Estudo comparativo da correlação entre macrófagos associados ao tumor e as alterações das fibras colágenas em neoplasias mamarias humanas e caninas

Abstract

The identification of alterations in the components of the tumor microenvironment in mammary neoplasms is essential for understanding the mechanisms that influence the different behaviors of mammary carcinomas and contribute to more accurate diagnoses. Despite advances in the understanding of breast cancer, there remains a significant gap in knowledge regarding how the interactions between collagen and tumor-associated macrophages (TAMs) influence tumor progression and prognosis. This is a retrospective study of 19 normal mammary gland samples, 12 fibroadenoma samples, 4 tubular carcinoma samples, 16 grade I invasive carcinoma samples, 21 grade III invasive carcinoma samples, and 17 invasive micropapillary carcinoma samples in humans, as well as 20 normal mammary gland samples, 15 benign mixed tumor samples, 14 carcinoma in mixed tumor samples, 6 cases of carcinosarcoma, 16 invasive micropapillary carcinoma samples, and 23 cases of solid arrangement carcinomas in dogs. Hematoxylin and eosin-stained slides of 15 representative areas from each sample were evaluated. Second harmonic generation and two-photon excited fluorescence microscopy images were used to assess collagen parameters and cell segment. The results indicate that in both human and canine mammary carcinomas, collagen fibers are more aligned compared to normal tissue. In carcinomas, the number of fibers and the area covered by them are greater, while the area covered by cells is smaller, compared to normal tissue, in both human and canine tumors. In human breast carcinoma, collagen fibers are more linear compared to normal tissue. Additionally, carcinomas with poor prognosis have shorter collagen fibers, and collagen parameters correlate with clinical and pathological data in both human and canine species. There is a clear association between the average fiber length and overall survival times in dogs, where patients diagnosed with carcinomas exhibiting shorter collagen fibers have poorer survival. Our findings demonstrated a significant correlation between collagen parameters and clinical and pathological data in both human and canine species. We identified a clear association between the average collagen fiber length and overall survival time in dogs, showing that patients diagnosed with carcinomas displaying shorter collagen fibers have a worse prognosis. The study also revealed that tumor-associated macrophages (TAMs) infiltrating carcinomas with favorable prognosis (such as tubular carcinoma and grade I invasive carcinoma in humans, and carcinoma in mixed tumor in dogs) simultaneously express both M1 and M2 markers, demonstrating the plasticity of these cells. In contrast, TAMs present in carcinomas with poor prognosis (such as grade III invasive carcinoma and invasive micropapillary carcinoma in humans, and carcinosarcoma, invasive micropapillary carcinoma, and solid arrangement carcinoma in dogs) exhibit a predominantly M2-like profile. These findings highlight the importance of the interaction between collagen fibers and TAMs in breast cancer progression and suggest that targeting this interaction may represent a new therapeutic approach. This work demonstrates that the canine species is a good model for studying stromal changes in human neoplastic mammary tissues. Our results expand the understanding of stromal changes in mammary carcinomas in both humans and dogs, supporting the use of comparative models to investigate tumor characteristics, potentially influencing future approaches in cancer research.