Medical Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

SIMPLE SUMMARY: Pancreatic cancer is a very deadly form of cancer with a low survival rate. One important characteristic of pancreatic cancer is the presence of a dense tissue called desmoplastic stroma, which creates an environment that promotes tumor growth. Within this environment, there are specialized cells called cancer-associated fibroblasts (CAFs) that play a crucial role. They are a diverse group of cells with different functions and surface markers. When activated, CAFs support the invasion, spread, and growth of cancer cells, as well as affect the immune system. Scientists have been studying how CAFs interact with cancer cells and immune cells to understand how they contribute to tumor growth and spread. However, there is still a lot we do not know about CAFs and their role in pancreatic cancer. Further research is needed to better understand CAFs and their impact on the development and progression of pancreatic cancer. ABSTRACT: Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF–tumor cell interaction, as well as CAF–immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.