Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth

Abstract

Damage-associated molecular patterns (DAMPs) are endogenous molecules released from the necrotic cells dying after exposure to various stressors. After binding to their receptors, they can stimulate various signaling pathways in target cells. DAMPs are especially abundant in the microenvironment of malignant tumors and are suspected to influence the behavior of malignant and stromal cells in multiple ways often resulting in promotion of cell proliferation, migration, invasion, and metastasis, as well as increased immune evasion. This review will start with a reminder of the main features of cell necrosis, which will be compared to other forms of cell death. Then we will summarize the various methods used to assess tumor necrosis in clinical practice including medical imaging, histopathological examination, and/or biological assays. We will also consider the importance of necrosis as a prognostic factor. Then the focus will be on the DAMPs and their role in the tumor microenvironment (TME). We will address not only their interactions with the malignant cells, frequently leading to cancer progression, but also with the immune cells and their contribution to immunosuppression. Finally, we will emphasize the role of DAMPs released by necrotic cells in the activation of Toll-like receptors (TLRs) and the possible contributions of TLRs to tumor development. This last point is very important for the future of cancer therapeutics since there are attempts to use TLR artificial ligands for cancer therapeutics.

Keywords: HMGB1; RAGE; Toll-like receptors; cancer; damage-associated molecular patterns (DAMPs); necrosis; tumor microenvironment (TME).

Figure 1

Schematic illustrations of various types of cell death. (A) Two broad categories are regulated (RCD) and accidental (ACD) cell death. RCD is the most common type. It includes necrotic and non-necrotic forms of cell death. Non-necrotic cell death includes apoptosis, also called programmed cell death (PCD), and cell death by autophagy. Necrotic regulated cell death includes necroptosis, ferroptosis, and pyroptosis. Other types of RCD are entotic cell death, NETotic cell death, parthanatos, lysosome-dependent cell death, and mitochondrial permeability transition (MPT)-driven necrosis. Accidental cell death usually has the form of a non-regulated necrosis. (B) represents the summary of different sorts of cell death.

Figure 2

Impact of biomolecules released by necrotic cells on malignant and stromal live cells in the tumor microenvironment (TME). Necrotic cells release DAMPs (HMGB1, HSPs, S100A, RNAs, and DNAs) into the TME. Malignant cells, cancer-associated fibroblasts (CAFs), and various types of infiltrating immune cells have pattern recognition receptors (PRRs). When binding these PRRs, damage-associated molecular patterns (DAMPs) can induce substantial changes in gene expression, resulting in inflammation, epithelial to mesenchymal transition (EMT), immunosuppression, local invasion, and metastases.