovarian tumor growth by stimulating the natural debris‐clearing process. A dual COX‐2/sEH inhibitor, PTUPB, suppressed debris‐induced cytokines (e.g. TNFα, CCL2, CCL4, CXCL2, G‐CSF, ICAM‐1, MMP‐9, and PAI‐1) and eicosanoids (e.g. PGF2a, PGD2, and PGJ2). PTUPB also delayed the onset of debris‐stimulated tumor growth in an ovarian cancer (ID8) model, achieving sustained survival over 80 days post‐injection. It is imperative to overcome the predicament between killing tumor cells and the inherent tumor‐promoting activity of the debris. Thus, dual inhibition of COX‐2/sEH may be a novel approach in cancer therapy to suppress the therapy‐induced cytokine/eicosanoid storm and debris‐stimulated tumor growth. Support or Funding Information National Cancer Institute grant RO1 01CA170549‐02; ROCA148633‐01A4; NIEHS Superfund Research Program RO1 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…PAF is a potent pro-inflammatory phospholipid and thus plays roles in many diseases, including anaphylaxis, sepsis, acute respiratory distress syn-drome, bronchial asthma, and G-protein-coupled PAF receptor (PAFR) mediated inflammatory signals [1,5,7]. PAF also promotes neovascularization [4] and tumorgenesis [8]. The deletion of VLDLR in mice not only causes hair loss phenotype on the skin of lactating pups [6], but also leads to severe neovascularization in retina [14,15].…”

Section: Discussionmentioning

confidence: 99%

“…PAFAH, a target of VLDLR signal, hydrolyzes PAF and protects the PAF-mediated inflammation in the skin of pups [6]. PAF binding to PAF receptor activates many physiological events including inflammation, angiogenesis and tumorgenesis [4,7,8]. PAF signal balance can be elaborately regulated by controlling PAF production, PAF hydrolyzation and PAF/PAF receptor pathways [7].…”

Section: Ivyspringmentioning

confidence: 99%

ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor

Xiao¹,

Xi²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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The diminished level of platelet-activating factor acetylhydrolase (PAFAH) in milk causes an enhanced level of platelet activating factor (PAF) in the skin, leading to a severe hair loss phenotype during neonatal pup's lactation. The deletion of very-low-density-lipoprotein receptor (VLDLR) prevents the expression and secretion of PAFAH. Here we revealed that deletion of Roundabout 4 (ROBO4) in mice ameliorated hair loss phenotype via reducing PAF concentration in skin. As a consequence, the neonatal pups with ROBO4 deletion lactated by mother with VLDLR deletion showed normal hair phenotype during lactation. In details,ROBO4 deletion reduced the protein but not mRNA expression of two PAF synthetic enzymes LPCAT1/LPCAT2 in macrophage as well as the expression of PAF receptor in both macrophage and ocular tissue, but increased PAFAH protein in serum. On the other hand, RNA expression profile analysis in macrophages revealed that the genes involving in oxidative phosphorylation and ribosome obviously decreased their expression in response to ROBO4 deletion. Moreover, through High Performance Liquid Chromatography (HPLC) analysis, we found that ATP concentration also reduced in ROBO4 deletion macrophages. Because ribosome and energy are very important factors for the mRNA translation, we then tested whether ROBO4 deletion affects LPCAT1/LPCAT2 mRNA translation using polyribosome assay. As expected, the mRNA level of LPCAT1/LPCAT2 significantly decreased in polyribosome in ROBO4 deletion macrophage comparing to that of wild type. Additionally, mice with ROBO4 deletion suppressed LPS-induced IL-6 expression as well as the phosphorylation of p44/42 and p65, but enhanced the AKT phosphorylation. Collectively, ROBO4 deletion alleviates PAF-and LPS-mediated inflammation. And above results also indicate PAF signal might be a crosstalk point of ROBO4-and VLDLR-activated pathways.

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Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy

Cited by 38 publications

References 34 publications

Lactate secreted by cervical cancer cells modulates macrophage phenotype

Lactate secreted by cervical cancer cells modulates macrophage phenotype

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor

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