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Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway

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Abstract

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils.

Graphical Abstract

Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase

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Data Availability

The data that support the findings of this study are available from the corresponding author, AMA, upon reasonable request.

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Acknowledgements

This study was funded by the Tehran University of Medical Sciences (grant number: 34686). We are also grateful for the financial support from the Iran National Science Foundation (INSF) (Grant number: 96011965).

Funding

None of the funding sources had any role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. Tehran University of Medical Sciences and Health Services,34686,Ali Mohammad Alizadeh

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Authors and Affiliations

  1. Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran

    Solmaz Khalighfard & Ebrahim Esmati

  2. Research Center on Developing Advanced Technologies, Tehran, Iran

    Solmaz Khalighfard

  3. Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Vahid Khori, Farahnazsadat Ahmadi, Taghi Amiriani, Amirhoushang Poorkhani & Somayeh Sadani

  4. International Center for Personalized Medicine (ICPM), Düsseldorf, Germany

    Saeed Khodayari & Hamid Khodayari

  5. Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Mohammad Reza Kalhori

  6. Department of Radiology, Tbilisi State Medical University (TSMU), Tbilisi, Georgia

    Pedram Keshavarz

  7. Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran

    Ali Mohammad Alizadeh

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  1. Solmaz Khalighfard
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Contributions

SK: data analysis, sample processing, and manuscript preparation. VK and EE: sample processing. FA, TA, AP, and SS: sample processing and manuscript revision. SK and HK: study concept and design. MRK: sample collection and processing. PK: manuscript preparation. AMA: study conception and design, sample processing, and manuscript revision.

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Correspondence to Ali Mohammad Alizadeh.

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Khalighfard, S., Khori, V., Esmati, E. et al. Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway. Med Oncol 40, 74 (2023). https://doi.org/10.1007/s12032-022-01935-1

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