The interactions between macrophages and fibroblasts in the context of cancer

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Abstract

It has long been recognised that the formation of cancer associated fibroblasts (CAFs) is dictated by cancer cells. However, recent reports have suggested that the alterations in stromal cells, including fibroblasts, might precede the transformation of epithelial cells and act as a driver of the tumorigenesis. However, little is known about the mechanism underpinning the reprogramming of normal fibroblasts to CAFs without the involvement of cancer cells. Here, we have suggested that chronic inflammation could play a pivotal role in this process. Chronic inflammation has been linked with the origin of cancer for decades. It is estimated that approximately 20% of all cancer cases emerge as a direct consequence of long-lasting, ‘smouldering’ inflammation. However, our knowledge about the exact mechanism(s) behind this vicious association remains elusive. Here, we have hypothesised that macrophages, the key orchestrators of chronic inflammation, could provoke the transformation of normal fibroblasts towards CAFs, in a similar manner as cancer cells do, and consequently create a favourable environment for malignant cells to arise, survive and then expand. To test our hypothesis, we have employed hTER-BJ1 fibroblasts and treated them with macrophage-conditioned media. Then, a series of experiments has been performed to assess whether these fibroblasts acquired the key characteristics of CAFs. Notably, we have suggested here for the first time that macrophages could trigger the reprogramming of normal fibroblasts towards CAF-like cells. More precisely, we have suggested that factors secreted by macrophages could provoke the acquisition of key features attributed to pro-tumourigenic CAFs, including the induction of oxidative stress, the metabolic switch from the mitochondrial oxidative phosphorylation to aerobic glycolysis, and the induction of autophagy and cellular senescence. All these processes, collectively, result in the formation of catabolic CAFs that produce and secrete energy-rich nutrients and regulatory factors that are known to support malignant cells. However, further experiments are required to explore whether these macrophage-activated fibroblasts (MAFs) alone are sufficient to prompt the malignant transformation of epithelial cells or whether the presence of MAFs acts as a catalyst that accelerates tumour formation when another carcinogen is co-present.

Keyword(s)

fibroblasts; inflammation ; macrophages

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