Epigenetic Mechanisms beyond Tumour-Stroma Crosstalk.

Teresa Gagliano,Claudio Brancolini

doi:10.3390/cancers13040914

Abstract

Simple SummaryIn this review article, we will deepen the topic of cancer cell communication with the surrounding non-cancerous cells. In particular, the non-mutational events that modified gene expression, namely “epigenetics”, involved in cell–cell interaction will be the center of this work. Many studies have described the mechanism of back-and-forth communication between cancer and stromal cells, and very recent studies suggested that epigenetics may play an important role in this setting. This work will describe recent advances in the field of epigenetic mechanisms involved in tumour–stroma crosstalk. Understanding these processes can be useful in future cancer therapy design.Despite cancer having been usually considered the result of genetic mutations, it is now well established that epigenetic dysregulations play pivotal roles in cancer onset and progression. Hence, inactivation of tumour suppressor genes can be gained not only by genetic mutations, but also by epigenetic mechanisms such as DNA methylation and histone modifications. To occur, epigenetic events need to be triggered by genetic alterations of the epigenetic regulators, or they can be mediated by intracellular and extracellular stimuli. In this last setting, the tumour microenvironment (TME) plays a fundamental role. Therefore, to decipher how epigenetic changes are associated with TME is a challenge still open. The complex signalling between tumour cells and stroma is currently under intensive investigation, and most of the molecules and pathways involved still need to be identified. Neoplastic initiation and development are likely to involve a back-and-forth crosstalk among cancer and stroma cells. An increasing number of studies have highlighted that the cancer epigenome can be influenced by tumour microenvironment and vice versa. Here, we discuss about the recent literature on tumour–stroma interactions that focus on epigenetic mechanisms and the reciprocal regulation between cancer and TME cells.

Highlights

To ensure genome stability, DNA accessibility has to be sophisticatedly regulated.Epigenetics consist of chemical modifications of DNA and chromatin which, in turn, regulate gene expression
We discuss about the recent literature on tumour–stroma interactions that focus on epigenetic mechanisms and the reciprocal regulation between cancer and tumour microenvironment (TME) cells
This research group identified a loop between the tumour and stromal component of metastases, formed by TNFα-TGFα-epidermal growth factor receptor (EGFR). These results suggest that cancer epigenetics may induce a loop of the cancer–stroma–cancer interaction that may promote peritoneal metastasis of Ovarian cancer (OC) cells via TNFα-TGFα-EGFR [32] (Figure 3)

Summary

Introduction

Epigenetics consist of chemical modifications of DNA and chromatin which, in turn, regulate gene expression. The setting of epigenetic changes is maintained across cell division through further epigenetic mechanisms or gene regulator loops that sustain adaptive clones, stimulating cancer progression [1]. Defects in chromatin regulators have been detected in both solid and blood cancers, and the importance of epigenetics in cancer cells has been demonstrated by several groups in different cancer types [2,3,4]. For long almost completely neglected by researchers, all non-tumoural cells interfacing with cancer cells, defined as the tumour microenvironment (TME), have a prominent role in cancer research. Many studies have reported a pivotal role for TME in cancer onset, progression and behavior. Stromal cells can influence cancer cells at different levels by promoting invasion, metastasis and resistance to treatment [6,7,8] (Figure 1)

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