Abstract
The tumor microenvironment (TME) is an intricate system within solid neoplasms. In this review, we aim to provide an updated insight into the TME with a focus on the effects of tumor necrosis factor-α (TNF-α) on its various components and the use of TNF-α to improve the efficiency of drug delivery. The TME comprises the supporting structure of the tumor, such as its extracellular matrix and vasculature. In addition to cancer cells and cancer stem cells, the TME contains various other cell types, including pericytes, tumor-associated fibroblasts, smooth muscle cells, and immune cells. These cells produce signaling molecules such as growth factors, cytokines, hormones, and extracellular matrix proteins. This review summarizes the intricate balance between pro-oncogenic and tumor-suppressive functions that various non-tumor cells within the TME exert. We focused on the interaction between tumor cells and immune cells in the TME that plays an essential role in regulating the immune response, tumorigenesis, invasion, and metastasis. The multifunctional cytokine, TNF-α, plays essential roles in diverse cellular events within the TME. The uses of TNF-α in cancer treatment and to facilitate cancer drug delivery are discussed. The effects of TNF-α on tumor neovasculature and tumor interstitial fluid pressure that improve treatment efficacy are summarized.
Highlights
The tumor microenvironment (TME) is a complex biological ecosystem of solid tumors encompassing all the cells and structures found in healthy organ tissue [1]
The role of tumor necrosis factor-a (TNF-a) in regulating the epithelialmesenchymal transition (EMT) in hepatocellular carcinoma cells (SMMC7721) was studied by Chen et al TNF-a is elevated in the supernatants of M2-tumor-associated macrophages (M2TAMs), promoting the EMT of SMMC-7721 cells in vitro [78]
Cancer cells caused neutrophils to secrete large amounts of TNF-a and transforming growth factor-beta (TGF-b) in a co-culture model, indicating that the cytokines were responsible for regulating the EMT and the metastasis [99]
Summary
The tumor microenvironment (TME) is a complex biological ecosystem of solid tumors encompassing all the cells and structures found in healthy organ tissue [1]. Glycoproteins, proteoglycans, cytokines, and growth factors provide structural support and information exchange [5] In both normal tissue and solid cancers, TNF-a has diverse regulatory roles in the TME depending on the type of cells. The innate immune cells of the TME secrete various cytokines such as TNF-a and interleukin-6 (IL-6), which can promote cancer cell survival [25] and induce the expression of vascular endothelial cell adhesion molecules (CAM) that facilitate extravasation of leukocytes [26]. TNF-a plays an important role in tumor metastasis It increases the expression of angiogenic factors such as basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) in endothelial cells of the TME.
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