Mast Cells as a Factor in Regulation of Breast Cancer Stromal Component Associated with Breast Cancer Aggressiveness.

Abstract

Background: It has been proven that changes in the morphology, representation, and organization of collagen fibers contribute to the formation of a unique microenvironment, which is associated with the metastatic potential of malignant neoplasms due to the initiation of cell migration and changes in polarization. Among the modulators of the collagen stroma, fibroblasts remain the most widely studied today. At the same time, much less attention is focused on the study of immune cells in the tumor microenvironment, in particular, mast cells (MCs).

Aim: To investigate the relationship between the MCs status and the features of the collagen matrix of breast cancer (BCa).

Materials and methods: The study was conducted on the postoperative material of 78 patients with BCa stage I-II. MCs were assessed by a histochemical method using toluidine blue. For estimation of the functional activity of MCs, a degranulation index was calculated. COL1A1, COL3A1, and MMP-9 expression in tumor tissue was assessed immunohistochemically. A visualization of collagen fibers was performed using the staining by Malory. Microphotographs were pre-processed in Adobe Photoshop SS 2019 and analyzed using the software packages CurveAlign v. 4.0 and ImageJ.

Results: Tumor tissue with a high density and functional activity of MCs was characterized by an increased expression of COL1A1 (p < 0.05), COL3A1 (p < 0.05), and MMP-9 (p < 0.05). In BCa tissue with the lower MCs degranulation index, collagen fibers become thicker (p < 0.05), shorter (p < 0.05), and denser (p < 0.05). At the same time, the existence of a relationship between the levels of miR-155-5p and the expression of COL1A1 (r = 0.703, p = 0.009), COL3A1 (r = 0.603, p = 0.043), and MMP-9 in tumor cells (r = 0.562, p = 0.039) and in the stroma (r = 0.546, p = 0.038), as well as the associations of the levels of this miRNA with the fiber length (r = -0.632, p = 0.013), width (r = -0.522, p = 0.048), and density (r = 0.699, p = 0.014) were found. Significantly higher rates of miR-155-5p expression (p < 0.05) were recorded in BCa tissue with a high index of MCs degranulation.

Conclusion: During the BCa progression, the role of MCs in the manifestation of the tumor development increases. A growing number of infiltrated MCs contributes to the activation of MMP and fibrillar collagen expression. These changes lead to increased remodeling of the tumor stroma, which is directly reflected in the spatial organization of the collagen matrix. The increased activity of proteases causes a decrease in the length and width of fibrils, which is explained by a decrease in the number of mature fibers and their disorganization in three-dimensional space. The obtained data allow us to assert that MCs play a key role not only in the formation of a specific immune microenvironment of BCa but also in determining the direction of changes in the tumor stroma, which promotes cancer aggressiveness.