Tumor-Associated Macrophages and Collagen Remodeling in Mammary Carcinomas: A Comparative Analysis in Dogs and Humans.

Abstract

The tumor microenvironment (TME) plays a central role in cancer progression, with tumor-associated macrophages (TAMs) and extracellular matrix (ECM) components such as collagen being key modulators of invasiveness and immune regulation. Although macrophage infiltration and ECM remodeling are well-documented individually, their coordinated contribution to mammary carcinoma aggressiveness remains underexplored, particularly in comparative oncology models. This study analyzed 117 mammary carcinoma samples-59 from dogs and 58 from women-using immunohistochemistry, immunofluorescence, and second-harmonic-generation (SHG) microscopy. We quantified TAM density and phenotype (CD206, iNOS, and S100A8/A9), assessed collagen fiber organization, and examined correlations with clinical-pathological variables and overall survival. Increased TAM infiltration was associated with a higher histological grade, aggressive molecular subtypes, enhanced cell proliferation, and shortened survival in dogs. High TAM density also correlated with decreased collagen fiber length and increased alignment, suggesting active immune-matrix remodeling in aggressive tumors. Macrophage phenotyping revealed heterogeneous populations, with CD206cells predominating in high-grade tumors, while S100A8/A9/iNOSphenotypes were enriched in less aggressive subtypes. The findings were consistent across species, reinforcing the relevance of canine models. Our results identify macrophage-collagen interactions as critical determinants of tumor aggressiveness in mammary carcinomas. This study bridges comparative oncology and translational research by proposing immune-ECM signatures as potential prognostic biomarkers and therapeutic targets. These insights contribute to the advancement of molecular oncology in Brazil by supporting innovative strategies that integrate immune modulation and matrix-targeted interventions in breast cancer.