In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression

Abstract

It has been widely accepted that tumor cells and normal stromal cells in the host environment coordinately modulate tumor progression. Mitogen-activated protein kinase pathways are the representative stress-responsive cascades that exert proper cellular responses to divergent environmental stimuli. Genetically engineered mouse models and chemically induced tumorigenesis models have revealed that components of the MAPK pathway not only regulate the behavior of tumor cells themselves but also that of surrounding normal stromal cells in the host environment during cancer pathogenesis. The individual functions of MAPK pathway components in tumor initiation and progression vary depending on the stimuli and the stromal cell types involved in tumor progression, in addition to the molecular isoforms of the components and the origins of the tumor. Recent studies have indicated that MAPK pathway components synergize with environmental factors (e.g. tobacco smoke and diet) to affect tumor initiation and progression. Moreover, some components play distinct roles in the course of tumor progression, such as before and after the establishment of tumors. Hence, a comprehensive understanding of the multifaceted functions of MAPK pathway components in tumor initiation and progression is essential for the improvement of cancer therapy. In this review, we focus on the reports that utilized knockout, conditional knockout, and transgenic mice of MAPK pathway components to investigate the effects of MAPK pathway components on tumor initiation and progression in the host environment.

Keywords: Carcinogenesis; genetic engineering; metastasis; proliferation/differentiation; signal transduction.

Fig 1

In mammalian MAPK pathways, upstream MAPK kinase kinase (MAP3K) phosphorylates and activates MAPK kinase (MAP2K) and MAP2K sequentially activates MAPK. Activated MAPK regulates the dynamics of intranuclear transcription factors that induce physiological responses. EGF, epidermal growth factor; ROS, reactive oxygen species; TGF, transforming growth factor.

Fig 2

Apoptosis signal-regulating kinase 1 (ASK1) and ASK2 regulate skin tumorigenesis. The ASK2–ASK1 heterocomplex exerts a tumor-suppressive function by inducing apoptosis through activation of JNK and p38 during the initiation stage. In contrast, the ASK1 homocomplex in inflammatory cells evokes pro-inflammatory cytokine production in the promotion stage, accelerating tumorigenesis. DMBA, 7,12-dimethylbenz(a)anthracene; ROS, reactive oxygen species.