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-SMA ^low IL-6 ^high 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.

Keywords: cancer-associated fibroblasts; diagnosis; hallmark; heterogeneity; pancreatic cancer; prognosis; therapy.

FIGURE 1

Heterogeneity of cancer-associated fibroblasts (CAFs) and their markers/pathways; the different subpopulations of CAFs are geographically segregated in PDAC tumor microenvironment. myCAFs, myofibroblastic cancer-associated fibroblasts; αSMA, α-smooth muscle actin; IL-6, interleukin-6; TGF-β, transforming growth factor-β; SMAD, Drosophila mothers against decapentaplegic protein; Ctgf, connective tissue growth factor; Col1α1, collagen type I alpha 1; TAGLN, transgelin; MYL9, myosin regulatory light chain 9; TPM1, tropomyosin 1; iCAFs, inflammatory cancer-associated fibroblasts; JAK, Janus kinase; STAT, signal transducer and activator of transcription; CXCL1, chemokine (C-X-C motif) 1; apCAFs, antigen-presenting cancer-associated fibroblasts; MHC II, major histocompatibility complex II; H2-Aa, encoding α-chains of MHC II; H2-Ab1, encoding β-chains of MHC II.

FIGURE 2

Hallmarks for diagnosis and prognosis of PDAC by CAFs. PDAC, pancreatic ductal adenocarcinoma; LIF, leukemia inhibitory factor; iCAFs, inflammatory cancer-associated fibroblasts; myCAFs, myofibroblastic cancer-associated fibroblasts; IL-33, interleukin-33; CXCL3, chemokine (C-X-C motif) 3; LRRC15, 15-leucine repeat membrane protein; JAK, Janus kinase; STAT, signal transducer and activator of transcription; CXCR2, C-X-C motif chemokine receptor 2.

FIGURE 3

Target IL1/LIF/JAK/STAT 3 pathway, which could activate iCAFs in pancreas. It may become potentially effective targeted therapies for PDAC. IL-1β, interleukin-1β; IL-1R, interleukin-1 receptor; LIF, leukemia inhibitory factor; JAK, Janus kinase; STAT 3, signal transducer and activator of transcription 3; iCAFs, inflammatory cancer-associated fibroblasts.

FIGURE 4

IL-6 is an important marker of iCAFs; it is worth to explore the effect of IL-6 inhibition or its receptor on PDAC progression. IL-6, interleukin-6; PDAC, pancreatic ductal adenocarcinoma; MAPK, mitogen-activated protein kinase; NK cell, natural killer cell; STAT 3, signal transducer and activator of transcription 3; SAA, serum amyloid A.

FIGURE 5

Target the CXCL12-CXCR4 axis is effective in preclinical study. CAFs, cancer-associated fibroblasts; CXCR12, C-X-C motif chemokine receptor 12; CXCR4, C-X-C motif chemokine receptor 4; SATB-1, special AT-rich sequence binding protein 1; PD-1, programmed death 1.