Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

“…These data show that collagen deposition in the PDAC SiaJ model resembles what has earlier been described in the literature in in vitro models [61]. TGF-ß has also been shown to be part of the PF to CAF transition [36]. Since the PFs resemble the CAF type III collagen production after stimulation by TGF-ß1, it could be interesting to investigate if the PFs achieved a more CAF-like or myofibroblast phenotype.…”

“…They have been directly linked to tumorigenesis, by being involved in cell proliferation, migration, invasion and metastasis, inflammation, and drug resistance [35]. As the amount and activity of CAFs and tumor fibrosis have been shown to be prognostic for survival in many types of cancer, several clinical trials are exploring drugs targeting CAFs, either directly, or by targeting downstream CAF signaling, such as anti-stromal therapies [36]. While CAFs and tumor fibrosis have promising potential as novel targets there are also challenges associated with this approach [37][38][39].…”

Mindin differentially regulates fibroblast subpopulations via distinct members of the Src family kinases during fibrogenesis

“…As shown in Figure 3A-B, Mindin differentially primes Sca1+ fibroblast to an inflammatory phenotype, which is consistent with iCAFs 25 . In a similar vein, treatment of Mindin can endow CD26+ fibroblasts to become more contractile and secrete elevated collagen (Figure 4B and F), which is consistent with a myCAF phenotype 25 . Furthermore, it has been shown that CD10, C5a, and GPR77 are signatures of a subset of CAFs in breast and lung cancer patients 51 .…”

Diagnostic Value, Prognostic Value, and Immune Infiltration of LOX Family Members in Liver Cancer: Bioinformatic Analysis

“…The MHCs, HLA-DOA, HLA-DPA1, and HLA-DPB1, positively associated with LOXL3 all belongs to MHC Class II molecules (104). MHC class II molecules were found to be expressed by antigen-presenting cells, including antigenpresenting cancer-associated fibroblasts (apCAFs) (105,106). Therefore, these positive association of the MHC Class II molecules might be indirect evidence of apCAFs in HCC, and drugs targeted on these apCAFs might have potential therapeutic values and future studies are needed for further clarification.…”