Membrane-to-Nucleus Signals and Epigenetic Mechanisms for Myofibroblastic Activation and Desmoplastic Stroma: Potential Therapeutic Targets for Liver Metastasis?

Abstract

Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment (TME), are a key source of the extracellular matrix (ECM) that constitutes the desmoplastic stroma. Through remodeling of the reactive tumor stroma and paracrine actions, CAFs regulate cancer initiation, progression, and metastasis, as well as tumor resistance to therapies. The CAFs found in stroma-rich primary hepatocellular carcinomas (HCC) and liver metastases of primary cancers of other organs predominantly originate from hepatic stellate cells (HSTC), which are pericytes associated with hepatic sinusoids. During tumor invasion, HSTCs transdifferentiate into myofibroblasts in response to paracrine signals emanating from either tumor cells or a heterogeneous cell population within the hepatic tumor microenvironment. Mechanistically, HSTC-to-myofibroblast transdifferentiation, also known as, HSTC activation, requires cell surface receptor activation, intracellular signal transduction, gene transcription, and epigenetic signals, which combined ultimately modulate distinct gene expression profiles that give rise to and maintain a new phenotype. The current review defines a paradigm that explains how HSTCs are activated into CAFs to promote liver metastasis. Furthermore, a focus on the most relevant intracellular signaling networks and epigenetic mechanisms that control HSTC activation is provided. Finally, we discuss the feasibility of targeting CAF/activated HSTCs, in isolation or in conjunction with targeting cancer cells, which constitutes a promising and viable therapeutic approach for the treatment of primary stroma-rich liver cancers and liver metastasis.

Figure 1. Paracrine mechanisms by which CAF/activated HSCs promote liver metastasis

CAF/activated HSCs release excessive growth factors, cytokines and chemokines to promote tumor cell proliferation and migration. TGF-β derived from CAF/activated HSCs promotes tumor cell migration and invasion by inducing EMT of cancer cells. CAF/activated HSCs also produce MMPs to breakdown ECM and cadherin based adherens junctions of cancer to further potentiate tumor cell migration. Furthermore, TGF-β suppresses anti-tumor responses of a variety of inflammatory cells. CAF/activated HSCs also promote tumor angiogenesis by releasing MMP9 and angiogenic factors. Excessive ECM and inflammatory cytokines within the desmoplastic stroma impair drug delivery, contributing to tumor resistance to conventional chemotherapy and radiation therapy. EMT: epithelial to mesenchymal transition; MΦ: macrophage.

Figure 2. HSC activation is regulated by receptor mediated an intracellular signaling network and downstream orchestrated gene transcriptional events

Only key receptor mediated signaling cascades and the downstream effectors are shown. In the nucleus, transcription of fibrogenic genes is turned on by recruitment of transcription factors, posttranscriptional modifications of transcription factors, and histone modifications to form an active chromatin structure, whereas transcription of adipogenic genes is turned off by epigenetic mechanisms such as DNA methylation, histone modifications to form a repressed chromatin structure and miRNAs. TFs: transcription factors; miRNAs: microRNAs; Ac: acetyl group; PM: plasma membrane; Nu: nucleus.