In Vivo Reprogramming Highlights Epigenetic Regulation That Shapes Cancer Hallmarks

Abstract

Douglas Hanahan added "non-mutational epigenetic reprogramming" and "unlocking phenotypic plasticity" as new hallmarks of cancer, proposing that cancer cells possess fundamental features that are not directly linked to their genetic abnormalities. In vivo reprogramming studies have demonstrated that non-mutational epigenetic regulation can cause cellular reprogramming, leading to cancer development at the organismal level. Given that epigenetic regulation functions as an interface between the cellular environment and gene expression, these results suggest that intercellular communications in the tumor microenvironment play a critical role in cancer development. This review first introduces genetic aberrations that cause cancer development. Then, it illustrates the impact of epigenetic abnormalities in cancer, especially with reference to studies that use in vivo reprogramming technologies. Finally, it discusses the importance of histological evaluations of tumor tissue to understand non-cell-autonomous epigenetic regulation that establishes cancer hallmarks.

Keywords: cell dedifferentiation; hallmarks of cancer; in vivo reprogramming; non‐mutational epigenetic reprogramming; unlocking phenotypic plasticity.

FIGURE 1

The concept of epigenetic cancer. Complete in vivo reprogramming in reprogrammable mice results in teratoma formation in various organs. In contrast, premature termination of in vivo reprogramming before teratoma formation causes cancers. The kidney cancer cells do not harbor major oncogenic mutations and are reprogrammed into pluripotent stem cells in vitro, eventually contributing to non‐neoplastic kidney cells in mice upon redifferentiation. These results suggest that epigenetic regulation toward pluripotency drives cancer development.

FIGURE 2

The importance of epigenetic alteration in pancreatic cancer development. Transient expression of reprogramming factors (Oct4, Sox2, Klf4, and Myc [OSKM]) in pancreatic acinar cells or pancreatitis induced by intraperitoneal injection of Caerulein, a common model of pancreatitis in mice, leads to the repression of acinar cell enhancers and results in acinar‐to‐ductal metaplasia. In Kras mutant mice, such OSKM expression immediately induces pancreatic ductal adenocarcinoma (PDAC), whereas the genetic alteration alone needs long latency for PDAC development, underscoring the importance of epigenetic alteration in pancreatic cancer development.

FIGURE 3

The impact of cellular reprogramming in germ cell tumor development. In vivo induction of higher levels of OSKM in mouse somatic cells results in the development of cancer that resembles human germ cell tumors with extraembryonic lineage cells. The tumor cells give rise to iPSCs, which contribute to both embryonic and extraembryonic lineage cells. These results underscore the impact of cellular reprogramming in the development of germ cell tumors and explain their unique differentiation propensity.

FIGURE 4

The contribution of histological analysis to understanding cancer epigenetics. Epigenetic alterations could be histologically manifested as dedifferentiation and transdifferentiation. Dedifferentiation through tumor progression is recognized as a morphological loss of unique features of the original lineage cells, represented by dedifferentiated liposarcoma. Transdifferentiation, represented by metaplasia, is also associated with both cancer initiation and progression. Considering epigenetic regulation is modulated by cellular environment, detailed investigations of non‐cell‐autonomous effects between cancer cells and the surrounding non‐cancerous cells at the tissue level should provide an important clue to understanding cancer epigenetics. Note that the tumor microenvironment consists of various cell types and structures, such as lymphocytes and fibroblasts, exemplified by pancreatic ductal adenocarcinoma (PDAC). Human PDAC and mouse models share histological features, including those of tumor microenvironment. The expression of aSMA (alpha‐smooth muscle actin) in stromal fibroblasts is confirmed in mouse PDAC.