The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging lethal tumors and has a very poor prognosis. In addition to cancer cells, the tumor microenvironment created by a repertoire of resident and recruited cells and the extracellular matrix also contribute to the acquisition of hallmarks of cancer. Among these factors, cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. CAFs originate from the activation of resident fibroblasts and pancreatic stellate cells, the differentiation of bone marrow-derived mesenchymal stem cells and epithelial-to-mesenchymal transition. CAFs acquire an activated phenotype via various cytokines and promote tumor proliferation and growth, accelerate invasion and metastasis, induce angiogenesis, promote inflammation and immune destruction, regulate tumor metabolism, and induce chemoresistance; these factors contribute to the acquisition of major hallmarks of PDAC. Therefore, an improved understanding of the impact of CAFs on the major hallmarks of PDAC will highlight the diagnostic and therapeutic values of these targeted cells.

Keywords: cancer-associated fibroblast; hallmarks of cancer; pancreatic cancer; tumor microenvironment.

Figure 1

Heterogeneous origins and activation of cancer-associated fibroblasts. (A) The tumor microenvironment is composed of heterogeneous cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), immune inflammatory cells, cancer cells, various progenitor cells, blood vessels and extracellular matrix. (B) The sources of CAFs include recruited bone marrow-derived mesenchymal stem cells (MSCs), resident fibroblasts, quiescent pancreatic stellate cells (PSCs) and epithelial-to-mesenchymal transition (EMT). Growth factors stimulate CAF activation. The inflammatory environment facilitates acquisition of contractile and secretory phenotypes. Stromal modification contributes to phenotype maintenance. Activated CAFs express several marker proteins, such as alpha-smooth muscle actin (α-SMA), fibroblast-specific protein 1 (FSP1) and fibroblast activation protein (FAP), indicating a switch from the quiescent state to the activated state. α-SMA: alpha-smooth muscle actin; DNA: deoxyribonucleic acid; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; TGF-β: transforming growth factor beta; TIMP: tissue inhibitor of metalloproteinases.

Figure 2

Impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Through crosstalk with the tumor microenvironment, cancer-associated fibroblasts (CAFs) acquire physiological functions that ultimately regulate major hallmarks of pancreatic cancer.

Figure 3

Cancer-associated fibroblasts crosstalk with the tumor microenvironment in pancreatic cancer. Cancer-associated fibroblasts (CAFs) promote cancer cell growth, survival, invasiveness and chemoresistance via paracrine, exosome-mediated or autophagic mechanisms. Some proteins expressed on CAFs also correlate with tumor progression and poor prognosis. In addition, CAFs mediate stromal remodeling, which affects cancer cell migratory tracking and drug delivery. Metabolic reprogramming of CAFs fuels proliferation and renders invasive advantages to pancreatic cancer cells. Furthermore, CAFs also regulate tumor angiogenesis and immunosuppression, which indirectly influence tumor growth and migration. CXCL: chemokine (C-X-C motif) ligand; CYR: cysteine-rich angiogenic inducer; Endo180: urokinase-type plasminogen activator receptor-associated protein; FAP: fibroblast activation protein; GEM: gemcitabine; GM-CSF: granulocyte-macrophage colony-stimulating factor; HGF: hepatocyte growth factor; IL: interleukin; IGF: insulin-like growth factor; miR-210: microRNA-210; M-CSF: macrophage colony-stimulating factor; MMP: matrix metalloproteinases; PDGF: platelet-derived growth factor; TIMP: tissue inhibitor of metalloproteinases; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.