ROLE OF STROMAL MICROENVIRONMENT IN THE FORMATION OF INVASIVE, ANGIOGENIC, AND METASTATIC POTENTIAL OF ENDOMETRIOID CARCINOMA OF ENDOMETRIUM
DOI:
https://doi.org/10.15407/exp-oncology.2023.01.051Keywords:
CD163+ macrophages, CXCL12+ fibroblasts, desmoplastic, endometrioid endometrial carcinoma, inflammatory stroma, microvessel densityAbstract
The aim of the study was to determine the association of indicators of the progression of endometrioid carcinoma of the endometrium (ECE) with the type of stromal microenvironment, the counts of CXCL12+ fibroblasts and CD163+ macrophages, and the expression of the chemokine CXCL12 and its receptor CXCR4 in tumor cells. Materials and Methods: Histological preparations of ECE samples (n = 51) were analyzed. Expression of CXCL2 and CXCR4 antigens in tumor cells, the content of CXCL12+ fibroblasts and CD163+ macrophages, and the density of microvessels were determined by the immunohistochemical method. Results: Groups of ECE with desmoplastic and inflammatory stromal reactions were delineated. The majority (80.0%) of tumors with desmoplasia were of low differentiation grade, deeply invading the myometrium; 65.0% of patients with these tumors were at stage III of the disease. In ECE cases of stages I–II, 77.4% of ECE showed an inflammatory type of stroma. The high angiogenic and invasive potential of EC of stages I–II was associated with an inflammatory stromal type, high counts of CD163+ macrophages and CXCL12+ fibroblasts in the tumor microenvironment, high expression of the chemokine receptor CXCR4, and reduced expression of its ligand CXCL12 in tumor cells. In the majority of EC of stage III, the increase in angiogenic, invasive, and metastatic potential was accompanied by the presence of desmoplastic stroma, increased expression of CXCR4 in tumor cells, and a high count of CXCL12+ fibroblasts. Conclusions: The obtained results showed that the morphological architecture of the stromal ECE component is related to the molecular features of its constituents and tumor cells. Their interaction modulates the phenotypic characteristics of ECE associated with the degree of malignancy.
References
Hanahan D, Coussens LM. Accessories to the crime: Functions of cells recruited to the tumor microenvironment cancer. Cell 2012; 21: 309–322. doi: 10.1016/j.ccr.2012.02.022
Sahoo SS, Zhang XD, Hondermarck H, Tanwar PS. The emerging role of the microenvironment in endometrial cancer. Cancers 2018; 10: 408; doi: 10.3390/cancers10110408
Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P. The role of tumor microenvironment in cancer metastasis: Molecular mechanisms and therapeutic opportunities. Cancers (Basel) 2021; 13: 2053. doi: 10.3390/cancers13092053
Meng W. Xue S, Chen Y. The role of CXCL12 in tumor microenvironment Gene 2018; 641: 105–110. doi:10.1016/j.gene.2017.10.015
Eckert F, Schilbach K, Klumpp L, et al. Potential role of CXCR4 targeting in the context of radiotherapy and immunotherapy of cancer. Front Immunol 2018; Available from: https://doi: 10.3389/fimmu.2018.03018
Werner RA, Kircher S, Higuchi T, et al. CXCR4-directed imaging in solid tumors. Front Oncol 2019; 9: 770. doi: 10.3389/fonc.2019.00770
Pein M, Insua-Rodríguez J, Hongu T, et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat Commun 2020; 11: 1–18. doi: 10.1038/s41467-020-15188-x
Shi Yi, Riese DJ, Shen J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front Pharmacol 2020; 11: 574667. doi: 10.3389/fphar.2020.574667
Liu W, Yang Z, Lu W, et al. Chemokines and chemokine receptors: A new strategy for breast cancer therapy. Cancer Med 2020; 9: 3786–3799. doi: 10.1002/cam4.3014
Bremnes RM, Dønnem T, Al-Saad S, et al. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. Thorac Oncol 2011; 6: 209–217.
doi: 10.1097/JTO.0b013e3181f8a1bd
Miles FL, Sikes RA. Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 2014; 12: 297–312. doi: 10.1158/1541-7786.MCR-13-0535
Gunaydin G. CAFs interacting with TAMs in tumor microenvironment to enhance tumorigenesis and immune evasion. Front Oncol 2021; 11: 668349. doi: 10.3389/fonc.2021.668349
Attieh Y, Clark AG, Grass C, et al. Cancer-associated fibroblasts
lead tumor invasion through integrin-beta3-dependent fibronectin assembly. J Cell Biol 2017; 216: 3509–3520. doi: 10.1083/jcb.201702033
Lo A, Wang LS, Scholler J, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res 2018; 75: 2800–2810.doi: 10.1158/0008-5472.CAN-14-3041
Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumor Biol 2014; 35: 2871–2882. doi: 10.1007/s13277-013-1511-7
Jones JO, Moody WM., Shields JD. Microenvironmental modulation of the developing tumour: an immune–stromal dialogue. Mol Oncol 2021; 15: 2600–2633. doi: 10.1002/1878-0261.12773
Zhou K, ChengT, Zhan J, et al. Тargeting tumor-associated macrophages the tumor microenvironment (Review). Oncol Lett 2020; 20: 234.doi: 10.3892/ol.2020.12097 234, 2020
Mezzapelle R, Leo M, Caprioglio F, et al. CXCR4/CXCL12 activities in the tumor microenvironment and implications for tumor immunotherapy. Cancers (Basel) 2022; 14: 2314. doi: 10.3390/cancers14092314
Goswami KK, Ghosh T, Ghosh S,et al. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol 2017; 316: 1–10. doi: 10.1016/j.cellimm.2017.04.005
Wei S, Conner MG, Zhang K, et al. Juxtatumoral stromal reactions in uterine endometrioid adenocarcinoma and their prognostic significance. Int J Gynecol Pathol 2010; 29: 562–567. doi: 10.1097/PGP.0b013e3181e36321
Espinosa I, Catasus L, D’Angelo E, et al. Stromal signatures in endometrioid endometrial carcinomas. Mod Pathol2014; 27: 631–639.doi:10.1038/modpathol.2013.131
Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of the female reproductive organs (IARC WHO Classification of Tumours). 4th Edition Series: IARC Press 2014; 307 p.
Movchan OM, Svintsitskiy VS, Tsip NP, et al. Features of recurrence of endometrioid type endometrial cancer of I stage. Exp Oncol 2021; 43: 365–369. doi:10.32471/exp-oncology.2312-8852.vol-43-no-4.17052
Lo A, Wang L-CS, Scholler J, et al. Tumor-promoting desmoplasia
is disrupted by depleting FAP-expressing stromal cells. Cancer Res 2018; 75: 2800–2810. doi: 10.1158/0008-5472.CAN-14-3041
Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation tocancer biology. J Exp Clin Cancer Res 2019; 38: 115. doi:10.1186/s13046–019–1110–6
Chen Y, Song Y, Du W, et al. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci 2019; 26: 78 doi: 10.1186/s12929-019-0568-z
Kübler К, Ayub TH, Weber SK, et al. Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma. Gynecol Oncol 2014; 135: 176–183. doi: 10.1016/j.ygyno.2014.08.028
Nesina IP, Iurchenko NP, Movchan OM, et al. The ratio of CD-68+ and CD-163+ macrophages in endometrial endometrioid carcinoma. Оncologiya 2022; 24: 1–5. doi: 10.32471/oncology.2663-7928.t-24-2-2022-g.10575 (in Ukrainian).
Patel MV, Shen Z, Rodriguez-Garcia M, et al. Endometrial cancer suppresses CD8+ T cell-mediated cytotoxicity in postmenopausal women. Front Immunol 2021; 12: 657326. doi: 10.3389/fimmu.2021.657326
Yao L, Heuser-Baker J, Barlic-DicenJ. Chemokine receptors on the defensive – the surprising role of CXCR4 in brown adipose tissue. Receptors Clin Invest 2015; 2: e397. doi:10.14800/rci.397
Mushtaq M, Jensen L, Davidsson S, et al. The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4- dependent migration of cancer cells. Sci Rep 2018; 8: 2268. doi: 10.1038/s41598-018-20765-8
Batlle E, Massagué J. Transforming grown factor-β signaling in immunity and cancer. Immunity2019; 50: 924–940. doi: 10.1016/j.immuni.2019.03.024
Wu W, Qian L, Chen X, et al. Prognostic significance of CXCL12, CXCR4, and CXCR7 in patients with breast cancer. J Clin Exp Pathol 2015; 8: 13217–13224.
Buchynska LG, Movchan OM, Iurchenko NP. Expression of chemokine receptor CXCR4 in tumor cells and content of CXCL12+-fibroblasts in endometrioid carcinoma of endometrium. Exp Oncol 2021; 43: 135–141. doi: 10.32471/exp-oncology.2312-8852.vol-43-no-2.16240
Luker GD, Yang J., Richmond A, et al. At the bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer. Leukoc Biol 2021; 109: 969–989. doi:10.1002/JLB.2BT1018-715RR
Behnes CL, Bremmer F, Hemmerlein B, et al. Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma. Virchows Arch 2014; 464: 191–196. doi:10.1007/s00428-013-1523-0
Boudot A, Kerdivel G, Habauzit D, et al. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS ONE 2011; 6: e20898. doi: 10.1371/journal.pone.0020898
Nesinа ІP, Iurchenko NP, Brieieva OV, et al. Serum steroid hormone levels in endometrial cancer patients with different menstrual function and indicators of genomic instability. Оncologiya 2016; 18: 210–215 (in Ukrainian).
Zavyalova MV, Denisov EV, Tashireva LA, et al. Intravasation as a key step in cancer metastasis. Biochemistry 2019; 84: 972–984 (in Russian).
Stanisavljević L, Aßmus J, Storli K, et al. CXCR4, CXCL12 and the relative CXCL12-CXCR4 expression as prognostic factors in colon cancer. Tumour Biol 2016; 37: 7441–7452. doi: 10.1007/s13277-015-4591-8
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