臺灣博碩士論文加值系統

神經纖維瘤是一種與遺傳性疾病—神經纖維瘤第一型（Neurofibromatosis type 1, NF1）相關的神經鞘腫瘤。目前臨床上對神經纖維瘤的治療仍然缺乏長期有效且安全的方法。神經纖維瘤的腫瘤細胞是帶有NF1雙等位基因突變的許旺細胞。在腫瘤微環境中，存在許多非腫瘤細胞，例如：纖維母細胞、巨噬細胞和嗜中性球，這些非腫瘤細胞與腫瘤細胞有複雜的互動關係，例如微環境細胞可能會因為受到腫瘤細胞的刺激，進而產生促進神經纖維瘤生成的物質。我們先前的研究分析了神經纖維瘤腫瘤細胞的分泌體，發現與正常的許旺細胞相比，神經纖維瘤細胞分泌體中的趨化因子CXCL1和CXCL8的表現量明顯上升。因此，在這個研究中，我們主要的研究目標是探討神經纖維瘤細胞所表現的CXCL1和CXCL8可以對腫瘤微環境中的非腫瘤細胞造成什麼影響。我們使用的研究策略是以全基因合成建構CXCL1和CXCL8的大量表現（Overexpression, OE）質體，並將其轉染至許旺細胞，接續將收集含其分泌體的培養液（Conditioned media, CM）處理巨噬細胞、嗜中性球和纖維母細胞，我們針對這些微環境細胞的行為改變進行分析，用以探討趨化因子CXCL1和CXCL8在神經纖維瘤腫瘤微環境中所扮演的角色。我們的研究結果顯示：（1）CXCL1/CXCL8-OE可以同時誘發許旺細胞中其他趨化因子的表現，呈現與神經纖維瘤分泌體非常相似之趨勢；（2） CXCL1/CXCL8-OE-CM可以刺激巨噬細胞往M1極化、促進吞噬能力和細胞浸潤；（3）CXCL1/CXCL8-OE-CM也刺激嗜中性球增生、往N1極化和促進吞噬能力；（4)CXCL1/CXCL8-OE-CM還會把纖維母細胞活化成發炎狀態、刺激細胞增生和浸潤。基於上述研究發現，我們結論趨化因子CXCL1和CXCL8是調節神經纖維瘤免疫微環境的關鍵因子，在神經纖維瘤微環境中可以刺激巨噬細胞、嗜中性球，並將纖維母細胞活化成發炎狀態。本研究證據顯示：針對趨化因子所調節的信號途徑可能是神經纖維瘤治療未來可以發展的治療標的。

Neurofibromas are a type of nerve sheath tumor associated with the genetic disorder neurofibromatosis type 1 (NF1). Currently, there is a lack of effective and safe treatment for all neurofibromas in the clinic. The tumor cells of neurofibromas are NF1 mutant Schwann cells (SCs). Fibroblasts, macrophages, and neutrophils are non-tumor cells found in the neurofibroma microenvironment; these cells have been suggested to be activated by the tumor cells and to have reciprocal interactions with neurofibroma tumor cells. One of our previous experiments analyzed the secretome of neurofibroma tumor cells and compared that of normal SCs; our results revealed robust upregulations of chemokines CXCL1 and CXCL8 in the neurofibroma secretome. In this project, we investigated the specific contributions of CXCL1 and CXCL8 from SCs to neurofibroma microenvironmental cells. We took the approach by introducing CXCL1 and CXCL8 overexpression (OE) plasmids into normal SCs. Then we harvested their conditioned media (CM) and used them to treat macrophages, neutrophils, and fibroblasts. The cellular behaviors of these cells were analyzed to define the roles of these chemokines in the dynamic microenvironmental regulations. Our data revealed that (1) CXCL1/ CXCL8-OE led to a cohort of other chemokine inductions in control SCs; importantly, the chemokine profile mimicked that in the neurofibroma cells. (2) CXCL1/ CXCL8-OE-CM stimulated macrophage M1 polarization, phagocytosis, and migration. (3) CXCL1/ CXCL8-OE-CM stimulated neutrophil proliferation, N1 polarization, and phagocytosis. (4) CXCL1/ CXCL8-OE-CM activated fibroblasts into inflammatory status, stimulated proliferation, and enhanced migration ability. In summary, our study identified that CXCL1 and CXCL8 are critical chemokines regulating the neurofibroma tumor microenvironment by stimulating macrophages and neutrophil polarization and fibroblast activation toward an inflammatory status. Our research findings suggest that targeting chemokine-regulated signaling might be a potential therapeutic strategy for future neurofibromatosis treatment.

誌謝 I
Abbreviations II
中文摘要 IV
Abstract V
Contents VI
I. Introduction 1
1. Epidemiology of neurofibromatosis 1
2. Pathogenesis of neurofibromatosis type 1 (NF1) 2
3. Types of neurofibromas 3
4. NF1-related malignancy: Malignant Peripheral Nerve Sheath Tumor (MPNST) 3
5. NF1 research models 4
6. Neurofibroma tumor microenvironmental (TME) cells 9
7. Neurofibroma TME immune cells 14
8. Cytokines in TME 18
9. Cytokines in neurofibroma TME 28
II. Hypothesis 30
III. Specific Aims 31
IV. Materials and Methods 32
1. Cell lines 32
2. Cell culture 33
3. Immunology Multiplex Assay 34
4. CXCL1/ CXCL8-overexpression (CXCL1/ CXCL8-OE) plasmids 34
5. Transfection and conditioned media (CM) preparation 34
6. Migration assay 35
7. Phagocytosis assay 35
8. Flow cytometry 36
9. Proliferation assay 36
10. RNA extraction and analysis 37
11. Western blotting 39
12. Wound healing assay 41
13. Immunohistochemistry (IHC) 42
14. Reparixin treatment 42
V. Results 43
1. Elevated expressions of immune molecules in neurofibroma tumor cells 43
2. CXCL8 was the common gene upregulated in four pathways in GSEA 43
3. CXCL1 expression was positively correlated with CXCL8 44
4. Generation of SCs with CXCL1 and CXCL8 overexpression 45
5. Phenotypic changes of monocytes affected by CXCL1 and CXCL8-mediated immune microenvironment 46
6. Phenotypic changes of macrophages affected by CXCL1- and CXCL8-mediated immune microenvironment 49
7. Phenotypic changes of promyelocytes affected by CXCL1- and CXCL8-mediated immune microenvironment 50
8. Phenotypic changes of neutrophils affected by CXCL1- and CXCL8-mediated immune microenvironment 52
9. Phenotypic changes of fibroblasts affected by CXCL1- and CXCL8-mediated immune microenvironment. 54
10. Expression of CXCL8 in the nerve and neurofibroma tissue slices of a neurofibroma mouse model 57
11. The inhibition of CXCL1/8 receptor, CXCR1/2, by Reparixin downregulated chemokine expressions 57
VI. Summary and Conclusion 59
VII. Discussion 60
Figures 71
Figure 1. Expressions of chemokines in SC and NF secretome. 71
Figure 2. Validation of cytokines, chemokines, and growth factors expressions in NFs relative to SCs by RT-qPCR. 72
Figure 3. Curves of GSEA enrichment scores for four inflammatory pathways in NFs related to SCs. 73
Figure 4. CXCL8 is the only common chemokine upregulated in these four enriched gene sets. 74
Figure 5. CXCL8 expression positively correlated with CXCL1 and other chemokines in the tibia nerves and skin tissues. 75
Figure 6. CXCL8 expression was not correlated with all upregulated chemokines in the Milliplex assay or qPCR in the tibia nerves and skin tissues. 76
Figure 7. Validation of CXCL1 plasmid by DNA sequencing. 77
Figure 8. Validation of CXCL8 plasmid by DNA sequencing. 78
Figure 9. Validation and examination of other chemokine changes after CXCL1 and CXCL8 overexpression. 79
Figure 10. Flow chart of TME cell treatment by CXCL1-OE CM and CXCL8-OE CM. 80
Figure 11. CXCL1-OE CM and CXCL8-OE CM increased THP1 monocyte attachment. 81
Figure 12. CXCL1-OE CM and CXCL8-OE CM polarized THP1 monocytes into M1 status. 82
Figure 13. CXCL1-OE CM and CXCL8-OE CM enhanced THP1 monocytes phagocytosis analyzed by fluorescent microscopy images. 83
Figure 14. CXCL1-OE CM and CXCL8-OE CM enhanced THP1 monocytes phagocytosis analyzed by flow cytometry. 84
Figure 15. CXCL1-OE CM and CXCL8-OE CM also stimulated MCP family gene expressions in THP1 monocytes. 85
Figure 16. CXCL1-OE CM and CXCL8-OE CM enhanced THP1 monocyte migration. 86
Figure 17. Differentiation of HL60 promyelocytes into HL60-M by PMA. 87
Figure 18. CXCL1-OE CM and CXCL8-OE CM enhanced HL60-M phagocytosis analyzed by fluorescent microscopy images. 88
Figure 19. CXCL1-OE CM and CXCL8-OE CM enhanced HL60-M phagocytosis analyzed by flow cytometry. 89
Figure 20. CXCL1-OE CM and CXCL8-OE CM polarized HL60 promyelocytes into N1 status. 90
Figure 21. CXCL8-OE CM enhanced HL60 promyelocytes phagocytosis. 91
Figure 22. CXCL1-OE CM and CXCL8-OE CM stimulated the proliferation of HL60 promyelocytes. 92
Figure 23. CXCL1-OE CM also stimulated MCP family gene expressions in HL60 promyelocytes. 93
Figure 24. Differentiation of HL60 promyelocytes into dHL60 neutrophils by 1% DMSO for 120 hours. 94
Figure 25. CXCL1-OE CM and CXCL8-OE CM polarized dHL60 neutrophils into N1 status. 95
Figure 26. CXCL1-OE CM and CXCL8-OE CM enhanced dHL60 neutrophils phagocytosis. 96
Figure 27. CXCL1-OE CM and CXCL8-OE CM stimulated the proliferation of dHL60 neutrophils. 97
Figure 28. CXCL1-OE CM and CXCL8-OE CM activated HDFs into iCAFs. 98
Figure 29. CXCL1-OE CM and CXCL8-OE CM affected some ECM remodeling protein expressions in HDFs. 99
Figure 30. Downregulation of COL1A1 and MMP1 in volcano plot of NFs versus SCs. 100
Figure 31. CXCL8-OE CM stimulated the proliferation of HDFs. 101
Figure 32. CXCL1-OE CM and CXCL8-OE CM enhanced the migration of HDFs. 102
Figure 33. CXCL1-OE CM and CXCL8-OE CM stimulated MCP family gene expressions in HDFs. 103
Figure 34. Neurofibroma and nerve tissues immunohistochemically stained for CXCL8 from low to high concentrations. 104
Figure 35. Reparixin, a CXCR1/2 inhibitor, downregulated the chemokine expression in NFs. 105
Tables 106
Table 1. Lists of Milliplex 48 plex panel containing cytokines/ chemokines/ growth factors. 106
Table 2. Sequence of primers used in this study. 107
Table 3. Antibodies used in this study. 108
References 109

1.Tamura, R., Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int J Mol Sci, 2021. 22(11).
2.Kresak, J.L. and M. Walsh, Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis. J Pediatr Genet, 2016. 5(2): p. 98-104.
3.Gutmann, D.H. and M. Giovannini, Mouse models of neurofibromatosis 1 and 2. Neoplasia, 2002. 4(4): p. 279-90.
4.Johannessen, C.M., et al., The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A, 2005. 102(24): p. 8573-8.
5.Jessen, W.J., et al., MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest, 2013. 123(1): p. 340-7.
6.Moualed, D., et al., Prevalence and natural history of schwannomas in neurofibromatosis type 2 (NF2): the influence of pathogenic variants. European Journal of Human Genetics, 2022. 30(4): p. 458-464.
7.Petrilli, A.M. and C. Fernández-Valle, Role of Merlin/NF2 inactivation in tumor biology. Oncogene, 2016. 35(5): p. 537-48.
8.Plotkin, S.R., et al., Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in Medicine, 2022. 24(9): p. 1967-1977.
9.Mo, J., et al., Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins. J Clin Invest, 2021. 131(1).
10.Napolitano, F., et al., Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype. Genes, 2022. 13(7): p. 1130.
11.Bergoug, M., et al., Neurofibromin Structure, Functions and Regulation. Cells, 2020. 9(11).
12.Le Douarin, N.M., et al., Neural crest cell plasticity and its limits. Development, 2004. 131(19): p. 4637-50.
13.Williams, A.L. and B.L. Bohnsack, Neural crest derivatives in ocular development: discerning the eye of the storm. Birth Defects Res C Embryo Today, 2015. 105(2): p. 87-95.
14.La Noce, M., et al., Neural crest stem cell population in craniomaxillofacial development and tissue repair. Eur Cell Mater, 2014. 28: p. 348-57.
15.Liao, C.P., et al., Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis. J Clin Invest, 2018. 128(7): p. 2848-2861.
16.Carroll, S.L. and N. Ratner, How does the Schwann cell lineage form tumors in NF1? Glia, 2008. 56(14): p. 1590-1605.
17.Maertens, O., et al., Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet, 2007. 81(2): p. 243-51.
18.Kolanczyk, M., et al., Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin. BMC Med, 2008. 6: p. 21.
19.Bajenaru, M.L., et al., Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res, 2003. 63(24): p. 8573-7.
20.Chamseddin, B.H. and L.Q. Le, Management of cutaneous neurofibroma: current therapy and future directions. Neurooncol Adv, 2020. 2(Suppl 1): p. i107-i116.
21.Boyd, K.P., B.R. Korf, and A. Theos, Neurofibromatosis type 1. J Am Acad Dermatol, 2009. 61(1): p. 1-14; quiz 15-6.
22.Nguyen, R., et al., Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Frequency and Associated Clinical Deficits. The Journal of Pediatrics, 2011. 159(4): p. 652-655.e2.
23.Korf, B.R., Plexiform neurofibromas. Am J Med Genet, 1999. 89(1): p. 31-7.
24.Gross, A.M., et al., Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med, 2020. 382(15): p. 1430-1442.
25.Fasih, S., et al., Malignant transformation of plexiform neurofibroma to MPNST while on MEK inhibitor. Neurooncol Adv, 2021. 3(1): p. vdab033.
26.Doorn, P.F., et al., Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis. Eur J Surg Oncol, 1995. 21(1): p. 78-82.
27.Ducatman, B.S., et al., Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer, 1986. 57(10): p. 2006-21.
28.Evans, D.G., et al., Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet, 2011. 19(11): p. 1187-91.
29.Sobczuk, P., et al., Systemic Treatment for Advanced and Metastatic Malignant Peripheral Nerve Sheath Tumors-A Sarcoma Reference Center Experience. J Clin Med, 2020. 9(10).
30.Miettinen, M.M., et al., Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview. Hum Pathol, 2017. 67: p. 1-10.
31.Gesundheit, B., et al., The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1. J Pediatr Hematol Oncol, 2010. 32(7): p. 548-53.
32.Osum, S.H., A.L. Watson, and D.A. Largaespada, Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1. Int J Mol Sci, 2021. 22(4).
33.Brannan, C.I., et al., Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev, 1994. 8(9): p. 1019-29.
34.Jacks, T., et al., Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet, 1994. 7(3): p. 353-61.
35.Legius, E., et al., Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet, 1993. 3(2): p. 122-6.
36.Gutmann, D.H., et al., Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene, 1999. 18(31): p. 4450-4459.
37.Silva, A.J., et al., A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nature Genetics, 1997. 15(3): p. 281-284.
38.Guo, H.-F., et al., A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature, 2000. 403(6772): p. 895-898.
39.Gitler, A.D., et al., Nf1 has an essential role in endothelial cells. Nat Genet, 2003. 33(1): p. 75-9.
40.Bajenaru, M.L., et al., Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol, 2002. 22(14): p. 5100-13.
41.Zhu, Y., et al., Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science, 2002. 296(5569): p. 920-2.
42.Yang, F.C., et al., Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Hum Mol Genet, 2006. 15(16): p. 2421-37.
43.Wu, J., et al., Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell, 2008. 13(2): p. 105-16.
44.Mayes, D.A., et al., Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res, 2011. 71(13): p. 4675-85.
45.Brosseau, J.P., et al., NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. Nat Commun, 2018. 9(1): p. 5014.
46.Chen, Z., et al., Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway. Cancer Discov, 2019. 9(1): p. 114-129.
47.White, K.A., et al., A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight, 2018. 3(12).
48.McLean, D.T., et al., Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model. Front Oncol, 2023. 13: p. 1253659.
49.Choi, K., et al., An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Scientific Reports, 2017. 7(1): p. 43315.
50.Nobeyama, Y., K.-i. Yasuda, and A. Asahina, Abnormal peripheral blood cell counts in neurofibromatosis type 1. Scientific Reports, 2022. 12(1): p. 18800.
51.Peltonen, J., et al., Cellular differentiation and expression of matrix genes in type 1 neurofibromatosis. Lab Invest, 1988. 59(6): p. 760-71.
52.Kluwe, L., R. Friedrich, and V.F. Mautner, Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. Genes Chromosomes Cancer, 1999. 24(3): p. 283-5.
53.Achilleos, A. and P.A. Trainor, Neural crest stem cells: discovery, properties and potential for therapy. Cell Research, 2012. 22(2): p. 288-304.
54.Ge, L.L., et al., Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development. Cancers (Basel), 2022. 14(18).
55.Chen, Z., et al., Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell, 2014. 26(5): p. 695-706.
56.Jessen, K.R. and R. Mirsky, Schwann Cell Precursors; Multipotent Glial Cells in Embryonic Nerves. Frontiers in Molecular Neuroscience, 2019. 12.
57.Woodhoo, A., et al., Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci, 2009. 12(7): p. 839-47.
58.Fricker, F.R. and D.L. Bennett, The role of neuregulin-1 in the response to nerve injury. Future Neurol, 2011. 6(6): p. 809-822.
59.Feltri, M.L., Y. Poitelon, and S.C. Previtali, How Schwann Cells Sort Axons: New Concepts. Neuroscientist, 2016. 22(3): p. 252-65.
60.Le, L.Q., et al., Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res, 2011. 71(13): p. 4686-95.
61.Yang, F.C., et al., Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. J Clin Invest, 2003. 112(12): p. 1851-61.
62.Zahalka, A.H. and P.S. Frenette, Nerves in cancer. Nat Rev Cancer, 2020. 20(3): p. 143-157.
63.Liao, C.P., et al., The role of nerve microenvironment for neurofibroma development. Oncotarget, 2016. 7(38): p. 61500-61508.
64.Pan, Y., et al., NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature, 2021. 594(7862): p. 277-282.
65.Anastasaki, C., et al., Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1. Nature Communications, 2022. 13(1): p. 2785.
66.Mesdom, P., et al., Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response. Curr Neuropharmacol, 2020. 18(4): p. 301-318.
67.Gabbiani, G., G.B. Ryan, and G. Majne, Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia, 1971. 27(5): p. 549-50.
68.Younesi, F.S., et al., Myofibroblast Markers and Microscopy Detection Methods in Cell Culture and Histology. Methods Mol Biol, 2021. 2299: p. 17-47.
69.Desmoulière, A., et al., Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol, 1993. 122(1): p. 103-11.
70.Dvorak, H.F., Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med, 1986. 315(26): p. 1650-9.
71.Chen, X. and E. Song, Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov, 2019. 18(2): p. 99-115.
72.Takebe, N., et al., Cancer-associated Fibroblasts and Therapies That Interfere with Their Activity. Tumor Microenvironment and Therapy, 2013. 1.
73.Chhabra, Y. and A.T. Weeraratna, Fibroblasts in cancer: Unity in heterogeneity. Cell, 2023. 186(8): p. 1580-1609.
74.Goliwas, K.F., et al., Mitochondrial transfer from cancer-associated fibroblasts increases migration in aggressive breast cancer. J Cell Sci, 2023. 136(14).
75.Feng, B., et al., Cancer-associated fibroblasts and resistance to anticancer therapies: status, mechanisms, and countermeasures. Cancer Cell International, 2022. 22(1): p. 166.
76.Mak, T.K., et al., The cancer-associated fibroblast-related signature predicts prognosis and indicates immune microenvironment infiltration in gastric cancer. Front Immunol, 2022. 13: p. 951214.
77.Min, K.-W., et al., Cancer-associated fibroblasts are associated with poor prognosis in solid type of lung adenocarcinoma in a machine learning analysis. Scientific Reports, 2021. 11(1): p. 16779.
78.Bartoschek, M., et al., Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nature Communications, 2018. 9(1): p. 5150.
79.Elyada, E., et al., Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts. Cancer Discov, 2019. 9(8): p. 1102-1123.
80.Yang, X., et al., Collagen 1-mediated CXCL1 secretion in tumor cells activates fibroblasts to promote radioresistance of esophageal cancer. Cell Reports, 2023. 42(10): p. 113270.
81.Yang, D., et al., Cancer-associated fibroblasts: from basic science to anticancer therapy. Experimental & Molecular Medicine, 2023. 55(7): p. 1322-1332.
82.Peltonen, J., et al., Collagens in neurofibromas and neurofibroma cell cultures. Ann N Y Acad Sci, 1986. 486: p. 260-70.
83.Atit, R.P., et al., The Nf1 Tumor Suppressor Regulates Mouse Skin Wound Healing, Fibroblast Proliferation, and Collagen Deposited by Fibroblasts. Journal of Investigative Dermatology, 1999. 112(6): p. 835-842.
84.Shinde, A.V., C. Humeres, and N.G. Frangogiannis, The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta Mol Basis Dis, 2017. 1863(1): p. 298-309.
85.Cialdai, F., C. Risaliti, and M. Monici, Role of fibroblasts in wound healing and tissue remodeling on Earth and in space. Frontiers in Bioengineering and Biotechnology, 2022. 10.
86.Le, L.Q. and L.F. Parada, Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene, 2007. 26(32): p. 4609-4616.
87.Munchhof, A.M., et al., Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. Hum Mol Genet, 2006. 15(11): p. 1858-69.
88.Viola, F., et al., Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology, 2012. 119(2): p. 369-75.
89.Lewis, R.A., et al., von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology, 1984. 91(8): p. 929-35.
90.Chen, S., et al., Nf1−/− Schwann Cell-Conditioned Medium Modulates Mast Cell Degranulation by c-Kit-Mediated Hyperactivation of Phosphatidylinositol 3-Kinase. The American Journal of Pathology, 2010. 177(6): p. 3125-3132.
91.Wernersson, S. and G. Pejler, Mast cell secretory granules: armed for battle. Nat Rev Immunol, 2014. 14(7): p. 478-94.
92.Ingram, D.A., et al., Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med, 2000. 191(1): p. 181-8.
93.Riccardi, V.M., Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen. Arch Dermatol, 1987. 123(8): p. 1011-6.
94.Riccardi, V.M., Ketotifen suppression of NF1 neurofibroma growth over 30 years. Am J Med Genet A, 2015. 167(7): p. 1570-7.
95.Robertson, K.A., et al., Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol, 2012. 13(12): p. 1218-24.
96.Yunna, C., et al., Macrophage M1/M2 polarization. Eur J Pharmacol, 2020. 877: p. 173090.
97.Wu, K., et al., The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. Blood, 2020. 136(4): p. 501-515.
98.Cutolo, M., et al., The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis. Frontiers in Immunology, 2022. 13.
99.Zhu, F., et al., Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol, 2016. 33(2): p. 17.
100.Arabpour, M., A. Saghazadeh, and N. Rezaei, Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes. Int Immunopharmacol, 2021. 97: p. 107823.
101.Hu, J.M., et al., CD163 as a marker of M2 macrophage, contribute to predicte aggressiveness and prognosis of Kazakh esophageal squamous cell carcinoma. Oncotarget, 2017. 8(13): p. 21526-21538.
102.Kwiecień, I., et al., CD163 and CCR7 as markers for macrophage polarization in lung cancer microenvironment. Cent Eur J Immunol, 2019. 44(4): p. 395-402.
103.Shapouri-Moghaddam, A., et al., Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol, 2018. 233(9): p. 6425-6440.
104.Martinez, F.O. and S. Gordon, The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep, 2014. 6: p. 13.
105.Prada, C.E., et al., Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol, 2013. 125(1): p. 159-68.
106.Park, S.-J., et al., Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Medicine, 2013. 11(1): p. 109.
107.Kay, A.B., Paul Ehrlich and the Early History of Granulocytes. Microbiol Spectr, 2016. 4(4).
108.Anderson, J.M., Biological Responses to Materials. Annual Review of Materials Research, 2001. 31(1): p. 81-110.
109.Selders, G.S., et al., An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater, 2017. 4(1): p. 55-68.
110.Wu, L., S. Saxena, and R.K. Singh, Neutrophils in the Tumor Microenvironment. Adv Exp Med Biol, 2020. 1224: p. 1-20.
111.Anselmi, M., et al., Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression. Cancers (Basel), 2022. 14(14).
112.Fridlender, Z.G., et al., Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell, 2009. 16(3): p. 183-94.
113.Mihaila, A.C., et al., Transcriptional Profiling and Functional Analysis of N1/N2 Neutrophils Reveal an Immunomodulatory Effect of S100A9-Blockade on the Pro-Inflammatory N1 Subpopulation. Front Immunol, 2021. 12: p. 708770.
114.Capucetti, A., F. Albano, and R. Bonecchi, Multiple Roles for Chemokines in Neutrophil Biology. Frontiers in Immunology, 2020. 11.
115.Sansores-España, L.D., et al., Neutrophil N1 and N2 Subsets and Their Possible Association with Periodontitis: A Scoping Review. Int J Mol Sci, 2022. 23(20).
116.Lasater, E.A., et al., Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. J Clin Invest, 2010. 120(3): p. 859-70.
117.Stansfield, B.K., et al., Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway. Hum Mol Genet, 2013. 22(5): p. 977-88.
118.Oliver, J.A., et al., The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes. Mol Immunol, 2013. 55(3-4): p. 292-302.
119.Ingram, D.A., et al., Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function. Blood, 2002. 100(10): p. 3656-62.
120.Zhang, J.M. and J. An, Cytokines, inflammation, and pain. Int Anesthesiol Clin, 2007. 45(2): p. 27-37.
121.Deshmane, S.L., et al., Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res, 2009. 29(6): p. 313-26.
122.Wu, X., et al., Lysophosphatidic acid induces interleukin-6 and CXCL15 secretion from MLO-Y4 cells through activation of the LPA(1) receptor and PKCθ signaling pathway. Int Immunopharmacol, 2019. 74: p. 105664.
123.Zlotnik, A. and O. Yoshie, Chemokines: a new classification system and their role in immunity. Immunity, 2000. 12(2): p. 121-7.
124.Van Lint, P. and C. Libert, Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol, 2007. 82(6): p. 1375-81.
125.Wu, T., et al., The Role of CXC Chemokines in Cancer Progression. Cancers (Basel), 2022. 15(1).
126.Zhou, C., et al., The role of CXCL family members in different diseases. Cell Death Discovery, 2023. 9(1): p. 212.
127.Hughes, C.E. and R.J.B. Nibbs, A guide to chemokines and their receptors. Febs j, 2018. 285(16): p. 2944-2971.
128.Rossi, D. and A. Zlotnik, The biology of chemokines and their receptors. Annu Rev Immunol, 2000. 18: p. 217-42.
129.Bachelerie, F., et al., International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev, 2014. 66(1): p. 1-79.
130.Wu, C.L., et al., A Review of CXCL1 in Cardiac Fibrosis. Front Cardiovasc Med, 2021. 8: p. 674498.
131.Cao, D.L., et al., Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2. Exp Neurol, 2014. 261: p. 328-36.
132.Sawant, K.V., et al., Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions. Scientific Reports, 2016. 6(1): p. 33123.
133.Ravindran, A., et al., Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor. J Biol Chem, 2013. 288(17): p. 12244-52.
134.Sepuru, K.M. and K. Rajarathnam, CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine: STRUCTURAL EVIDENCE FOR TWO DISTINCT NON-OVERLAPPING BINDING DOMAINS. J Biol Chem, 2016. 291(8): p. 4247-55.
135.Schröder, J.M., N.L. Persoon, and E. Christophers, Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity. J Exp Med, 1990. 171(4): p. 1091-100.
136.Zou, A., et al., Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins. BMC Cancer, 2014. 14(1): p. 781.
137.le Rolle, A.-F., et al., The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts. Journal of Translational Medicine, 2015. 13(1): p. 199.
138.Cheng, W.L., et al., Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer. Ann Oncol, 2011. 22(10): p. 2267-76.
139.O'Kane, C.M., et al., Monocyte-dependent fibroblast CXCL8 secretion occurs in tuberculosis and limits survival of mycobacteria within macrophages. J Immunol, 2007. 178(6): p. 3767-76.
140.Kendrick, A.A., et al., The dynamics of interleukin-8 and its interaction with human CXC receptor I peptide. Protein Sci, 2014. 23(4): p. 464-80.
141.Cambier, S., M. Gouwy, and P. Proost, The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cellular & Molecular Immunology, 2023. 20(3): p. 217-251.
142.Reeves, E.P., et al., Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis. Am J Respir Crit Care Med, 2011. 183(11): p. 1517-23.
143.Martin, D., R. Galisteo, and J.S. Gutkind, CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex. J Biol Chem, 2009. 284(10): p. 6038-42.
144.Jovanović, M., et al., Interleukin-8 (CXCL8) stimulates trophoblast cell migration and invasion by increasing levels of matrix metalloproteinase (MMP)2 and MMP9 and integrins alpha5 and beta1. Reproduction, 2010. 139(4): p. 789-98.
145.Arger, N.K., et al., CXCL9 and CXCL10 are differentially associated with systemic organ involvement and pulmonary disease severity in sarcoidosis. Respir Med, 2020. 161: p. 105822.
146.Tokunaga, R., et al., CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy. Cancer Treat Rev, 2018. 63: p. 40-47.
147.Anand, N., K.H. Peh, and J.M. Kolesar, Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma. Int J Mol Sci, 2023. 24(3).
148.Wang, P., et al., CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils. J Hepatocell Carcinoma, 2024. 11: p. 787-800.
149.Pei, L., et al., Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer, 2023. 22(1): p. 29.
150.Ohta, K., et al., Differential regulation by IFN‑γ on TNF‑α‑induced chemokine expression in synovial fibroblasts from temporomandibular joint. Mol Med Rep, 2017. 16(5): p. 6850-6857.
151.Liu, M., S. Guo, and J.K. Stiles, The emerging role of CXCL10 in cancer (Review). Oncol Lett, 2011. 2(4): p. 583-589.
152.Pandey, V., et al., CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions. Elife, 2021. 10.
153.Timperi, E. and E. Romano, Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts. Front Immunol, 2023. 14: p. 1194642.
154.Laing, K.J. and C.J. Secombes, Chemokines. Developmental & Comparative Immunology, 2004. 28(5): p. 443-460.
155.Van Coillie, E., J. Van Damme, and G. Opdenakker, The MCP/eotaxin subfamily of CC chemokines. Cytokine & Growth Factor Reviews, 1999. 10(1): p. 61-86.
156.Forssmann, U., et al., Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med, 1997. 185(12): p. 2171-6.
157.Montes-Vizuet, R., et al., CC chemokine ligand 1 is released into the airways of atopic asthmatics. Eur Respir J, 2006. 28(1): p. 59-67.
158.Provost, V., et al., CCL26/eotaxin-3 is more effective to induce the migration of eosinophils of asthmatics than CCL11/eotaxin-1 and CCL24/eotaxin-2. J Leukoc Biol, 2013. 94(2): p. 213-22.
159.Bianconi, V., et al., The regulation and importance of monocyte chemoattractant protein-1. Curr Opin Hematol, 2018. 25(1): p. 44-51.
160.Xu, M., et al., Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting. Cell Prolif, 2021. 54(10): p. e13115.
161.Aldinucci, D. and A. Colombatti, The inflammatory chemokine CCL5 and cancer progression. Mediators Inflamm, 2014. 2014: p. 292376.
162.Zeng, Z., et al., CCL5/CCR5 axis in human diseases and related treatments. Genes Dis, 2022. 9(1): p. 12-27.
163.An, G., et al., Effects of CCL5 on the biological behavior of breast cancer and the mechanisms of its interaction with tumor‑associated macrophages. Oncol Rep, 2019. 42(6): p. 2499-2511.
164.Fioretti, F., et al., Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor. J Immunol, 1998. 161(1): p. 342-6.
165.Liu, Y., et al., Crucial biological functions of CCL7 in cancer. PeerJ, 2018. 6: p. e4928.
166.Gong, W., et al., Monocyte Chemotactic Protein-2 Activates CCR5 and Blocks CD4/CCR5-mediated HIV-1 Entry/Replication*. Journal of Biological Chemistry, 1998. 273(8): p. 4289-4292.
167.Sozzani, S., et al., Receptors and transduction pathways for monocyte chemotactic protein-2 and monocyte chemotactic protein-3. Similarities and differences with MCP-1. J Immunol, 1994. 152(7): p. 3615-22.
168.Zhou, H., et al., Lactate-Induced CCL8 in Tumor-Associated Macrophages Accelerates the Progression of Colorectal Cancer through the CCL8/CCR5/mTORC1 Axis. Cancers (Basel), 2023. 15(24).
169.Zhang, X., et al., CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling. Laboratory Investigation, 2020. 100(4): p. 619-629.
170.Li, L., et al., CCL13 and human diseases. Front Immunol, 2023. 14: p. 1176639.
171.Liu, Z., et al., Tumor-Associated Macrophages Promote Metastasis of Oral Squamous Cell Carcinoma via CCL13 Regulated by Stress Granule. Cancers (Basel), 2022. 14(20).
172.Franzén, B., et al., Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer. Mol Oncol, 2019. 13(2): p. 376-391.
173.Dinarello, C.A., Historical insights into cytokines. Eur J Immunol, 2007. 37 Suppl 1(Suppl 1): p. S34-45.
174.Gajdács, M., et al., A World of Wonders: Interleukin-1 (IL-1) and IL-2 Families. 2021. p. 1-15.
175.Brocker, C., et al., Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum Genomics, 2010. 5(1): p. 30-55.
176.Rébé, C. and F. Ghiringhelli, Interleukin-1β and Cancer. Cancers (Basel), 2020. 12(7).
177.Schauer, I.G., et al., Interleukin-1β promotes ovarian tumorigenesis through a p53/NF-κB-mediated inflammatory response in stromal fibroblasts. Neoplasia, 2013. 15(4): p. 409-20.
178.Li, S., et al., IL-1β mediates MCP-1 induction by Wnt5a in gastric cancer cells. BMC Cancer, 2014. 14: p. 480.
179.Kaler, P., L. Augenlicht, and L. Klampfer, Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene, 2009. 28(44): p. 3892-902.
180.Krelin, Y., et al., Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res, 2007. 67(3): p. 1062-71.
181.Tanaka, T., M. Narazaki, and T. Kishimoto, IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol, 2014. 6(10): p. a016295.
182.Kong, L., et al., Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res, 2016. 35(1): p. 131.
183.Madeddu, C., et al., Microenvironmental M1 tumor-associated macrophage polarization influences cancer-related anemia in advanced ovarian cancer: key role of interleukin-6. Haematologica, 2018. 103(9): p. e388-e391.
184.Cheng, Y., et al., Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis, 2018. 9(4): p. 422.
185.Silva-Filho, J.L., C. Caruso-Neves, and A.A.S. Pinheiro, IL-4: an important cytokine in determining the fate of T cells. Biophys Rev, 2014. 6(1): p. 111-118.
186.Ul-Haq, Z., S. Naz, and M.A. Mesaik, Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box. Cytokine & Growth Factor Reviews, 2016. 32: p. 3-15.
187.Keegan, A.D., W.J. Leonard, and J. Zhu, Recent advances in understanding the role of IL-4 signaling. Fac Rev, 2021. 10: p. 71.
188.Hallett, M.A., K.T. Venmar, and B. Fingleton, Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res, 2012. 72(24): p. 6338-43.
189.Tone, M., et al., IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J Immunol, 2000. 165(1): p. 286-91.
190.Ruffell, B., et al., Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell, 2014. 26(5): p. 623-37.
191.Yang, L., et al., IL-10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF-κB/Notch1 pathway in non-small cell lung cancer. International Journal of Cancer, 2019. 145(4): p. 1099-1110.
192.Zhang, S., et al., Tumor associated neutrophils governs tumor progression through an IL-10/STAT3/PD-L1 feedback signaling loop in lung cancer. Transl Oncol, 2024. 40: p. 101866.
193.Sparmann, A. and D. Bar-Sagi, Ras oncogene and inflammation: partners in crime. Cell Cycle, 2005. 4(6): p. 735-6.
194.Pong, W.W., et al., Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol, 2013. 73(2): p. 303-8.
195.Solga, A.C., et al., RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth. Neoplasia, 2015. 17(10): p. 776-88.
196.Fletcher, J.S., et al., Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice. JCI Insight, 2019. 4(3).
197.Kershner, L.J., et al., Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment. JCI Insight, 2022. 7(18).
198.Li, H., et al., Immortalization of human normal and NF1 neurofibroma Schwann cells. Lab Invest, 2016. 96(10): p. 1105-15.
199.Ferrer, M., et al., Pharmacological and genomic profiling of neurofibromatosis type 1 plexiform neurofibroma-derived schwann cells. Scientific Data, 2018. 5(1): p. 180106.
200.Chanput, W., J.J. Mes, and H.J. Wichers, THP-1 cell line: An in vitro cell model for immune modulation approach. International Immunopharmacology, 2014. 23(1): p. 37-45.
201.Collins, S.J., The HL-60 Promyelocytic Leukemia Cell Line: Proliferation, Differentiation, and Cellular Oncogene Expression. Blood, 1987. 70(5): p. 1233-1244.
202.David, S., et al., Netome: The Molecular Characterization of Neutrophil Extracellular Traps (NETs). bioRxiv, 2020: p. 2020.05.18.102772.
203.Kisiel, M.A. and A.S. Klar, Isolation and Culture of Human Dermal Fibroblasts, in Skin Tissue Engineering: Methods and Protocols, S. Böttcher-Haberzeth and T. Biedermann, Editors. 2019, Springer New York: New York, NY. p. 71-78.
204.Tang, Z., et al., GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res, 2019. 47(W1): p. W556-w560.
205.Doherty, D.E., et al., Human monocyte adherence: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endothelium. J Immunol, 1987. 138(6): p. 1762-71.
206.Liu, J., et al., New insights into M1/M2 macrophages: key modulators in cancer progression. Cancer Cell International, 2021. 21(1): p. 389.
207.Hao, Q., J.V. Vadgama, and P. Wang, CCL2/CCR2 signaling in cancer pathogenesis. Cell Communication and Signaling, 2020. 18(1): p. 82.
208.Giese, M.A., L.E. Hind, and A. Huttenlocher, Neutrophil plasticity in the tumor microenvironment. Blood, 2019. 133(20): p. 2159-2167.
209.Guo, Y., et al., Differentiation of HL-60 cells in serum-free hematopoietic cell media enhances the production of neutrophil extracellular traps. Exp Ther Med, 2021. 21(4): p. 353.
210.Linares, J., et al., Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy. Front Cell Dev Biol, 2020. 8: p. 621070.
211.Ma, Y., et al., Dynamic Mast Cell–Stromal Cell Interactions Promote Growth of Pancreatic Cancer. Cancer Research, 2013. 73(13): p. 3927-3937.
212.Baschieri, F., et al., Fibroblasts generate topographical cues that steer cancer cell migration. Sci Adv, 2023. 9(33): p. eade2120.
213.Cen, R., et al., Dermal Fibroblast Migration and Proliferation Upon Wounding or Lipopolysaccharide Exposure is Mediated by Stathmin. Front Pharmacol, 2021. 12: p. 781282.
214.Canale DJ, B.J., Von Recklinghausen disease of the nervous system, in Handbook of clinical neurology, B.G. Vinken PJ, Editor. 1972, Amsterdam: Holland Publishing Company. p. pp. 132–162.
215.Yuan, S.M., et al., Surgical management of giant neurofibroma in soft tissue: a single-center retrospective analysis. Int J Clin Exp Med, 2015. 8(4): p. 5245-53.
216.Chopra, R., et al., Radiotherapy and radiosurgery for benign neurofibromas. Am J Clin Oncol, 2005. 28(3): p. 317-20.
217.Wentworth, S., et al., Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors. International Journal of Radiation Oncology*Biology*Physics, 2009. 73(1): p. 208-213.
218.Grill, J., et al., Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol, 1999. 45(3): p. 393-6.
219.Beyer, R.A., et al., Moyamoya pattern of vascular occlusion after radiotherapy for glioma of the optic chiasm. Neurology, 1986. 36(9): p. 1173-1173.
220.Grill, J., F. Dhermain, and J.L. Habrand, Risks of radiation therapy in patients with neurofibromatosis. Int J Radiat Oncol Biol Phys, 2009. 75(2): p. 632.
221.Gandhi, N.G., Treatment of neuro-ophthalmic and orbitofacial manifestations of neurofibromatosis type 1. Curr Opin Ophthalmol, 2013. 24(5): p. 506-11.
222.Tang, Y. and D.H. Gutmann, Neurofibromatosis Type 1-Associated Optic Pathway Gliomas: Current Challenges and Future Prospects. Cancer Management and Research, 2023. 15(null): p. 667-681.
223.El-Hemaly, A., et al., Efficacy of different salvage regimens in progressive unresectable pediatric low-grade glioma. Oncol Lett, 2022. 24(5): p. 407.
224.Packer, R.J., et al., Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg, 1997. 86(5): p. 747-54.
225.Lafay-Cousin, L., et al., Weekly vinblastine in pediatric low-grade glioma patients with carboplatin allergic reaction. Cancer, 2005. 103(12): p. 2636-42.
226.Lancaster, D.L., J.A. Hoddes, and A. Michalski, Tolerance of nitrosurea-based multiagent chemotherapy regime for low-grade pediatric gliomas. J Neurooncol, 2003. 63(3): p. 289-94.
227.Fisher, M.J., et al., Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol, 2012. 14(6): p. 790-7.
228.Kotch, C., et al., Vinblastine/Methotrexate for Debilitating and Progressive Plexiform Neurofibroma in Children and Young Adults with Neurofibromatosis Type 1: A Phase 2 Study. Cancers (Basel), 2023. 15(9).
229.Ciombor, K.K. and T. Bekaii-Saab, Selumetinib for the treatment of cancer. Expert Opinion on Investigational Drugs, 2015. 24(1): p. 111-123.
230.Gross, A.M., et al., Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol, 2022. 24(11): p. 1978-1988.
231.O'Sullivan Coyne, G.H., et al., Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). Journal of Clinical Oncology, 2020. 38(15_suppl): p. 3612-3612.
232.Fangusaro, J., et al., A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study. Neuro-Oncology, 2021. 23(10): p. 1777-1788.
233.Nagarsheth, N., M.S. Wicha, and W. Zou, Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol, 2017. 17(9): p. 559-572.
234.Steelman, L.S., et al., JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004. 18(2): p. 189-218.
235.Mughees, M., et al., Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Seminars in Cancer Biology, 2022. 86: p. 497-512.
236.Sharma, G., et al., Chemokines network in bone metastasis: Vital regulators of seeding and soiling. Semin Cancer Biol, 2022. 86(Pt 3): p. 457-472.
237.Kuo, P.L., et al., CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation. Carcinogenesis, 2012. 33(12): p. 2477-87.
238.Miyake, M., et al., Monoclonal Antibody against CXCL1 (HL2401) as a Novel Agent in Suppressing IL6 Expression and Tumoral Growth. Theranostics, 2019. 9(3): p. 853-867.
239.Salazar, N., et al., Chemokines and chemokine receptors as promoters of prostate cancer growth and progression. Crit Rev Eukaryot Gene Expr, 2013. 23(1): p. 77-91.
240.Wilson, C., et al., Chemotherapy-induced CXC-chemokine/CXC-chemokine receptor signaling in metastatic prostate cancer cells confers resistance to oxaliplatin through potentiation of nuclear factor-kappaB transcription and evasion of apoptosis. J Pharmacol Exp Ther, 2008. 327(3): p. 746-59.
241.Courtney, D., et al., Breast cancer recurrence: factors impacting occurrence and survival. Ir J Med Sci, 2022. 191(6): p. 2501-2510.
242.Walens, A., et al., CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors. Elife, 2019. 8.
243.Pervaiz, A., et al., CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer. Cell Oncol (Dordr), 2019. 42(1): p. 93-106.
244.Goldberg-Bittman, L., et al., The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines. Immunol Lett, 2004. 92(1-2): p. 171-8.
245.Kim, M., et al., Role of CXCL10 in the progression of in situ to invasive carcinoma of the breast. Sci Rep, 2021. 11(1): p. 18007.
246.Ginestier, C., et al., CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest, 2010. 120(2): p. 485-97.
247.Fernando, R.I., et al., IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res, 2011. 71(15): p. 5296-306.
248.Valeta-Magara, A., et al., Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network. Cancer Res, 2019. 79(13): p. 3360-3371.
249.Perdriger, A., Infliximab in the treatment of rheumatoid arthritis. Biologics, 2009. 3: p. 183-91.
250.Yoshida, Y. and T. Tanaka, Interleukin 6 and rheumatoid arthritis. Biomed Res Int, 2014. 2014: p. 698313.
251.Todd, C.M., et al., The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects. Pulmonary Pharmacology & Therapeutics, 2016. 41: p. 34-39.
252.Miao, M., E. De Clercq, and G. Li, Clinical significance of chemokine receptor antagonists. Expert Opinion on Drug Metabolism & Toxicology, 2020. 16(1): p. 11-30.
253.Blanpain, C., et al., CCR5 and HIV infection. Recept Channels, 2002. 8(1): p. 19-31.
254.Woollard, S.M. and G.D. Kanmogne, Maraviroc: a review of its use in HIV infection and beyond. Drug Des Devel Ther, 2015. 9: p. 5447-68.
255.De Clercq, E., Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother, 2019. 27: p. 2040206619829382.
256.Jiao, H., et al., Structure basis for the modulation of CXC chemokine receptor 3 by antagonist AMG487. Cell Discovery, 2023. 9(1): p. 119.
257.Chen, L.-Y., et al., Chemometric-Guided Exploration of Marine Anti-Neurofibroma Leads. Frontiers in Marine Science, 2022. 9.
258.Sica, A. and A. Mantovani, Macrophage plasticity and polarization: in vivo veritas. J Clin Invest, 2012. 122(3): p. 787-95.
259.Wang, S., et al., Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. npj Precision Oncology, 2024. 8(1): p. 31.
260.Manji, G.A., et al., A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res, 2021. 27(20): p. 5519-5527.
261.Choi, M.R., et al., A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. Nano Lett, 2007. 7(12): p. 3759-65.
262.Yue, Y., et al., Novel myeloma patient-derived xenograft models unveil the potency of anlotinib to overcome bortezomib resistance. Front Oncol, 2022. 12: p. 894279.
263.Brosseau, J.-P., C.-P. Liao, and L.Q. Le, Translating current basic research into future therapies for neurofibromatosis type 1. British Journal of Cancer, 2020. 123(2): p. 178-186.
264.Fang, J., et al., TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection. Cells, 2022. 11(17).
265.Kim, H., et al., Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing. Advanced Science, 2019. 6(20): p. 1900513.
266.Gong, Y.-T., et al., Neutrophils as potential therapeutic targets for breast cancer. Pharmacological Research, 2023. 198: p. 106996.
267.Wariss, B.R., et al., Effectiveness of four inflammatory markers in predicting prognosis in 2374 women with breast cancer. Maturitas, 2017. 101: p. 51-56.
268.Ethier, J.L., et al., Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res, 2017. 19(1): p. 2.
269.Tritz, R., et al., MEK inhibition exerts temporal and myeloid cell-specific effects in the pathogenesis of neurofibromatosis type 1 arteriopathy. Scientific Reports, 2021. 11(1): p. 24345.
270.Zhang, H., et al., CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene, 2017. 36(15): p. 2095-2104.
271.Nywening, T.M., et al., Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut, 2018. 67(6): p. 1112-1123.
272.Patel, S.P., et al., Safety and efficacy of first-in-class CXCR1/2 inhibitor SX-682 in combination with pembrolizumab (pem) in patients (pts) with metastatic melanoma (mMEL) with disease progression on anti–PD-1 therapy. Journal of Clinical Oncology, 2024. 42(16_suppl): p. 9508-9508.
273.Goldstein, L.J., et al., A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer. Breast Cancer Res, 2020. 22(1): p. 4.
274.Widemann, B.C., et al., Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatr Blood Cancer, 2014. 61(9): p. 1598-602.
275.Babovic-Vuksanovic, D., et al., Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology, 2006. 67(10): p. 1860-2.
276.Tsuji, G., et al., Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine. Cell Death & Disease, 2021. 12(6): p. 513.