Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent
Abstract Background Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, sug...
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04577-7 |
| _version_ | 1797647180973998080 |
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| author | Lei Wang Yu-jie Wang Rong Wang Fu-lian Gong Yu-huan Shi Sheng-nan Li Pan-pan Chen Yong-fang Yuan |
| author_facet | Lei Wang Yu-jie Wang Rong Wang Fu-lian Gong Yu-huan Shi Sheng-nan Li Pan-pan Chen Yong-fang Yuan |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Abstract Background Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, suggesting that glucose reduction by energy restriction (calorie restriction or short-term fasting) may has a significant impact on TAMs. The purpose of this study is to verify the effect of fasting-mimicking diet (FMD) on TAMs, and to determine whether FMD synergizes with anti-angiogenic drug apatinib via TAMs. Methods The effect of FMD on TAMs and its synergistic effects with apatinib were observed using an orthotopic mouse breast cancer model. An in vitro cell model, utilizing M2 macrophages derived from THP-1 cell line, was intended to assess the effects of low glucose on TAMs under hypoxic and normoxic conditions. Bioinformatics was used to screen for potential mechanisms of action, which were then validated both in vivo and in vitro. Results FMD significantly inhibit the pro-tumor function of TAMs in vivo and in vitro, with the inhibitory effect being more pronounced under hypoxic conditions. Additionally, the combination of FMD-mediated TAMs inhibition with apatinib results in synergistic anti-tumor activity. This effect is partially mediated by the downregulation of CCL8 expression and secretion by the mTOR-HIF-1α signaling pathway. Conclusions These results support further clinical combination studies of FMD and anti-angiogenic therapy as potential anti-tumor strategies. Graphical Abstract |
| first_indexed | 2024-03-11T15:12:36Z |
| format | Article |
| id | doaj.art-3ee77fc037254e95ba7254caf62d6d68 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-11T15:12:36Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-3ee77fc037254e95ba7254caf62d6d682023-10-29T12:35:02ZengBMCJournal of Translational Medicine1479-58762023-10-0121111310.1186/s12967-023-04577-7Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agentLei Wang0Yu-jie Wang1Rong Wang2Fu-lian Gong3Yu-huan Shi4Sheng-nan Li5Pan-pan Chen6Yong-fang Yuan7Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineSchool of Medicine, National Children’s Medical Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong UniversityDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, suggesting that glucose reduction by energy restriction (calorie restriction or short-term fasting) may has a significant impact on TAMs. The purpose of this study is to verify the effect of fasting-mimicking diet (FMD) on TAMs, and to determine whether FMD synergizes with anti-angiogenic drug apatinib via TAMs. Methods The effect of FMD on TAMs and its synergistic effects with apatinib were observed using an orthotopic mouse breast cancer model. An in vitro cell model, utilizing M2 macrophages derived from THP-1 cell line, was intended to assess the effects of low glucose on TAMs under hypoxic and normoxic conditions. Bioinformatics was used to screen for potential mechanisms of action, which were then validated both in vivo and in vitro. Results FMD significantly inhibit the pro-tumor function of TAMs in vivo and in vitro, with the inhibitory effect being more pronounced under hypoxic conditions. Additionally, the combination of FMD-mediated TAMs inhibition with apatinib results in synergistic anti-tumor activity. This effect is partially mediated by the downregulation of CCL8 expression and secretion by the mTOR-HIF-1α signaling pathway. Conclusions These results support further clinical combination studies of FMD and anti-angiogenic therapy as potential anti-tumor strategies. Graphical Abstracthttps://doi.org/10.1186/s12967-023-04577-7Fasting-mimicking dietAnti-angiogenic drugHypoxiaTAMs |
| spellingShingle | Lei Wang Yu-jie Wang Rong Wang Fu-lian Gong Yu-huan Shi Sheng-nan Li Pan-pan Chen Yong-fang Yuan Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent Journal of Translational Medicine Fasting-mimicking diet Anti-angiogenic drug Hypoxia TAMs |
| title | Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent |
| title_full | Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent |
| title_fullStr | Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent |
| title_full_unstemmed | Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent |
| title_short | Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent |
| title_sort | fasting mimicking diet inhibits tumor associated macrophage survival and pro tumor function in hypoxia implications for combination therapy with anti angiogenic agent |
| topic | Fasting-mimicking diet Anti-angiogenic drug Hypoxia TAMs |
| url | https://doi.org/10.1186/s12967-023-04577-7 |
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