Immunosuppressive Tumor Microenvironment and Uterine Fibroids: Role in Collagen Synthesis

Overview

Journal Cytokine Growth Factor Rev

Date 2023 Oct 15

PMID 37839993

Authors

Eslam E Saad

Rachel Michel

Mostafa A Borahay

Affiliations

Soon will be listed here.

Abstract

Uterine fibroids (UF), also called uterine leiomyoma, is one of the most prevalent uterine tumors. UF represents a serious women's health global problem with a significant physical, emotional, and socioeconomic impact. Risk factors for UF include racial disparities, age, race, hormonal factors, obesity, and lifestyle (diet, physical activity, and stress. There are several biological contributors to UF pathogenesis such as cellular proliferation, angiogenesis, and extracellular matrix (ECM) accumulation. This review addresses tumor immune microenvironment as a novel mediator of ECM deposition. Polarization of immune microenvironment towards the immunosuppressive phenotype has been associated with ECM deposition. Immunosuppressive cells include M2 macrophage, myeloid-derived suppressor cells (MDSCs), and Th17 cells, and their secretomes include interleukin 4 (IL-4), IL-10, IL-13, IL-17, IL-22, arginase 1, and transforming growth factor-beta (TGF-β1). The change in the immune microenvironment not only increase tumor growth but also aids in collagen synthesis and ECM disposition, which is one of the main hallmarks of UF pathogenesis. This review invites further investigations on the change in the UF immune microenvironment as well as a novel targeting approach instead of the traditional UF hormonal and supportive treatment.

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References

Menjivar R, Nwosu Z, Du W, Donahue K, Hong H, Espinoza C . Arginase 1 is a key driver of immune suppression in pancreatic cancer. Elife. 2023; 12. PMC: 10260021. DOI: 10.7554/eLife.80721. View

Firszt R, Francisco D, Church T, Thomas J, Ingram J, Kraft M . Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma. Eur Respir J. 2013; 43(2):464-73. PMC: 6747688. DOI: 10.1183/09031936.00068712. View

Porro C, Cianciulli A, Panaro M . The Regulatory Role of IL-10 in Neurodegenerative Diseases. Biomolecules. 2020; 10(7). PMC: 7407888. DOI: 10.3390/biom10071017. View

Mosser D, Hamidzadeh K, Goncalves R . Macrophages and the maintenance of homeostasis. Cell Mol Immunol. 2020; 18(3):579-587. PMC: 7491045. DOI: 10.1038/s41423-020-00541-3. View

Cordeiro Mitchell C, Islam M, Afrin S, Brennan J, Psoter K, Segars J . Mechanical stiffness augments ligand-dependent progesterone receptor B activation via MEK 1/2 and Rho/ROCK-dependent signaling pathways in uterine fibroid cells. Fertil Steril. 2021; 116(1):255-265. DOI: 10.1016/j.fertnstert.2020.12.011. View

Liang H, Zhang Z, Yan J, Wang Y, Hu Z, Mitch W . The IL-4 receptor α has a critical role in bone marrow-derived fibroblast activation and renal fibrosis. Kidney Int. 2017; 92(6):1433-1443. PMC: 5696054. DOI: 10.1016/j.kint.2017.04.021. View

Lagana A, Salmeri F, Ban Frangez H, Ghezzi F, Vrtacnik-Bokal E, Granese R . Evaluation of M1 and M2 macrophages in ovarian endometriomas from women affected by endometriosis at different stages of the disease. Gynecol Endocrinol. 2019; 36(5):441-444. DOI: 10.1080/09513590.2019.1683821. View

Beider K, Abraham M, Begin M, Wald H, Weiss I, Wald O . Interaction between CXCR4 and CCL20 pathways regulates tumor growth. PLoS One. 2009; 4(4):e5125. PMC: 2659745. DOI: 10.1371/journal.pone.0005125. View

Huang H, Kim H, Chang E, Lee Z, Hwang S, Kim H . IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009; 16(10):1332-43. DOI: 10.1038/cdd.2009.74. View

10.

Moore A, Yu L, Swartz C, Zheng X, Wang L, Castro L . Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture. Cell Commun Signal. 2010; 8:10. PMC: 2897788. DOI: 10.1186/1478-811X-8-10. View

11.

Warnken M, Haag S, Matthiesen S, Juergens U, Racke K . Species differences in expression pattern of arginase isoenzymes and differential effects of arginase inhibition on collagen synthesis in human and rat pulmonary fibroblasts. Naunyn Schmiedebergs Arch Pharmacol. 2010; 381(4):297-304. DOI: 10.1007/s00210-009-0489-6. View

12.

Liu J, Shang B, Bai J . IL-22/IL-22R1 promotes proliferation and collagen synthesis of MRC-5 cells via the JAK/STAT3 signaling pathway and regulates airway subepithelial fibrosis. Exp Ther Med. 2020; 20(3):2148-2156. PMC: 7401847. DOI: 10.3892/etm.2020.8931. View

13.

Sosna O, Kolesar L, Slavcev A, Skibova J, Fait T, Mara M . Th1/Th2 cytokine gene polymorphisms in patients with uterine fibroid. Folia Biol (Praha). 2010; 56(5):206-10. View

14.

Lu M, Qin X, Yao J, Yang Y, Zhao M, Sun L . Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression. Acta Physiol (Oxf). 2020; 230(3):e13537. DOI: 10.1111/apha.13537. View

15.

Yang Q, Ciebiera M, Bariani M, Ali M, Elkafas H, Boyer T . Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment. Endocr Rev. 2021; 43(4):678-719. PMC: 9277653. DOI: 10.1210/endrev/bnab039. View

16.

Kadomoto S, Izumi K, Mizokami A . The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci. 2020; 21(15). PMC: 7432448. DOI: 10.3390/ijms21155186. View

17.

Chang S . T helper 17 (Th17) cells and interleukin-17 (IL-17) in cancer. Arch Pharm Res. 2019; 42(7):549-559. DOI: 10.1007/s12272-019-01146-9. View

18.

Malutan A, Drugan T, Ciortea R, Mocan-Hognogi R, Bucuri C, Rada M . Serum anti-inflammatory cytokines for the evaluation of inflammatory status in endometriosis. J Res Med Sci. 2015; 20(7):668-74. PMC: 4638069. DOI: 10.4103/1735-1995.166215. View

19.

Bao H, Sin T, Zhang G . Activin A induces tumorigenesis of leiomyoma via regulation of p38β MAPK-mediated signal cascade. Biochem Biophys Res Commun. 2020; 529(2):379-385. DOI: 10.1016/j.bbrc.2020.05.079. View

20.

Law A, Valdes-Mora F, Gallego-Ortega D . Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells. 2020; 9(3). PMC: 7140518. DOI: 10.3390/cells9030561. View