Medical Biology of Cancer-Associated Fibroblasts in 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.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors

“…Homogeneous enhancement was characterized by all tumor regions displaying an enhancement ratio of >1, whereas heterogeneous enhancement was defined as the presence of a mixture of nonenhanced and enhanced regions within the tumor. Using the classification criteria established by d’Assignies et al [ 13 ] and Palazzo et al [ 14 ], we classified the 79 PNET specimens into two groups: homogeneously enhanced tumors ( n = 45; Fig. 1ia ) and nonenhanced or heterogeneously enhanced tumors ( n = 34; Fig.…”

“…These fibroblasts play crucial roles in shaping the tumor microenvironment (TME). CAFs facilitate the production of extracellular matrix proteins and ligands that promote tumor growth, metastasis, therapeutic resistance, and immune evasion and are thus promising therapeutic targets [ 13 , 14 ]. Although previous attempts to deplete CAFs failed to benefit patients with PDAC [ 15 ], the discovery of heterogeneity among PDAC CAFs potentially explains the limitations of previous strategies [ 13 , 16 ].…”

Tumor Stroma as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

“…CAFs also contribute to the immunosuppressive tumor microenvironment observed in PDAC by secreting cytokines such as interleukin-6 (IL-6) and interleukin-10 (IL-10), which can inhibit the function of immune cells and further facilitate tumor growth and metastasis ( Morgan et al ., 2023 ). CAFs significantly influence the pancreatic cancer progression through their role in ECM remodeling, secretion of growth factors and cytokines, and contribution to an immunosuppressive microenvironment ( Wright et al ., 2023 ).…”

The hidden messengers: cancer associated fibroblasts—derived exosomal miRNAs as key regulators of cancer malignancy

“…According to the findings of published studies, the primary sources of CAFs are as follows: (1) resident fibroblasts ( O’Connor et al, 2023 ; Buechler and Turley, 2018 ); (2) bone marrow mesenchymal stem cells ( Liubomirski et al, 2019 ); (3) vascular adventitia and smooth muscle cells ( Zeltz et al, 2019 ); (4) endothelial cells ( Chu et al, 2022 ; Shinkawa et al, 2022 ); (5) human adipose tissue-derived stem cells ( Sato et al, 2023 ); (6) stationary pancreatic stellate cells ( Morgan et al, 2023 ) and hepatic stellate cells ( Yin et al, 2013 ; Wang S. S. et al, 2021 ; Sankar et al, 2023 ); and (7) cancer stem cells ( Najafi et al, 2019 ) ( Figure 1 ). Understanding the origins of different CAFs can shed light on their functions and phenotypes.…”