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.

Necrotic Cells from Head and Neck Carcinomas Release Biomolecules That Are Activating Toll-like Receptor 3

“…However, this is contradictory to the fact that tumors with large amounts of necrosis are generally the most aggressive. This might be explained to some extent by the high rate of necrosis, reflecting a very rapid proliferation, with angiogenesis lagging well behind, but it might also be explained by the deleterious effects of some categories of biomolecules released by necrotic cells [6]. In this regard, it is interesting to note that TLR3 is frequently expressed by tumor cells in human malignancies.…”

“…Necrotic cells undergo cell lysis and release various types of biomolecules, either in native or altered configurations. A number of these diffusible necrotic biomolecules induce changes in the phenotype and behavior of distinct living cells with the status of target cells (for a review, see [6]). Many of these changes result from the binding of necrotic biomolecules to Toll-like receptors (TLRs) expressed by the target cells.…”

The Conjugate of Rhein–Artesunate for Inducing Immunogenic Cell Death to Prepare Cancer Vaccine and Suppress Tumor Growth

“…Moreover, HMGB1 released from the nucleus enhances the antigen presentation effect of DCs [6,7]. The interaction between DAMPs and the immune system transforms the tumor microenvironment from an immunologically "cold" state to an immunogenic "hot" state, promoting anti-tumor immune responses [8,9]. Given the stressor-dependent nature of ICD induction, various strategies have been employed to design small molecules, metallic compounds, or nano-platforms to induce ICD by eliciting stress in cancer cells [10][11][12].…”