Chemoradiation and granulocyte-colony or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): time to think out of the box?

Benna, Marouan; Guy, Jean‐Baptiste; Bosacki, Claire; Jmour, Omar; Mrad, Majed Ben; Ogorodniitchouk, Oleksandr; Soltani, Saïd; Lan, Meiling; Daguenet, Élisabeth; Méry, Benoîte; Sotton, Sandrine; Magné, Nicolas; Vallard, Alexis

doi:10.1259/bjr.20190147

Cited by 16 publications

(12 citation statements)

References 65 publications

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“…In view of observation GM-CSF is overexpressed in tumor cells after radiotherapy and induced tumor migration ( Vilalta et al, 2014 ; Vilalta et al, 2018 ). GM-CSF combined with chemoradiation could trigger abscopal effect ( Benna et al, 2020 ). Highly expressed granulocyte colony-stimulating factor (G-CSF) and granulocyte colony-stimulating factor receptor (G-CSFR) leads to poor survival in gastric cancer ( Fan et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer

Xue

Chen

et al. 2022

Front. Pharmacol.

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Chemotherapy serves as the first choice in clinic to treat advanced gastric cancer. However, emerging evidence indicated the induction of drug resistance and cancer stem cells occasionally by chemotherapy, which seriously limit the therapeutic effects, but the regulatory mechanism remains unclear. Here we treated two human gastric cancer cell lines SGC7901 and BGC823 with 5-Fluorouracil (5-Fu) or Cisplatin (DDP) in vitro. The survived cells showed significant increase of drug resistance, cell stemness and cytokine GM-CSF expression and secretion. As such, GM-CSF was applied to stimulate gastric cancer cells, followed by the subpopulation of CD133+ CSC analysis, sphere formation assay and stemness genes expression analysis. As a result, CSCs showed induction by GM-CSF treatment. A gastric cancer animal model further indicated that the gastric cancer cells significantly promoted tumor growth after GM-CSF treatment in vivo. High-throughput miRNA and mRNA sequencing analyses identified a subset of miRNAs and mRNAs under regulation of both 5-Fu and GM-CSF in gastric cancer cells, including upregulation of miR-877-3p and downregulation of SOCS2. Targeted overexpression or knockdown of miR-877-3p in gastric cancer cells revealed the oncogenic function of miR-877-3p in regulating gastric cancer by suppressing target gene SOCS2. Jak2/Stat3 signaling pathway, as a downstream target of SOCS2, showed activation in vitro and in vivo after treatment with miR-877-3p or GM-CSF. Our findings not only revealed a novel mechanism through which chemotherapy induced CSCs in gastric cancer via GM-CSF-miRNA-Jak2/Stat3 signaling, but also provided an experimental evidence for appropriate dose reduction of adjuvant chemotherapy in treatment of cancer patients.

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Section: Resultsmentioning

confidence: 99%

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer

Xue

Chen

et al. 2022

Front. Pharmacol.

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“…In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected. However, though there were concerns regarding the safety and efficacy of combination treatment of G-CSF and CCRT, Benna et al also pointed out that no abnormal infield event was reported in patients received CSFs-chemoradiation so far (52). G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy including neutropenia for the treatment of NSCLC (53).…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy programs neutrophils to an antitumor phenotype by inducing mesenchymal-epithelial transition

Liu

Hao

et al. 2021

Transl Lung Cancer Res

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Background: Neutrophils can play a pro-tumor or anti-tumor role depending on the tumor microenvironment. The effects of concurrent treatment with granulocyte colony-stimulating factor (G-CSF) and radiotherapy (RT) on neutrophils have not yet to be described.Methods: Hypofractionated radiation of 8 Gy ×3 fractions was administered with or without recombinant G-CSF to Lewis lung carcinoma tumor-bearing C57BL/6 model mice. The activation status of cytotoxic T cells in the mice was measured, along with the levels of tumor-associated neutrophils, cytotoxic T cells, and Treg cells. Tumor growth, survival, cytokine expression, and signaling pathways underlying antitumor effects of tumor-associated neutrophils after treatment were also studied. To ascertain the effects of concurrent RT and G-CSF on tumor-associated neutrophils, neutrophil depletion was performed.Results: RT affected early neutrophil infiltration, which is the first-line immune response. Subsequently, enhanced accumulation of lymphocytes, particularly CD8 cytotoxic T cells, was observed. Notably, lymphocytic infiltration was inhibited by neutrophil depletion but enhanced by G-CSF treatment. RT generated persistent DNA damage, as evidenced by an accumulation of phosphorylation of histone H2AX (γH2AX), and subsequently triggered inflammatory chemokine secretion. The chemokines CXCL1, CXCL2, and CCL5 were upregulated in both radiation-treated cells and the corresponding supernatants. Neutrophils that were newly recruited after RT improved radiosensitivity by inhibiting epithelial-mesenchymal transition via the reactive oxygen species-mediated PI3K/Akt/Snail signaling pathway, and G-CSF treatment enhanced this effect. Conclusions:The results of this study suggest that RT activates neutrophil recruitment and polarizes newly recruited neutrophils toward an antitumor phenotype, which is enhanced by the concurrent administration of G-CSF. Mesenchymal-epithelial transition induced by reactive oxygen species accumulation plays a major role in this process. Thus, the polarization of tumor-associated neutrophils might play a role in future cancer immunotherapies.

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“…Bone marrow depression is the most important limiting factor for using these agents in cancer treatment. Being a chemical injury to the bone marrow, cyclophosphamide is associated with de novo synthesis and release of various PGs, which could have a further adverse effect on hemopoiesis colony stimulating factors synthesized in situ by T-lymphocytes and macrophages which is also essential for proliferation and maturation of granulocytes and non granulocytes (22).…”

Section: Discussionmentioning

confidence: 99%

Aspirin Protective Effect Against Cyclophosphamide Hematological Toxicity In Experimental Animals

Hashim

Al-Attar

Hamdan

2021

Preprint

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Bone marrow toxicity is the most important factor limiting the use of cytotoxic drugs like alkylating agents in cancer treatment. Recently PG synthase enzyme inhibitors have been reported to potentiate the cytotoxic effects of these agents on cancer cells but little is known if they can affect the toxicity of these agents on bone marrow or other tissues. Cyclophosphamide is one of the most commonly used alkylating agent. In the present work, the effect of these PG synthase enzyme inhibitors, aspirin on cyclophosphamide myelotoxicity was determined employing the peripheral blood count to reflect bone marrow injury. The effect on body weight changes caused by cyclophosphamide was also determined. 1. Cyclophosphamide in doses of 25, 50 and 75 mg/kg i. v. produced as a dose dependent reduction in total WBC count, granulocyte, non granulocyte, and Hb% which was maximum on second day after injection and still present on 5th day post injection. It also produced a dose dependent reduction in body weight on day 5 after injection. 2. Aspirin in doges of 75, 150 and 300 mg/kg i. m. protected against the reduction in WBC counts 'measured for 5 days after injection of cyclophosphamide (50 mg/kg). This protection was not dose dependent, though it was more optimum with 300 mg/kg and disappeared largely when a dose of 450 mg/kg was used. Aspirin did not prevent the changes in Hb% but retard the reduction in body weight caused by cyclophosphamide. 3. It is concluded that aspirin can help to reduce injury and enhance recovery from bone marrow toxicity caused by cytotoxic agents such as the alkylating drugs cyclophosphamide for which no specific antidote is available. Aspirin produces this effect possibly by eliminating the harmful inhibitory effect of excess PGs or leukotrienes, released by bone marrow injury on growth factors of haemopoietic progenitor cells. The magnitude of this protection on WBC counts does not seem to differ between either PG synthase enzyme inhibitors or steroids when used alone or in combination although a synergistic effect in protecting erythropoiesis is observed.

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Chemoradiation and granulocyte-colony or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): time to think out of the box?

Cited by 16 publications

References 65 publications

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer

Radiotherapy programs neutrophils to an antitumor phenotype by inducing mesenchymal-epithelial transition

Aspirin Protective Effect Against Cyclophosphamide Hematological Toxicity In Experimental Animals

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