Oxygen, Angiogenesis, Cancer and Immune Interplay in Breast Tumor Micro-Environment: A Computational Investigation

원문 초록

Breast cancer is one of the most challenging global health problems among women. This study investigates the intricate breast tumor microenvironment (TME) dynamics utilizing data from Mammary-specific Polyomavirus Middle T Antigen Overexpression mouse models (MMTV-PyMT). It incorporates Endothelial Cells (ECs), oxygen, and Vascular Endothelial Growth Factors (VEGF) to examine the interplay of angiogenesis, hypoxia, VEGF, and the immune cells in cancer progression. We introduce an approach to impute the immune cell fractions within the TME using single-cell RNA-sequencing (scRNA-seq) data from MMTV-PyMT mice. We further quantify our analysis by estimating cell counts using cell size data and laboratory findings from existing literature. Parameter estimation is carried out via a Hybrid Genetic Algorithm (HGA). Our simulations reveal various TME behaviors, emphasizing the critical role of adipocytes, angiogenesis, hypoxia, and oxygen transport in driving immune responses and cancer progression. The global sensitivity analyses highlight potential therapeutic intervention points, such as VEGFs' critical role in EC growth and oxygen transportation and severe hypoxia's effect on the cancer and the total number of cells. The VEGF-mediated production rate of ECs shows an essential time-dependent impact, highlighting the importance of early intervention in slowing cancer progression. These findings align with the observations from the clinical trials demonstrating the efficacy of VEGF inhibitors and suggest a timely intervention for better outcomes.