THE SIGNIFICANCE OF HOMING-ASSOCIATED PROTEIN EXPRESSION IN PROGRESSION OF LUMINAL SUBTYPE A BREAST CANCER
DOI:
https://doi.org/10.32471/oncology.2663-7928.t-23-3-2021-g.9509Keywords:
CD163+-macrophages, chemokine CXCL12, chemokine receptor CXCR4, luminal A breast cancerAbstract
Aim: to evaluate the expression of chemokine receptor CXCR4, its ligand — chemokine CXCL12, — mitochondrial ribosomal protein S18-2 and Кі-67 protein in tumor cells as well as the content of CD163+-macrophages in the stromal microenvironment of luminal A breast carcinomas of stage I-II. Object and methods: surgical samples of 55 patients with luminal A breast cancer (ВС) of stage I-II. The average age of patients was 58.4 ± 2.1 years. The study used clinical, morphological, immunohistochemical (IHC) and statistical methods. Results: In patients with luminal A BC, higher expression of CXCR4 and its ligand (64.7 ± 6.2 and 66.6 ± 5.1% respectively) was found in tumor cells of patients with stage I than in patients with stage II tumor process (47.5 ± 6.1 and 36.7% ± 6.4%, p <0.05, respectively). In addition, there were determined the differences in the expression of the studied markers in the group of patients with stage II BC depending on the presence or absence of metastases. An increase in the expression of CXCR4 (42.0 ± 10.2%), S18-2 (11.9 ± 1.7%), a decrease of CXCL12 (21.8 ± 7.6%) and the significantly greater number of cells expressing Ki-67 (23.1 ± 2.6%) were found in breast carcinomas of patients with metastases compared to those of patients with no metastases (respectively 33.9 ± 6.8 and 4.6 ± 0.8%; 54.3 ± 6.5%, (p <0.05) and 15.8 ± 2.2%,(p <0.05)). In the stromal component of breast carcinomas in patients with metastases a significantly higher content of CD163+-macrophages (17.5 ± 6.6%) was found compared to breast carcinomas of patients without metastatic lesions (5.6 ± 1.2%, p <0.05). The study demonstrated the heterogeneity of breast cancer in the expression of chemokine CXCL12, its receptor CXCR4, and the content of such immunosuppressive cells of the tumor environment as macrophages type 2 within one molecular subtype and one stage of the disease. Conclusions: in luminal A breast cancer, the intertumor heterogeneity of the expression of chemokine CXCL12, its receptor CXCR4, protein S18-2 in tumor cells, as well as of the content of CD163+-macrophages in the stromal microenvironment was shown. It was found that the lower expression of CXCL12, high CXCR4 and S18-2 in tumor cells together with the higher content of CD163+-macrophages in stromal microenvironment is associated with such signs of the tumor process aggressiveness as high proliferative potential, metastases in the lymph nodes and the obesity. The obtained data allow identifying more malignant breast cancer of luminal A subtype.
References
Poudel Р, Nyamundanda G, Patil Y, et al. Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses. NPJ Breast Cancer. 2019; 5: 21. DOI: 10.1038/s41523-019-0116-8.
Fragomeni SM, Sciallis A, Jeruss JS. Molecular subtypes and local-regional control of breast cancer. Surg Oncol Clin N Am 2018; 27(1): 95–120. DOI: 10.1016/j.soc.2017.08.005.
Ciriello G, Sinha R, Hoadley KA, et al. The molecular diversity of luminal A breast tumors. Breast Cancer Res Treat 2013; 141 (3): 409–20. DOI: 10.1007/s10549-013-2699-35.
Netanely D, Avraham A, Ben-Baruch A, et al. Expression and methylation patterns partition luminal-A breast tumors into distinct prognostic subgroups. Breast Cancer Res 2016; 18: 74. DOI: 10.1186/s13058-016-0724-2.
Janssens R, Struyf S, Proost P. Pathological roles of the homeostatic chemokine CXCL12. Cytokine Growth Factor Rev 2018; 44: 51–68. DOI:10.1016/j.cytogfr.2018.10.004.
Samarendra H, Jones K, Petrinic T, et al. A meta-analysis of CXCL12 expression for cancer prognosis. Br J Cancer 2017; 117: 124–35. DOI: 10.1038/bjc.2017.134.
Zhao H, Guo L, Zhao H. et al. CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget 2015; 6: 5022–40.
Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res 2013; 3: 46–57.
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 (2): 135–41. doi: 10.32471/exp-oncology.2312-8852.vol-43-no-2.16240.
Zielińska KA, Katanaev VL. The signaling duo CXCL12 and CXCR4: chemokine fuel for breast cancer tumorigenesis. Cancers (Basel) 2020; 12 (10): 3071. DOI: 10.3390/cancers12103071.
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.
Meng W, Xue S, Chen Y. The role of CXCL12 in tumor microenvironment. Gene 2018. DOI:10.1016/j.gene.2017.10.015.
Liu W, Yang Z, Lu W, et al. Chemokines and chemokine receptors: A new strategy for breast cancer therapy. Cancer Med 2020; 9 (11): 3786–99. DOI: 10.1002/cam4.3014.
Kobayashi T, Tsuda H, Moriya T, et al. Expression pattern of stromal cell-derived factor-1 chemokine in invasive breast cancer is correlated with estrogen receptor status and patient prognosis. Breast Cancer Res Treat 2010; 123 (3): 733–45.
Felix A, Stone R, Chivukula M, et al. Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression. Int J Cancer 2013. DOI: 10.1002/ijc.27317.
Ghoneum A, Afify H, Salih Z, et al. Role of tumor microenvironment in ovarian cancer pathobiology. Oncotarget 2018; 9 (32): 22832–49.
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.
Jackute J, Zemaitis M, Pranys D, et al. Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer. BMC Immunology 2018; 19: 3. DOI 10.1186/s12865-018-0241-4.
Ahirwar DK, Nasser MW, Ouseph MM, et al. Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. Oncogene 2018; 37, 4428–42. DOI: 10.1038/s41388-018-0263-7.
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
Mints M, Mushtaq M, Iurchenko N, et al. Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1. Oncotarget 2016; 7 (16): 22150–8. DOI: 10.18632/oncotarget.7905.
Buchynska LG, Iurchenko NP, Kashuba EV, et al. Оverexpression of the mitochondrial ribosomal protein S18-2 in the invasive breast carcinomas Exp Oncol 2018; 40 (4): 303–8.
Wendt MK, Johanesen PA, Kang-Decker N, et al. Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 2006; 25 (36): 4986–97.
Chattopadhyay E, Singh R, Ray A, et al. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer. Sci Rep 2016; 6: 32735. DOI: 10.1038/srep32735
Yao L, Heuser-Baker J, Barlic-Dicen J. Chemokine receptors on the defensive — the surprising role of CXCR4 in brown adipose tissue. Recept Clin Invest 2015; 2: e397. DOI: 10.14800/rci.397.
Nesina IP, Zadvorny TV, Nespryadko SV, et al. Contents of adiponectin and leptin in peripheral blood serum of brest and endometrial cancer patients with obesity. Oncology 2019; 21 (1): 17–22 (In Ukrainian).
Raschioni C, Bottai G, Sagona A. et al. CXCR4/CXCL12 signaling and protumor macrophages in primary tumors and sentinel lymph nodes are involved in luminal B breast cancer progression. Dis Markers 2018: 5018671. DOI: 10.1155/2018/5018671.
Sun Q, Zhou H, Binmadi NO, Basile JR. Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J Biol Chem 2009; 284: 32066–074.
Janssens R, Struyf S, Proost P. The unique structural and functional features of CXCL12. Cell Mol Immunol 2018; 15(4): 299–311 DOI: 10.1038/cmi.2017.107.
Teng F, Tian WY, Wang YM, et al. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol 2016; 9: 8. DOI: 10.1186/s13045-015-0231-4.
Zavyalova MV, Denisov EV, Tashireva LA, et al. Intravasation as a key step in cancer metastasis. Biochemistry. 2019; 84(7): 972–84 (in Russian).
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 (10): 13217–24.
Kircher M. Herhaus P, Schottelius M. et al. CXCR4-directed theranostics in oncology and inflammation. Ann Nucl Med 2018; 32 (8): 503–51. DOI: 10.1007/s12149-018-1290-8.34. Joshi RS, Kanugula SS, Sudhir S. et al. The role of cancer-associated fibroblasts in tumor progression. Cancers 2021; 13 (6): 1399. DOI: 10.3390/cancers13061399.
