Iron oxide polyaniline-coated nanoparticles modulate tumor microenvironment in breast cancer: an in vitro study on the reprogramming of tumor-associated macrophages
Tóm tắt
Breast cancer is the neoplastic disease with the highest incidence and mortality in the female population worldwide. Treatment remains challenging due to various factors. Therefore, it is of great importance to develop new therapeutic strategies that promote the safe destruction of neoplastic cells without compromising patients' quality of life. Among advances in the treatment of breast cancer, immunotherapy stands out as a promising trend. Recent studies have demonstrated the potential of iron oxide nanoparticles in promoting the reprogramming of M2 macrophages (pro-tumor phenotype) into M1 macrophages (anti-tumor phenotype) within the tumor microenvironment, resulting in potent antitumor effects. In this study, the effect of polyaniline-coated iron oxide nanoparticles (Pani/y-Fe2O3) on macrophage polarization and breast cancer cell death was investigated. The non-cytotoxic concentration of nanoparticles was determined using the MTT assay. For in vitro co-culture experiments, breast cancer cell lines MCF -7 and MDA-MB -231 and macrophages THP-1 were co-cultured in a Transwell system and then the effects of Pani/y-Fe2O3 on cell viability, gene expression, cytokine profile, and oxidative stress markers were investigated. The results showed that Pani/y-Fe2O3 nanoparticles induced M2-to-M1 macrophage polarization in both cell lines through different pathways. In MCF -7 and THP-1 macrophage co-culture, the study showed a decrease in cytokine levels IL -1β, upregulation of M1-associated genes (IL-12, TNF-α) in macrophages, resulting in increased MCF -7 cell death by apoptosis (caspase 3/7+). In MDA-MB -231 co-cultures, increases in cytokines IL -6, IL -1β, and oxidative stress markers were observed, as well as upregulation of the inducible nitric oxide synthase (iNOS) gene in macrophages, leading to tumor cell death via apoptosis-independent pathways (Sytox+). These findings highlight the potential of Pani/y-Fe2O3 as a promising therapeutic approach in the context of breast cancer treatment by effectively reprogramming M2 macrophages into an anti-tumor M1 phenotype, Pani/y-Fe2O3 nanoparticles demonstrated the ability to elicit antitumor effects in both MCF-7 and MDA-MB-231 breast cancer cell lines.
Tài liệu tham khảo
Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M et al (2006) Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour–host interactions. Eur J Cancer 42:751–759. https://doi.org/10.1016/j.ejca.2006.01.010
Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M et al (2022) The current and future burden of breast cancer: global statistics for 2020 and 2040. The Breast 66:15–23. https://doi.org/10.1016/j.breast.2022.08.010
Ásgeirsson KS, Ólafsdóttir K, Jónasson JG, Ögmundsdóttir HM (1998) The effects of il-6 on cell adhesion and e-cadherin expression in breast cancer. Cytokine 10:720–728. https://doi.org/10.1006/cyto.1998.0349
Baker KJ, Houston A, Brint E (2019) IL-1 family members in cancer; two sides to every story. Front Immunol 10:1197. https://doi.org/10.3389/fimmu.2019.01197
Barbieri I, Pensa S, Pannellini T, Quaglino E, Maritano D, Demaria M et al (2010) Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of cten. Cancer Res 70:2558–2567. https://doi.org/10.1158/0008-5472.CAN-09-2840
Baston-Büst D, Böddeker SJ, Altergot O, Ziegler D, Krüssel J-S, Hess AP (2012) Angiogenic factor composition of decidualized endometrial stromal cells is modified by knock-down of syndecan-1 followed by imitation of embryo contact. J Reprod Immunol 94:59–60. https://doi.org/10.1016/j.jri.2012.03.347
Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896. https://doi.org/10.1038/ni.1937
Biswas SK, Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metab 15:432–437. https://doi.org/10.1016/j.cmet.2011.11.013
Bober P, Zasonska BA, Humpolíček P, Kuceková Z, Varga M, Horák D et al (2016) Polyaniline–maghemite based dispersion: electrical, magnetic properties and their cytotoxicity. Synth Met 214:23–29. https://doi.org/10.1016/j.synthmet.2016.01.010
Castaño Z, San Juan BP, Spiegel A, Pant A, DeCristo MJ, Laszewski T et al (2018) IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat Cell Biol. https://doi.org/10.1038/s41556-018-0173-5
Chen K, Satlof L, Stoffels G, Kothapalli U, Ziluck N, Lema M et al (2020) Cytokine secretion in breast cancer cells—MILLIPLEX assay data. Data Brief 28:104798. https://doi.org/10.1016/j.dib.2019.104798
Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thürlimann B et al (2016) Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the international breast cancer study group trials I to V. J Clin Oncol 34:927–935. https://doi.org/10.1200/JCO.2015.62.3504
Corna G, Campana L, Pignatti E, Castiglioni A, Tagliafico E, Bosurgi L et al (2010) Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 95:1814–1822. https://doi.org/10.3324/haematol.2010.023879
Costada Silva M, Breckwoldt MO, Vinchi F, Correia MP, Stojanovic A, Thielmann CM et al (2017) Iron induces anti-tumor activity in tumor-associated macrophages. Front Immunol 8:1479. https://doi.org/10.3389/fimmu.2017.01479
Cronin SJF, Woolf CJ, Weiss G, Penninger JM (2019) The role of iron regulation in immunometabolism and immune-related disease. Front Mol Biosci 6:116. https://doi.org/10.3389/fmolb.2019.00116
Dalzon B, Guidetti M, Testemale D, Reymond S, Proux O, Vollaire J et al (2019) Utility of macrophages in an antitumor strategy based on the vectorization of iron oxide nanoparticles. Nanoscale 11:9341–9352. https://doi.org/10.1039/C8NR03364A
Dethlefsen C, Højfeldt G, Hojman P (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138:657–664. https://doi.org/10.1007/s10549-013-2488-z
Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J (2015) The role of cytokines in breast cancer development and progression. J Interferon Cytokine Res 35:1–16. https://doi.org/10.1089/jir.2014.0026
Gu Z, Liu T, Tang J, Yang Y, Song H, Tuong ZK et al (2019) Mechanism of iron oxide-induced macrophage activation: the impact of composition and the underlying signaling pathway. J Am Chem Soc 141:6122–6126. https://doi.org/10.1021/jacs.8b10904
Harbeck N, Gnant M (2017) Breast cancer. The Lancet 389:1134–1150. https://doi.org/10.1016/S0140-6736(16)31891-8
Huang A, Cao S, Tang L (2017) The tumor microenvironment and inflammatory breast cancer. J Cancer 8:1884–1891. https://doi.org/10.7150/jca.17595
Humpolicek P, Kasparkova V, Saha P, Stejskal J (2012) Biocompatibility of polyaniline. Synth Met 162:722–727. https://doi.org/10.1016/j.synthmet.2012.02.024
Jin R, Liu L, Zhu W, Li D, Yang L, Duan J et al (2019) Iron oxide nanoparticles promote macrophage autophagy and inflammatory response through activation of toll-like Receptor-4 signaling. Biomaterials 203:23–30. https://doi.org/10.1016/j.biomaterials.2019.02.026
Johnston PG, Rondinone CM, Voeller D, Allegra CJ (1992) Identification of a protein factor secreted by 3T3-L1 preadipocytes inhibitory for the human MCF-7 breast cancer cell line. Cancer Res 52:6860–6865
Jung M, Mertens C, Tomat E, Brüne B (2019) Iron as a central player and promising target in cancer progression. Int J Mol Sci 20:273. https://doi.org/10.3390/ijms20020273
Kaler P, Galea V, Augenlicht L, Klampfer L (2010) Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1β- dependent stabilization of snail in tumor cells. PLoS ONE 5:e11700. https://doi.org/10.1371/journal.pone.0011700
Kašpárková V, Humpolíček P, Stejskal J, Capáková Z, Bober P, Skopalová K et al (2019) Exploring the critical factors limiting polyaniline biocompatibility. Polymers (basel) 11:362. https://doi.org/10.3390/polym11020362
Kerr AJ, Dodwell D, McGale P, Holt F, Duane F, Mannu G et al (2022) Adjuvant and neoadjuvant breast cancer treatments: a systematic review of their effects on mortality. Cancer Treat Rev 105:102375. https://doi.org/10.1016/j.ctrv.2022.102375
Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF et al (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. https://doi.org/10.1038/nature11412
Krelin Y, Voronov E, Dotan S, Elkabets M, Reich E, Fogel M et al (2007) Interleukin-1β–driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res 67:1062–1071. https://doi.org/10.1158/0008-5472.CAN-06-2956
Laskar A, Eilertsen J, Li W, Yuan X-M (2013) SPION primes THP1 derived M2 macrophages towards M1-like macrophages. Biochem Biophys Res Commun 441:737–742. https://doi.org/10.1016/j.bbrc.2013.10.115
Leslie K, Gao SP, Berishaj M, Podsypanina K, Ho H, Ivashkiv L et al (2010) Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. Breast Cancer Res 12:R80. https://doi.org/10.1186/bcr2725
Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J (2012) IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. https://doi.org/10.1186/1476-4598-11-87
Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S et al (2022) Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol 15:121. https://doi.org/10.1186/s13045-022-01341-0
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system is in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686. https://doi.org/10.1016/j.it.2004.09.015
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416. https://doi.org/10.1038/nrclinonc.2016.217
Medina-Llamas JC, Chávez-Guajardo AE, Andrade CAS, Alves KGB, de Melo CP (2014) Use of magnetic polyaniline/maghemite nanocomposite for DNA retrieval from aqueous solutions. J Colloid Interface Sci 434:167–174. https://doi.org/10.1016/j.jcis.2014.08.002
Mulens-Arias V, Rojas JM, Pérez-Yagüe S, Morales MP, Barber DF (2015) Polyethylenimine-coated SPIONs trigger macrophage activation through TLR-4 signaling and ROS production and modulate podosome dynamics. Biomaterials 52:494–506. https://doi.org/10.1016/j.biomaterials.2015.02.068
Mulens-Arias V, Rojas JM, Barber DF (2021) The use of iron oxide nanoparticles to reprogram macrophage responses and the immunological tumor microenvironment. Front Immunol 12:693709. https://doi.org/10.3389/fimmu.2021.693709
Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. https://doi.org/10.1016/j.immuni.2014.06.008
Nascimento CS, Alves ÉAR, de Melo CP, Corrêa-Oliveira R, Calzavara-Silva CE (2021) Immunotherapy for cancer: effects of iron oxide nanoparticles on polarization of tumor-associated macrophages. Nanomedicine 16:2633–2650. https://doi.org/10.2217/nnm-2021-0255
Nascimento C, Castro F, Domingues M, Lage A, Alves É, de Oliveira R et al (2023) Reprogramming of tumor-associated macrophages by polyaniline-coated iron oxide nanoparticles applied to treatment of breast cancer. Int J Pharm 636:122866. https://doi.org/10.1016/j.ijpharm.2023.122866
Petters C, Irrsack E, Koch M, Dringen R (2014) Uptake and metabolism of iron oxide nanoparticles in brain cells. Neurochem Res 39:1648–1660. https://doi.org/10.1007/s11064-014-1380-5
Recalcati S, Cairo G (2021) Macrophages and iron: a special relationship. Biomedicines. https://doi.org/10.3390/biomedicines9111585
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3:1101–1108. https://doi.org/10.1038/nprot.2008.73
Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073. https://doi.org/10.1189/jlb.0609385
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G (2019) The molecular machinery of regulated cell death. Cell Res 29:347–364. https://doi.org/10.1038/s41422-019-0164-5
Tarantino P, Corti C, Schmid P, Cortes J, Mittendorf EA, Rugo H et al (2022) Immunotherapy for early triple negative breast cancer: research agenda for the next decade. NPJ Breast Cancer 8:23. https://doi.org/10.1038/s41523-022-00386-1
Theodossiou TA, Ali M, Grigalavicius M, Grallert B, Dillard P, Schink KO et al (2019) Simultaneous defeat of MCF7 and MDA-MB-231 resistances by a hypericin PDT–tamoxifen hybrid therapy. NPJ Breast Cancer 5:13. https://doi.org/10.1038/s41523-019-0108-8
Vercammen E, Staal J, Van Den Broeke A, Haegman M, Vereecke L, Schotte P et al (2008) Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism. Oncogene 27:3780–3788. https://doi.org/10.1038/onc.2008.4
Weagel E, Curren S, Liu PG, Robison R, O’Neill K (2015) Macrophage polarization and its role in cancer. J Clin Cell Immunol 6:338. https://doi.org/10.4172/2155-9899.1000338
Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD et al (2010) Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 30:15–35. https://doi.org/10.1038/jcbfm.2009.192
Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A et al (2016) Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol 11:986–994. https://doi.org/10.1038/nnano.2016.168
Zhang L, Tan S, Liu Y, Xie H, Luo B, Wang J (2019) In vitro inhibition of tumor growth by low-dose iron oxide nanoparticles activating macrophages. J Biomater Appl 33:935–945. https://doi.org/10.1177/0885328218817939
Zhang W, Cao S, Liang S, Tan CH, Luo B, Xu X et al (2020) Differently charged super-paramagnetic iron oxide nanoparticles preferentially induced M1-like phenotype of macrophages. Front Bioeng Biotechnol 8:537. https://doi.org/10.3389/fbioe.2020.00537
Zhou Y, Que K-T, Tang H-M, Zhang P, Fu Q-M, Liu Z-J (2020) Anti-CD206 antibody-conjugated Fe3O4-based PLGA nanoparticles selectively promote tumor-associated macrophages to polarize to the pro-inflammatory subtype. Oncol Lett 20:1–10. https://doi.org/10.3892/ol.2020.12161