M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide
Open accessAbstract
BACKGROUND: Tumor associated macrophages (TAMs) are present in high density in solid tumors. TAMs share many characteristics with alternatively activated macrophages, also called M2. They have been shown to favor tumor development and a role in chemoresistance has also been suggested. Here, we investigated the effects of M2 in comparison to M1 macrophages on cancer cell sensitivity to etoposide. METHODS: We set up a model of macrophage polarization, starting from THP-1 monocytes differentiated into macrophages using PMA (Phorbol 12-myristate 13-acetate). Once differentiated (M0 macrophages), they were incubated with IL-4 and IL-13 in order to obtain M2 polarized macrophages or with IFN-gamma and LPS for classical macrophage activation (M1). To mimic the communication between cancer cells and TAMs, M0, M1 or M2 macrophages and HepG2 or A549 cancer cells were co-cultured during respectively 16 (HepG2) or 24 (A549) hours, before etoposide exposure for 24 (HepG2) or 16 (A549) hours. After the incubation, the impact of etoposide on macrophage polarization was studied and cancer cell apoptosis was assessed by western-blot for cleaved caspase-3 and cleaved PARP-1 protein, caspase activity assay and FACS analysis of Annexin V and PI staining. RESULTS: mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages, which provide a new, easy and well-characterized model of polarized human macrophages. Etoposide-induced cancer cell apoptosis was markedly reduced in the presence of THP-1 M2 macrophages, while apoptosis was increased in cells co-cultured with M1 macrophages. On the other hand, etoposide did not influence M1 or M2 polarization. CONCLUSIONS: These results evidence for the first time a clear protective effect of M2 on the contrary to M1 macrophages on etoposide-induced cancer cell apoptosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The presence of M2 macrophages accelerates tumor progression.
“Other cellular components—for example, immune cells—play key roles in the evolution of a tumor (i.e., the presence of M2 macrophages accelerates tumor progression) [77,78,79,80].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [78]
M2 macrophages are mainly conducive for angiogenesis and stimulate tumour cell metastasis, whereas M1 macrophages are tumour suppressors.
“M2 macrophages are mainly conducive for angiogenesis and stimulate tumour cell metastasis [35]; by the contrast, M1 macrophages are the tumour suppressors as per the effects of pro-inflammatory and cytotoxic cell expression.”
From Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells (2022) · cites this paper as [35]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · see citing works
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
MANTOVANI, A., SOZZANI, S., LOCATI, M., ALLAVENA, P., & SICA, A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02302-5 · Cited by 5,528 · see citing works
Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy
Jain, R. K. (2005) · Science · doi:10.1126/science.1104819 · Cited by 5,527 · cited 1× · see citing works
“[40] showed that when primary macrophages were incubated in direct co-culture with MCF-7 cells, they produced TNF-α that induced MCF-7 cell apoptosis.”
BackgroundMonocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · see citing works
Tumour-educated macrophages promote tumour progression and metastasis
Pollard, J. W. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1256 · Cited by 3,365 · see citing works
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · see citing works
Martínez, F. O., Gordon, S., Locati, M., & Mantovani, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.7303 · Cited by 2,336 · see citing works
Distinct role of macrophages in different tumor microenvironments
Lewis, C. E., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4005 · Cited by 2,225 · see citing works
Sica, A., Schioppa, T., Mantovani, A., & Allavena, P. (2006) · European Journal of Cancer · doi:10.1016/j.ejca.2006.01.003 · Cited by 1,451 · see citing works
Mitchem, J. B., Brennan, D. J., Knolhoff, B. L., Belt, B. A., Zhu, Y., Sanford, D. E., Belaygorod, L., Carpenter, D. H., Collins, L. I., Piwnica-Worms, D. R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2731 · Cited by 943 · see citing works
Differential macrophage programming in the tumor microenvironment
Ruffell, B., Affara, N. I., & Coussens, L. M. (2012) · Trends in Immunology · doi:10.1016/j.it.2011.12.001 · Cited by 855 · see citing works
Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins
Holness, C. L. L., & Simmons, D. (1993) · Blood · doi:10.1182/blood.v81.6.1607.1607 · Cited by 716 · see citing works
Biswas, S. K. (2005) · Blood · doi:10.1182/blood-2005-01-0428 · Cited by 693 · see citing works
The macrophage: Past, present and future
Gordon, S. (2007) · European Journal of Immunology · doi:10.1002/eji.200737638 · Cited by 625 · see citing works
The interaction of anticancer therapies with tumor-associated macrophages
Mantovani, A., & Allavena, P. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150295 · Cited by 617 · see citing works
Optimized THP-1 differentiation is required for the detection of responses to weak stimuli
Park, E., Jung, H., Yang, H.-I., Yoo, M., Kim, C., & Kim, K. S. (2007) · Inflammation Research · doi:10.1007/s00011-007-6115-5 · Cited by 601 · see citing works
Wellington, C. L., Ellerby, L., Hackam, A. S., Margolis, R. L., Trifiro, M. A., Singaraja, R. R., McCutcheon, K. M., Salvesen, G. S., Propp, S. S., Bromm, M., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.15.9158 · Cited by 562 · see citing works
Tumor-associated macrophages: Functional diversity, clinical significance, and open questions
Biswas, S. K., Allavena, P., & Mantovani, A. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0367-7 · Cited by 551 · see citing works
Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer
Shree, T., Olson, O. C., Elie, B. T., Kester, J. C., Garfall, A. L., Simpson, K., Bell-McGuinn, K. M., Zabor, E. C., Brogi, E., & Joyce, J. A. (2011) · Genes & Development · doi:10.1101/gad.180331.111 · Cited by 541 · see citing works
A regenerative approach to the treatment of multiple sclerosis
Deshmukh, V. A., Tardif, V., Lyssiotis, C. A., Green, C. C., Kerman, B., Kim, H. J., Padmanabhan, K., Swoboda, J. G., Ahmad, I., Kondo, T., et al. (2013) · Nature · doi:10.1038/nature12647 · Cited by 522 · see citing works
Saccani, A., Schioppa, T., Porta, C., Biswas, S. K., Nebuloni, M., Vago, L., Bottazzi, B., Colombo, M. P., Mantovani, A., & Sica, A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1867 · Cited by 454 · see citing works
Biswas, S. K., Sica, A., & Lewis, C. E. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.4.2011 · Cited by 434 · see citing works
Ginderachter, J. A. V., Movahedi, K., Ghassabeh, G. H., Meerschaut, S., Beschin, A., Raes, G., & BAETSELIER, P. D. (2006) · Immunobiology · doi:10.1016/j.imbio.2006.06.002 · Cited by 370 · see citing works
Land, R., Engler, G., Kral, A., & Engel, A. K. (2015) · Cited by 346 · see citing works
Different responses to oxidized low-density lipoproteins in human polarized macrophages
Hirose, K., Iwabuchi, K., Shimada, K., Kiyanagi, T., Iwahara, C., Nakayama, H., & Daida, H. (2011) · Lipids in Health and Disease · doi:10.1186/1476-511x-10-1 · Cited by 297 · see citing works
Huh, H., Pearce, S., Yesner, L. M., Schindler, J., & Silverstein, R. (1996) · Blood · doi:10.1182/blood.v87.5.2020.2020 · Cited by 269 · see citing works
Rey-Giraud, F., Hafner, M., & Ries, C. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042656 · Cited by 256 · see citing works
Dias, S., Choy, M., Alitalo, K. K., & Rafii, S. (2002) · Blood · doi:10.1182/blood.v99.6.2179 · Cited by 251 · see citing works
Kodelja, V., Müller, C., Politz, O., Hakij, N., Orfanos, C. E., & Goerdt, S. (1998) · PubMed · Cited by 249 · see citing works
Regulation of macrophage function in tumors: the multifaceted role of NF-κB
Hagemann, T., Biswas, S. K., Lawrence, T., Sica, A., & Lewis, C. E. (2009) · Blood · doi:10.1182/blood-2008-12-172825 · Cited by 246 · see citing works
Kodelja, V., Müller, C., Politz, O., Hakij, N., Orfanos, C. E., & Goerdt, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.3.1411 · Cited by 223 · see citing works
Characterization of polarized THP-1 macrophages and polarizing ability of LPS and food compounds
Chanput, W. P., Mes, J. J., Savelkoul, H. F. J., & Wichers, H. J. (2012) · Food & Function · doi:10.1039/c2fo30156c · Cited by 190 · see citing works
Andreesen, R., Osterholz, J., Bodemann, H. H., Bross, K., Costabel, U., & L�hr, G. W. (1984) · Annals of Hematology · doi:10.1007/bf00319822 · Cited by 112 · see citing works
Notte, A., Ninane, N., Arnould, T., & Michiels, C. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.167 · Cited by 96 · see citing works
Self-citationCell Autonomous Apoptosis Defects in Acid Sphingomyelinase Knockout Fibroblasts
Lozano, J., Menéndez, S., Morales, A., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006353200 · Cited by 95 · see citing works
Kaler, P., Galea, V. P., Augenlicht, L. H., & Klampfer, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011700 · Cited by 89 · see citing works
Ohmori, T., Yang, J.-L., Price, J. O., & Arteaga, C. L. (1998) · Experimental Cell Research · doi:10.1006/excr.1998.4261 · Cited by 83 · see citing works
Angst, E., Reber, H. A., Hines, O. J., & Eibl, G. (2008) · Surgery · doi:10.1016/j.surg.2008.03.024 · Cited by 59 · see citing works
Natoli, A., Lüpertz, R., Merz, C., Müller, W. W., Köhler, R., Krammer, P. H., & Li‐Weber, M. (2013) · International Journal of Cancer · doi:10.1002/ijc.28189 · Cited by 47 · see citing works
Phenotypic investigation of mononuclear phagocytes by flow cytometry
Steinbach, F., & Thiele, B. (1994) · Journal of Immunological Methods · doi:10.1016/0022-1759(94)90015-9 · Cited by 45 · see citing works
Sinha, B. K., Kumar, A., Bhattacharjee, S., et al. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.207928 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Interaction between bone and immune cells: Implications for postmenopausal osteoporosis
Fischer, V., & Haffner-Luntzer, M. (2022) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2021.05.014 · Cited by 759 · see citing works
Casagrande, M., Favieri, F., Tambelli, R., & Forte, G. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.05.011 · Cited by 735 · see citing works
Identification of bacteria-derived HLA-bound peptides in melanoma
Kalaora, S., Nagler, A., Nejman, D., Alon, M., Barbolin, C., Barnea, E., Ketelaars, S. L. C., Cheng, K., Vervier, K., Shental, N., et al. (2021) · Nature · doi:10.1038/s41586-021-03368-8 · Cited by 457 · see citing works
Wang, D., Yang, L., Yue, D., Cao, L., Li, L., Wang, D., Ping, Y., Shen, Z., Zheng, Y., Wang, L., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.03.040 · Cited by 183 · see citing works
Trujillo-de Santiago, G., Flores-Garza, B. G., Tavares-Negrete, J. A., Lara-Mayorga, I. M., González-Gamboa, I., Zhang, Y. S., Rojas-Martínez, A., Ortiz-López, R., & Álvarez, M. M. (2019) · Materials · doi:10.3390/ma12182945 · Cited by 184 · see citing works
Aung, A., Kumar, V., Theprungsirikul, J., Davey, S. K., & Varghese, S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-0342 · Cited by 146 · see citing works
Wang, J., Man, G. C. W., Chan, T. H., Kwong, J., & Wang, C. C. (2018) · Cancer Letters · doi:10.1016/j.canlet.2017.09.054 · Cited by 127 · see citing works
Matrix stiffness‐mediated effects on macrophages polarization and their LOXL2 expression
Xing, X., Wang, Y., Zhang, X., Gao, X., Li, M., Wu, S., Zhao, Y., Chen, J., Gao, D., Chen, R., et al. (2021) · The FEBS Journal · doi:10.1111/febs.15566 · Cited by 92 · see citing works
Self‐Reinforced MOF‐Based Nanogel Alleviates Osteoarthritis by Long‐Acting Drug Release
Sun, Y., Ding, S., Zhao, X., Sun, D., Yang, Y., Chen, M., Zhu, C., Jiang, B., Gu, Q., Liu, H., et al. (2024) · Advanced Materials · doi:10.1002/adma.202401094 · Cited by 96 · see citing works
Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer
Cowman, S. J., Fuja, D. G., Liu, X.-D., Tidwell, R. S. S., Kandula, N., Sirohi, D., Agarwal, A. M., Emerson, L. L., Tripp, S. R., Mohlman, J. S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3890 · Cited by 76 · see citing works
Berger Fridman, I., Ugolini, G. S., VanDelinder, V., Cohen, S., & Konry, T. (2021) · Biofabrication · doi:10.1088/1758-5090/abdb88 · Cited by 46 · see citing works
Chakraborty, J., Roy, S., Murab, S., Ravani, R., Kaur, K., Devi, S., Singh, D., Sharma, S., Mohanty, S., Dinda, A. K., et al. (2019) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b00251 · Cited by 42 · see citing works
Skowron, M. A., Eul, K., Stephan, A., Ludwig, G. F., Wakileh, G. A., Bister, A., Söhngen, C., Raba, K., Petzsch, P., Poschmann, G., et al. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13282 · Cited by 20 · see citing works
Nilkhet, S., Mongkolpobsin, K., Sillapachaiyaporn, C., Wongsirojkul, N., Tencomnao, T., & Chuchawankul, S. (2024) · Scientific Reports · doi:10.1038/s41598-024-58208-2 · Cited by 21 · see citing works
Huang, M.-Y., Liu, X.-Y., Shao, Q., Zhang, X., Miao, L., Wu, X.-Y., Xu, Y.-X., Wang, F., Wang, H.-Y., Zeng, L., et al. (2022) · BMC Gastroenterology · doi:10.1186/s12876-021-02073-0 · Cited by 15 · see citing works
- Authors
- Genin, M., Clement, F., Fattaccioli, A., Raes, M., & Michiels, C.
- Affiliations
- University of Namur (BE)
- Corresponding author
- Michiels, Carine
- Venue
- BMC Cancer
- Published
- 2015-08-08
- Volume
- 15
- Issue
- 1
- Pages
- 577-577
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC4545815
- OpenAlex
- W1918028620
- Cited by
- 1,090
- References
- 42
- Citations by year
- 2026: 102 · 2025: 127 · 2024: 180 · 2023: 141 · 2022: 140 · 2021: 112 · 2020: 100 · 2019: 71 · 2018: 73 · 2017: 23 · 2016: 17 · 2015: 3
- FWCI
- 19.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the University of Namur (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
- Université de Namur
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor-associated macrophages, M1 macrophages, M2 macrophages, macrophage polarization, etoposide, chemosensitivity, chemoresistance, tumor cell apoptosis, THP-1 cells, HepG2 cells, A549 cells, caspase-3, PARP1
- MeSH terms
- Antineoplastic Agents, Phytogenic, Cell Communication, Cell Differentiation, Etoposide, Humans, Macrophage Activation, Macrophages, Neoplasms, Cytokines, Apoptosis, Inflammation Mediators, Drug Resistance, Neoplasm, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
