Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

Abstract

Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

Antcin K Inhibits TNF-α, IL-1β and IL-8 Expression in Synovial Fibroblasts and Ameliorates Cartilage Degradation: Implications for the Treatment of Rheumatoid Arthritis

“…Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease with a complex pathogenesis that is not fully understood, but is known to involve the infiltration of inflammatory cells into the joints and subsequent swelling, synoviocyte proliferation, cartilage damage and bone erosion ( 1 , 2 ). The production of proinflammatory cytokines from activated RA synovial fibroblasts (RASFs) disrupts the microenvironment that mediates bone homeostasis ( 3 , 4 ). RASFs are considered to be the main catabolic factor in cartilage bone degradation, as they stimulate the production of proinflammatory cytokines typically associated with RA disease, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), IL-8 and IL-6 ( 5 ).…”

New Immunometabolic Strategy Based on Cell Type-Specific Metabolic Reprogramming in the Tumor Immune Microenvironment

“…Metabolic reprogramming of CAFs [ 122 ] leads to immunosuppression [ 123 , 124 ]. As modulators of cancer metabolism in the TIME, CAFs affect the proliferation and growth of tumors [ 121 , 125 ]. Thus, lipid metabolic reprogramming of CAFs in colorectal cancer has been shown to affect cancer cell metastasis [ 126 ].…”

“…Thus, lipid metabolic reprogramming of CAFs in colorectal cancer has been shown to affect cancer cell metastasis [ 126 ]. Current studies on the metabolic reprogramming of fibroblasts have focused on glucose metabolic pathways and highlighted metabolic reprogramming as an important event that contributes to the transition of fibroblasts from quiescent to active and recalcitrant cells [ 125 ]. Quiescent fibroblasts exhibit high metabolic activity [ 127 ].…”

Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

“…Interestingly, transplantation of tumor cells together with cancer-associated fibroblast (CAFs) leads to more malignant cancers compared to tumor cells alone or with normal fibroblasts. From the immunometabolic perspective, oxygen depletion in the TME promotes, via epigenetic reprogramming, a metabolic switch in CAFs leading to a glycolytic metabolism that fuels biosynthetic pathways of cancer cells, including the PPP and nucleic acid metabolism (56,57). Metabolites secreted by CAFs and taken up by tumors include lactate (58), glutamine (59,60) and lipids (61), among others.…”