Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. MAF Isolation and Generation of MAF-Derived Conditioned Media
2.3. Flow Cytometry Characterization of MAFs
2.4. In Vitro Osteogenic Differentiation and Alizarin Red S Staining
2.5. In Vitro Adipogenic Differentiation and Oil Red O Staining
2.6. qRT-PCR Measurements of Osteogenic and Adipocenic Differantiated MAFs
2.7. Immunostaining of Melanoma Samples for FAP and Iba-1
2.8. Primary Monocyte Isolation
2.9. M1/M2 Differentiation Assay
2.10. Cell Culture Assays
2.11. Generation of Untreated and Chemotherapy or Small-Molecule Inhibitor-Treated Conditioned Media
2.12. Inhibitor Assay
2.13. ELISA
2.14. Statistical Analysis
3. Results
3.1. MAFs Expressed Traditionally Accepted MSC Markers and Were Also Able to Differentiate towards Osteogenic and Adipogenic Lineages
3.2. MAFs Were in Intimate Contact with Macrophages In Vivo
3.3. MAFs Increased IL-10 Secretion in THP-1 Cells and Primary Macrophages
3.4. Thicker Melanomas Harbored More Immunosuppressive MAFs Compared to Thinner Tumors
Patient | MAF Origin | Gender | Age | Primary Melanoma Details | BRAF | LNM | DM | Relative IL-10 Change | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Subtype | Breslow (mm) | Clark | MI | Ulceration | ||||||||
1 | CM | M | 90 | unclassifiable | 5.4 | V | 14 | yes | wt | yes | yes | 2.14 |
2 | CM | F | 79 | SSM | 2 | IV | positive | yes | yes | 1.84 | ||
PT | F | 79 | SSM | 2 | IV | positive | yes | yes | −0.39 | |||
3 | CM | F | 80 | NM | 4 | III | yes | wt | yes | yes | 1.99 | |
4 | CM | M | 73 | SSM | 0,87 | II | 6 | yes | wt | yes | yes | 0.82 |
5 | CM | M | 69 | SSM | 1 | II | positive | yes | yes | −0.29 | ||
6 | PT | M | 84 | LMM | 5.15 | IV | 22 | no | wt | yes | 0.79 | |
7 | PT | F | 76 | NM | 4.64 | IV | 15 | no | positive | no | no | −0.27 |
8 | CM | F | 66 | NM | 9 | V | positive | yes | yes | 63.98 | ||
9 | PT | M | 23 | unclassifiable | 7.51 | V | 28 | no | positive | yes | 1.15 | |
10 | CM | M | 70 | NM | 5.2 | IV | 18 | yes | positive | yes | 2.02 | |
11 | PT | F | 50 | SSM | 2.92 | IV | 14 | no | positive | yes | 3.48 | |
12 | PT | M | 56 | SSM | 1.77 | III | 4 | no | yes | −0.18 | ||
13 | PT | M | 85 | unclassifiable | 10.26 | IV | 24 | yes | positive | no | 0.91 | |
14 | PT | M | 74 | NM | 6.23 | IV | 18 | yes | wt | yes | −0.09 | |
15 | CM | F | 62 | ALM | 9.1 | V | 12 | yes | positive | yes | 0.19 | |
16 | CM | F | 54 | unclassifiable | 18.21 | V | 42 | yes | wt | yes | yes | 0.15 |
17 | CM | F | 62 | NM | 9 | IV | wt | yes | yes | 1.34 | ||
18 | CM | M | 75 | unclassifiable | 3.34 | IV | 14 | yes | wt | yes | yes | 1.12 |
19 | CM | M | 72 | unclassifiable | 2.71 | IV | 18 | no | positive | yes | yes | 0.12 |
20 | CM | F | 52 | SSM | 10.58 | V | 28 | no | positive | yes | 0.51 | |
21 | CM | M | 43 | SSM | 0.953 | III | 4 | yes | positive | yes | yes | 0.06 |
22 | CM | F | 82 | Unknown primary | wt | yes | yes | 0.45 | ||||
23 | PT | M | 48 | unclassifiable | 17.5 | V | 26–29 | yes | wt | yes | −0.26 | |
24 | PT | F | 90 | NM | 13.24 | IV | 46 | yes | 0.85 | |||
25 | CM | M | 41 | SSM | 0.9 | III | 6 | yes | positive | yes | yes | 0.28 |
26 | CM | M | 67 | SSM | 6.18 | V | 5 | yes | positive | yes | yes | 0.01 |
27 | PT | M | 70 | SSM | 3.364 | IV | 3 | yes | wt | 0.39 | ||
28 | PT | M | 51 | NM | 5.17 | IV | 16 | yes | wt | no | no | 1.25 |
29 | PT | M | 81 | SSM | 5.336 | IV | 6–−8 | yes | wt | yes | yes | 0.87 |
30 | PT | M | 74 | NM | 13.24 | V | 48 | yes | positive | yes | 1.15 | |
31 | PT | M | 57 | unclassifiable | 12.3 | V | 18 | yes | positive | yes | yes | 0.56 |
32 | CM | F | 71 | SSM | 3.4 | IV | 12 | no | positive | yes | yes | 0.46 |
3.5. Prior Exposure to Untreated or BRAF Inhibitor- or Chemotherapy-Treated Melanoma Cells Boosted IL-10-Increasing Ability of MAFs
3.6. Indoleamine 2,3-Dioxygenase (IDO) and the Cyclooxygenase (COX) Pathway Played a Critical Role in MAF-Driven IL-10 Increase
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Papaccio, F.; Kovacs, D.; Bellei, B.; Caputo, S.; Migliano, E.; Cota, C.; Picardo, M. Profiling Cancer-Associated Fibroblasts in Melanoma. Int. J. Mol. Sci. 2021, 22, 7255. [Google Scholar] [CrossRef] [PubMed]
- Schoepp, M.; Ströse, A.J.; Haier, J. Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment. Cancers 2017, 9, 54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Monteran, L.; Erez, N. The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment. Front. Immunol. 2019, 10, 1835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Villanueva, J.; Herlyn, M. Melanoma and the tumor microenvironment. Curr. Oncol. Rep. 2008, 10, 439–446. [Google Scholar] [CrossRef] [Green Version]
- Hilmi, M.; Nicolle, R.; Bousquet, C.; Neuzillet, C. Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion. Cancers 2020, 12, 2969. [Google Scholar] [CrossRef]
- Frenette, P.S.; Pinho, S.; Lucas, D.; Scheiermann, C. Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche and a Stepping-Stone for Regenerative Medicine. Annu. Rev. Immunol. 2013, 31, 285–316. [Google Scholar] [CrossRef]
- Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186. [Google Scholar] [CrossRef] [Green Version]
- Balsamo, M.; Scordamaglia, F.; Pietra, G.; Manzini, C.; Cantoni, C.; Boitano, M.; Queirolo, P.; Vermi, W.; Facchetti, F.; Moretta, A.; et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA 2009, 106, 20847–20852. [Google Scholar] [CrossRef] [Green Version]
- Ziani, L.; Ben Safta-Saadoun, T.; Gourbeix, J.; Cavalcanti, A.; Robert, C.; Favre, G.; Chouaib, S.; Thiery, J. Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion. Oncotarget 2017, 8, 19780–19794. [Google Scholar] [CrossRef] [Green Version]
- Érsek, B.; Silló, P.; Cakir, U.; Molnár, V.; Bencsik, A.; Mayer, B.; Mezey, E.; Kárpáti, S.; Pós, Z.; Németh, K. Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity. Cell. Mol. Life Sci. 2020, 78, 661–673. [Google Scholar] [CrossRef] [Green Version]
- Németh, K.; Leelahavanichkul, A.; Yuen, P.; Mayer, B.; Parmelee, A.; Doi, K.; Robey, P.; Leelahavanichkul, K.; Koller, B.H.; Brown, J.M.; et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 2009, 15, 42–49. [Google Scholar] [CrossRef] [Green Version]
- Nemeth, K.; Keane-Myers, A.; Brown, J.M.; Metcalfe, D.D.; Gorham, J.D.; Bundoc, V.G.; Hodges, M.G.; Jelinek, I.; Madala, S.; Kárpáti, S.; et al. Bone marrow stromal cells use TGF- to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc. Natl. Acad. Sci. USA 2010, 107, 5652–5657. [Google Scholar] [CrossRef] [Green Version]
- Caldwell, I.M.; Hogden, C.; Nemeth, K.; Boyajian, M.; Krepuska, M.; Szombath, G.; Macdonald, S.; Abshari, M.; Moss, J.; Vitale-Cross, L.; et al. Bone Marrow-Derived Mesenchymal Stromal Cells (MSCs) Modulate the Inflammatory Character of Alveolar Macrophages from Sarcoidosis Patients. J. Clin. Med. 2020, 9, 278. [Google Scholar] [CrossRef] [Green Version]
- Raaijmakers, M.I.G. A new live-cell biobank workflow efficiently recovers heterogeneous melanoma cells from native biopsies. Exp. Dermatol. 2015, 24, 377–380. [Google Scholar] [CrossRef]
- Tóth, Z.E.; Mezey, E. Simultaneous Visualization of Multiple Antigens with Tyramide Signal Amplification using Antibodies from the same Species. J. Histochem. Cytochem. 2007, 55, 545–554. [Google Scholar] [CrossRef] [Green Version]
- Serbulea, V.; Upchurch, C.M.; Schappe, M.S.; Voigt, P.; DeWeese, D.E.; Desai, B.N.; Meher, A.; Leitinger, N. Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc. Natl. Acad. Sci. USA 2018, 115, E6254–E6263. [Google Scholar] [CrossRef] [Green Version]
- Raggi, F.; Pelassa, S.; Pierobon, D.; Penco, F.; Gattorno, M.; Novelli, F.; Eva, A.; Varesio, L.; Giovarelli, M.; Bosco, M.C. Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1. Front. Immunol. 2017, 8, 1097. [Google Scholar] [CrossRef]
- Xu, Z.-J.; Gu, Y.; Wang, C.-Z.; Jin, Y.; Wen, X.-M.; Ma, J.-C.; Tang, L.-J.; Mao, Z.-W.; Qian, J.; Lin, J. The M2 macrophage marker CD206: A novel prognostic indicator for acute myeloid leukemia. OncoImmunology 2020, 9, 1683347. [Google Scholar] [CrossRef] [Green Version]
- Edin, S.; Wikberg, M.L.; Dahlin, A.M.; Rutegård, J.; Öberg, Å.; Oldenborg, P.-A.; Palmqvist, R. The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer. PLoS ONE 2012, 7, e47045. [Google Scholar] [CrossRef] [Green Version]
- Tiainen, S.; Tumelius, R.; Rilla, K.; Hämäläinen, K.; Tammi, M.; Tammi, R.; Kosma, V.-M.; Oikari, S.; Auvinen, P. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology 2015, 66, 873–883. [Google Scholar] [CrossRef]
- Genin, M.; Clement, F.; Fattaccioli, A.; Raes, M.; Michiels, C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer 2015, 15, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Amici, S.A.; Young, N.A.; Miranda, J.N.; Jablonski, K.A.; Arcos, J.; Rosas, L.; Papenfuss, T.L.; Torrelles, J.B.; Jarjour, W.N.; Guerau-De-Arellano, M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018, 9, 1593. [Google Scholar] [CrossRef] [Green Version]
- Surdziel., E. Multidimensional pooled shRNA screens in human THP-1 cells identify candidate modulators of macrophage polarization. PLoS ONE 2017, 12, e0183679. [Google Scholar] [CrossRef] [Green Version]
- Li, P.; Hao, Z.; Wu, J.; Ma, C.; Xu, Y.; Li, J.; Lan, R.; Zhu, B.; Ren, P.; Fan, D.; et al. Comparative Proteomic Analysis of Polarized Human THP-1 and Mouse RAW264.7 Macrophages. Front. Immunol. 2021, 12, 2536. [Google Scholar] [CrossRef]
- Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.C.; Krause, D.S.; Deans, R.J.; Keating, A.; Prockop, D.J.; Horwitz, E.M. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef]
- Jackson, M.V.; Morrison, T.J.; Doherty, D.F.; McAuley, D.F.; Matthay, M.A.; Kissenpfennig, A.; O’Kane, C.M.; Krasnodembskaya, A.D. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells 2016, 34, 2210–2223. [Google Scholar] [CrossRef] [Green Version]
- Maximov, V.; Chen, Z.; Wei, Y.; Robinson, M.H.; Herting, C.J.; Shanmugam, N.; Rudneva, V.A.; Goldsmith, K.C.; Macdonald, T.J.; Northcott, P.A.; et al. Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma. Nat. Commun. 2019, 10, 1–11. [Google Scholar] [CrossRef]
- Puré, E.; Blomberg, R. Pro-tumorigenic roles of fibroblast activation protein in cancer: Back to the basics. Oncogene 2018, 37, 4343–4357. [Google Scholar] [CrossRef]
- Romano, V. Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape. Int. J. Mol. Sci. 2021, 22, 5283. [Google Scholar] [CrossRef]
- Mantovani, A.; Sica, A.; Locati, M. Macrophage Polarization Comes of Age. Immunity 2005, 23, 344–346. [Google Scholar] [CrossRef] [Green Version]
- Itakura, E.; Huang, R.-R.; Wen, D.-R.; Paul, E.; Wünsch, P.H.; Cochran, A.J. IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod. Pathol. 2011, 24, 801–809. [Google Scholar] [CrossRef]
- Chen, L.; Shi, Y.; Zhu, X.; Guo, W.; Zhang, M.; Che, Y.; Tang, L.; Yang, X.; You, Q.; Liu, Z. IL-10 secreted by cancer-associated macrophages regulates proliferation and invasion in gastric cancer cells via c-Met/STAT3 signaling. Oncol. Rep. 2019, 42, 595–604. [Google Scholar] [CrossRef] [PubMed]
- Dummer, W.; Becker, J.C.; Schwaaf, A.; Leverkus, M.; Moll, T.; Bröcker, E.B. Elevated serum levels of interleukin-10 in patients with metastatic malignant melanoma. Melanoma Res. 1995, 5, 67–68. [Google Scholar] [CrossRef] [PubMed]
- Nemunaitis, J.; Fong, T.; Shabe, P.; Martineau, D.; Ando, D. Comparison of Serum Interleukin-10 (IL-10) Levels Between Normal Volunteers and Patients with Advanced Melanoma. Cancer Investig. 2001, 19, 239–247. [Google Scholar] [CrossRef] [PubMed]
- Shinomiya, S.; Naraba, H.; Ueno, A.; Utsunomiya, I.; Maruyama, T.; Ohuchida, S.; Ushikubi, F.; Yuki, K.; Narumiya, S.; Sugimoto, Y.; et al. Regulation of TNFα and interleukin-10 production by prostaglandins I2 and E2: Studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem. Pharmacol. 2001, 61, 1153–1160. [Google Scholar] [CrossRef]
- Yavuz, B.G.; Gunaydin, G.; Gedik, M.E.; Kosemehmetoglu, K.; Karakoc, D.; Ozgür, F.F.; Guc, D. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs. Sci. Rep. 2019, 9, 1. [Google Scholar] [CrossRef]
- Cheng, H.; Terai, M.; Kageyama, K.; Ozaki, S.; McCue, P.A.; Sato, T.; Aplin, A.E. Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma. Cancer Res. 2015, 75, 2737–2748. [Google Scholar] [CrossRef] [Green Version]
- Li, Z.; Zhou, J.; Zhang, J.; Li, S.; Wang, H.; Du, J. Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5. Int. J. Cancer 2019, 145, 1946–1957. [Google Scholar] [CrossRef] [Green Version]
- García-Hernández, M.L.; Hernández-Pando, R.; Gariglio, P.; Berumen, J. Interleukin-10 promotes B16-melanoma growth by inhibition of macrophage functions and induction of tumour and vascular cell proliferation. Immunology 2002, 105, 231–243. [Google Scholar] [CrossRef]
- Michielon, E.; González, M.L.; Burm, J.L.A.; Waaijman, T.; Jordanova, E.S.; de Gruijl, T.D.; Gibbs, S. Micro-environmental crosstalk in an organotypic human melanoma-in-skin model directs M2-like monocyte differentiation via IL-10. Cancer Immunol. Immunother. 2020, 69, 2319–2331. [Google Scholar] [CrossRef]
- Redondo, P.; Sánchez-Carpintero, I.; Bauzá, A.; Idoate, M.; Solano, T.; Mihm, M.C., Jr. Immunologic escape, and angiogenesis in human malignant melanoma. J. Am. Acad. Dermatol. 2003, 49, 255–263. [Google Scholar] [CrossRef]
- Howell, W.M.; Turner, S.J.; Bateman, A.; Theaker, J.M. IL-10 promoter polymorphisms influence tumour development in cutaneous malignant melanoma. Genes Immun. 2001, 2, 25–31. [Google Scholar] [CrossRef] [Green Version]
- Hegyi, B.; Kudlik, G.; Monostori, E.; Uher, F. Activated T-cells and pro-inflammatory cytokines differentially regulate prostaglandin E2 secretion by mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2012, 419, 215–220. [Google Scholar] [CrossRef]
- English, K.; Barry, F.P.; Field-Corbett, C.P.; Mahon, B. IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol. Lett. 2007, 110, 91–100. [Google Scholar] [CrossRef]
- Meisel, R.; Zibert, A.; Laryea, M.; Göbel, U.; Däubener, W.; Dilloo, D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004, 103, 4619–4621. [Google Scholar] [CrossRef] [Green Version]
- Hinden, L.; Shainer, R.; Almogi-Hazan, O.; Or, R. Ex Vivo Induced Regulatory Human/Murine Mesenchymal Stem Cells as Immune Modulators. Stem Cells 2015, 33, 2256–2267. [Google Scholar] [CrossRef]
- Gasparri, A.M.; Jachetti, E.; Colombo, B.; Sacchi, A.; Curnis, F.; Rizzardi, G.-P.; Traversari, C.; Bellone, M.; Corti, A. Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ. Mol. Cancer Ther. 2008, 7, 3859–3866. [Google Scholar] [CrossRef] [Green Version]
- Stolina, M.; Sharma, S.; Lin, Y.; Dohadwala, M.; Gardner, B.; Luo, J.; Zhu, L.; Kronenberg, M.; Miller, P.W.; Portanova, J.; et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J. Immunol. 2000, 164, 361–370. [Google Scholar] [CrossRef] [Green Version]
- Vane, J.R.; Bakhle, Y.S.; Botting, R.M. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 1998, 38, 97–120. [Google Scholar] [CrossRef]
- Liu, B.; Qu, L.; Yan, S. Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity. Cancer Cell Int. 2015, 15, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Tudor, D.V.; Bâldea, I.; Lupu, E.A.M.; Kacso, T.; Kutasi, E.; Hopârtean, A.; Stretea, R.; Filip, A.G. COX-2 as a potential biomarker and therapeutic target in melanoma. Cancer Biol. Med. 2020, 17, 20–31. [Google Scholar] [CrossRef]
- Rubel, F.; Kern, J.S.; Technau-Hafsi, K.; Uhrich, S.; Thoma, K.; Häcker, G.; von Bubnoff, N.; Meiss, F.; von Bubnoff, D. Indoleamine 2,3-Dioxygenase Expression in Primary Cutaneous Melanoma Correlates with Breslow Thickness and Is of Significant Prognostic Value for Progression-Free Survival. J. Investig. Dermatol. 2018, 138, 679–687. [Google Scholar] [CrossRef] [Green Version]
- Prendergast, G.C.; Malachowski, W.J.; Mondal, A.; Scherle, P.; Muller, A.J. Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer. Int. Rev. Cell Mol. Biol. 2018, 336, 175–203. [Google Scholar] [CrossRef]
- Hennequart, M. Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. Cancer Immunol. Res. 2017, 5, 695–709. [Google Scholar] [CrossRef] [Green Version]
- Ding, Z.; Ogata, D.; Roszik, J.; Qin, Y.; Kim, S.-H.; Tetzlaff, M.T.; Lazar, A.J.; Davies, M.A.; Ekmekcioglu, S.; Grimm, E.A. iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation. Front. Oncol. 2021, 11, 631766. [Google Scholar] [CrossRef]
- Ekmekcioglu, S.; Ellerhorst, J.; Smid, C.M.; Prieto, V.G.; Munsell, M.; Buzaid, A.C.; Grimm, E.A. Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin. Cancer Res. 2000, 6, 4768–4775. [Google Scholar]
- Berdiel-Acer, M.; Sanz-Pamplona, R.; Calon, A.; Cuadras, D.; Berenguer, A.; Sanjuan, X.; Paules, M.J.; Salazar, R.; Moreno, V.; Batlle, E.; et al. Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information. Mol. Oncol. 2014, 8, 1290–1305. [Google Scholar] [CrossRef]
Co-culture | IDO Inhibitor | L-NAME iNOS Inhibitor | SC-560 COX-1 Inhibitor | NS-398 COX-2 Inhibitor |
---|---|---|---|---|
MAF + THP-1 | not inhibited | not inhibited | inhibited | inhibited |
MAF + primary macrophage | inhibited | not inhibited | not inhibited | inhibited |
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Çakır, U.; Hajdara, A.; Széky, B.; Mayer, B.; Kárpáti, S.; Mezey, É.; Silló, P.; Szakács, G.; Füredi, A.; Pós, Z.; et al. Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner. Cancers 2021, 13, 6173. https://doi.org/10.3390/cancers13246173
Çakır U, Hajdara A, Széky B, Mayer B, Kárpáti S, Mezey É, Silló P, Szakács G, Füredi A, Pós Z, et al. Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner. Cancers. 2021; 13(24):6173. https://doi.org/10.3390/cancers13246173
Chicago/Turabian StyleÇakır, Uğur, Anna Hajdara, Balázs Széky, Balázs Mayer, Sarolta Kárpáti, Éva Mezey, Pálma Silló, Gergely Szakács, András Füredi, Zoltán Pós, and et al. 2021. "Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner" Cancers 13, no. 24: 6173. https://doi.org/10.3390/cancers13246173
APA StyleÇakır, U., Hajdara, A., Széky, B., Mayer, B., Kárpáti, S., Mezey, É., Silló, P., Szakács, G., Füredi, A., Pós, Z., Érsek, B., Sárdy, M., & Németh, K. (2021). Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner. Cancers, 13(24), 6173. https://doi.org/10.3390/cancers13246173