Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

Abstract

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy.

Keywords: cancer therapy; cancer-associated fibroblasts; extracellular matrix; immune cells; stress; tumor microenvironment.

Figure 1

CAF component of TME plays a critical role in promoting tumorigenesis and determines tumor fate in solid tumors. The relationship between TME components (CAF compartment, immune compartment, and vascular compartment; as represented in oval shapes), TME functions (as represented in a square), and tumor end-points (as illustrated in hexagonal shapes) are diagrammatically presented. The diagram is presented in three layers. The top layer presents three TME components, the middle layer presents various functions of the CAF compartment, immune compartment, and vascular compartment in an established tumor, and the bottom layer presents tumor end-points. In an established tumor, TME influences (1) tumor growth and proliferation, (2) metastasis-associated phenotypes and EMT, (3) tumor-associated stemness, (4) tumor-associated stromagenesis, (5) evasion of immune surveillance, and (6) tumor-induced angiogenesis. The immune component is involved in the evasion of immune surveillance of the tumor cells (violet arrow), while the vascular component is involved in tumor-induced angiogenesis and thus influences metastasis-associated phenotypes (Green Arrow). Unlike the other two components of TME, it is noteworthy that the CAF component of TME plays a critical role in promoting every function of TME (orange arrow). Black arrows connect various functions of TME with tumor end-points. The diagram attempts to visualize how CAF influences tumor end-points, which in turn determines the clinical outcome of a disease. Tumorigenesis may lead to metastatic progression (single arrow) and/or may exhibit resistance to drug (double arrow), leading to a dismal clinical outcome.

Figure 2

Mediators of CAF functions in the development of resistance to therapy: The development of resistance to various treatments involves dialogues of CAF with (1) tumor cells (CAF-tumor cell crosstalk), (2) tumor-infiltrating immune cells (CAF-immune cell crosstalk), and (3) endothelial cells (CAF-angiogenic cell crosstalk). CAF plays a critical role in the development of resistance to therapy in solid tumors. The CAF-tumor cell crosstalk occurs via several mechanisms involving upregulation (Red Arrow), downregulation (Green Arrow), and complex mediation (Broken Arrow) of signals in different solid tumors. Several cell signaling pathways are upregulated in the CAF-tumor cell crosstalk, including IGF, HGF-cMET, MEK-ERK, JNK, PDGF, NF kappaB, NRG1-HER3, FGFR/c-SRC, and JAK-STAT3 pathways. The crosstalk also involves several miRNAs, including miR-22, miR-98-5p, miR-92a-3p, miR-196a, miR-93-5p, miR-590-3p, miR-522, as well as cytokines like IL-6, IL-11, SDF-1, and TGFbeta. CAF also downregulated apoptosis and ferroptosis of tumor cells (A). CAF interacts directly with the angiogenic component and immune component in the development of resistance to therapy in solid tumors. The interaction involves both upregulation (Red Arrow) and complex mediation (Broken Arrow) of signals. CAF influence a number of immune cells, including MDSC, T-cells, tumor-associated macrophages, antigen-presenting cells, monocytes, tumor-associated neutrophils, natural killer cells, and mast cells. The types and mediators of interactions are either specific to an organ-type tumor or common to some solid tumors. The mediators of CAF-immune cells crosstalk are several growth factors, cytokines, chemokines, monocyte chemotactic protein-1, DNAM-1 /NKp44 /NKp30, TNFalpha, interferon-gamma, NOX4, Tenascin C, and STAT3. The interaction of vascular cells and CAF involves the Lipoma-Preferred Partner (LPP) gene (B).