Fibroblasts as Modulators of Local and Systemic Cancer Metabolism

Abstract

Fibroblast activation is an accompanying feature of solid tumor progression, resembling a conserved host response to tissue damage. Cancer-associated fibroblasts (CAFs) comprise a heterogeneous and plastic population with increasingly appreciated roles in tumor growth, metastatic capacity, and response to therapy. Classical features of fibroblasts in a wound-healing response, including profound extracellular matrix production and cytokine release, are recapitulated in cancer. Emerging evidence suggests that fibroblastic cells in the microenvironments of solid tumors also critically modulate cellular metabolism in the neoplastic compartment through mechanisms including paracrine transfer of metabolites or non-cell-autonomous regulation of metabolic signaling pathways. These metabolic functions may represent common mechanisms by which fibroblasts stimulate growth of the regenerating epithelium during a wound-healing reaction, or may reflect unique co-evolution of cancer cells and surrounding stroma within the tumor microenvironment. Here we review the recent literature supporting an important role for CAFs in regulation of cancer cell metabolism, and relevant pathways that may serve as targets for therapeutic intervention.

Keywords: cancer metabolism; cancer-associated fibroblast; tumor-stroma crosstalk.

Figure 1

CAF secretions of immunomodulatory factors regulate anti-tumor immune response. CAF secretion of CXCL12/SDF1, M-CSF/CSF-1, IL-6, and CCL2/MCP-1 recruits tumor-associated macrophages to the TME and helps differentiate them to an M2 Immunosuppressive phenotype. CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, and CCL2 recruits tumor-associated neutrophils and polarizes them to an N2 pro-tumoral phenotype. CAF and cancer cell secretion of TGF-β induces miR-183 to inhibit DAP12 transcription and reduce natural killer (NK) activating receptors (NKp30, NKp44, NKG2D), while PGE2 and IDO secretion decreases NK cell cytotoxicity against cancer cells. TGF-β also promotes cell death of CD8+ T cells by inhibiting expression of Bcl-2 and causes dendritic cells (DC) to downregulate expression of MHC class II, CD40, CD80, and CD86 leading to decreased antigen presentation efficiency along with decreased production of TNF-α, IFN-γ, and IL-12. TDO2 and IDO1 secretion promotes tryptophan metabolism to kynurenines (Kyn), inhibiting DC differentiation and damages T cell response by catabolizing tryptophan degradation into Kyn, causing T cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. VEGF secretion inhibits DC generation and maturation by reducing MHC class II expression and antigen presenting abilities. Secretion of CCL2, CCL5, and CCL17 along with polarizing cytokines IL-1, IL-6, IL-13, and IL-26 switch CD4+ helper T lymphocytes from an anti-tumor T_H1 response to a pro-tumor T_H2 and T_H17 response.

Figure 2

A role for fibroblast-derived metabolites in tumor-stroma interactions. (A) illustrates metabolic reprogramming in CAFs and (B) illustrates the effect of metabolites derived from CAFs to cancer cells in the TME. (1) Activated CAFs uptake excess TME lactate produced by glycolytic cells in the TME. (2) p62 deficient CAFs are autophagy defective and have upregulation of ATF4 which activates metabolic flux through pyruvate carboxylase (PC) → asparagine synthase (ASNS) pathway producing asparagine that is consumed by cancer cells. (3) CAFs characterized by upregulation of anapleurotic glutamine metabolism where cancer cell-derived aspartate, asparagine, and glutamate are used to generate glutamate that is fed to cancer cells; glutamine amino ligase (GLUL) is overexpressed in these CAFs. (4) Cancer cells induce autophagy in CAFs increasing turnover of non-essential amino acids, alanine has been shown to be up-taken by cancer cells to support growth. (5) Upon activation pancreatic and hepatic CAFs shift from lipid storing to lipid-secreting wherein CAF-derived lipids support proliferation and migratory potential of cancer cells. (6) Exosome releasing CAFs pack metabolic molecules used by cancer cells. (7) CAV1 deficient CAFs are known to upregulate glycolytic metabolism, as well as, fibroblast activation by PDGF and TGFβ. (A) describes metabolic alterations in CAFs in dashed boxes. In both figures metabolic pathways are denoted with green arrows, cellular processes are assigned specific colors, and metabolic molecules are underlined.