Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

Abstract

Defining tumor cell immune evasion Mouse models used to study cancer often lack a full immune system, allowing implantation of human tumors into the mice. By contrast, naturally evolving tumors must contend with a fully functional immune system and its destruction of some of the cells (see the Perspective by Ho and Wood). Two groups now report studies on mouse models with a fully intact immune system. Martin et al . started with preexisting murine tumor cell lines and examined their continued evolution in vivo, whereas Del Poggetto et al . examined the development of new pancreatic tumors in the context of inflammation, as is often seen in human patients. In each study, the authors found that the immune system exerted a selective pressure on cells that would give rise to tumors, promoting the survival of those that had lost expression of tumor suppressor genes or activated a specific oncogene. The findings suggest a major role for the immune system in driving tumor evolution across multiple types of cancer. —YN

An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas

“…Whether this feature might be owing to diminished expression of the cholecystokinin receptor at the cell surface or of other intermediate signaling molecules is unclear. These data diverge from recent findings 22 suggesting that the propensity for ADM is heightened by memory of prior inflammation, although these studies were performed with a 28 day recovery period. Indeed, we also observe that a short recovery (21 days) yields an enhanced effect with prior caerulein, which we attribute to residual inflammation and the ongoing molecular dynamics in the first several weeks after inflammation.…”

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

“…One well-known risk factor for PDAC is chronic pancreatitis, which fits the already established general association between tumors and inflammation [42]. Epigenetic changes are linked to the early stages of oncogenesis in pancreatic cancer driven by inflammation [10,11]. The damage experienced by pancreatic epithelium during bouts of pancreatitis causes sustained transcriptional and epigenetic reprogramming, providing an epithelial memory, which is protective during future insults.…”

“…Epigenetic alterations have been linked to cancer for several decades. Increasingly, epigenetic mechanisms are appreciated as crucial drivers of the malignant phenotype [5,6] and several epigenetic changes are found in PDAC [7][8][9][10][11][12]. As the epigenome is involved in several aspects of tumorigenesis, epigenetic alterations may also serve as therapeutic targets.…”

Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity

“…This response was solidified by somatic KRAS mutations. On the downside, epithelial memory together with KRAS mutations are not only protected from future inflammation-related injury but are also predisposed to the development of cancer [14]. Somatic mutations themselves can also arise as a consequence of chronic inflammation among others by activating innate immune cells to produce genotoxic agents such as oxygen or nitrogen radicals [15][16][17].…”