Role of the inflammatory microenvironment in the progression of colorectal cancer and type 2 diabets

Resum

The microenvironment is becoming critical to understand how different cells behave in different contexts. The present thesis manuscript includes two chapters in which the phenotype of different immune cells is altered by changes in the microenvironment. The first chapter discusses the impact of type 2 diabetes (T2D) on adipose tissue mast cells while the second chapter focuses on the population dynamics and phenotypical changes of neutrophils, eosinophils, plasmacytoid dendritic cells, conventional dendritic cells, and mast cells in colorectal cancer. Type 2 diabetes (T2D) is a rapidly growing global health concern, driven by factors such as poor dietary choices and sedentary lifestyles. It is associated with severe chronic conditions and significant strain on healthcare systems. While adipocytes and macrophages were traditionally considered the primary contributors to adipose tissue expansion, recent research highlights the important role of mast cells in this process. Angiogenesis, critical for a physiological adipose tissue expansion, is compromised in T2D, contributing to hypoxic stress and inflammation. Mast cells, which release various proangiogenic factors, play a pivotal role in angiogenesis and glucose-dependent adipogenesis, contributing to metabolically healthy adipose tissue expansion. Nevertheless, there was some controversy since some authors claim that mast cells exacerbate the inflammatory response in adipose tissue during T2D while others claim that mast cells play a beneficial role. The first chapter of this thesis manuscript shows that T2D reduce the number of mast cells in adipose tissue and the surface abundance of some important proteins for their physiological functioning: CD45, CD117, FceRI, and CD203c. Importantly, those changes were more prominent in the omental (o-WAT) than in the subcutaneous white adipose tissue (s-WAT). Therefore, contrary to previous notions, mast cells do not appear to be central drivers of adipose tissue inflammation in T2D. Colorectal cancer (CRC) ranks as the fourth most prevalent global cancer and the second leading cause of cancer-related fatalities. The TME plays a pivotal role in CRC, encompassing a complex interplay of immune cells, stromal components, and signaling molecules that are essential for tumor origin and progression. Chronic inflammation within the TME, particularly in conditions like inflammatory bowel disease, contributes to CRC development. The second chapter of this thesis shows that neutrophils, plasmacytoid dendritic cells, conventional dendritic cells, and mast cells counts increase in the CRC compared to the normal mucosa, while the count of eosinophils decrease. Besides, neutrophils, eosinophils, plasmacytoid dendritic cells, and conventional dendritic cells decrease the surface abundance of CD45 in CRC. CD45 plays an important role in signal transduction in innate immune cells. Therefore, this may be novel mechanism of immune scape employed by the tumor.