Tumor promotion via injury- and death-induced inflammation

Abstract

Inhibition of programmed cell death is considered to be a major aspect of tumorigenesis. Indeed, several key oncogenic transcription factors, such as NF-κB and STAT3, exert their tumor-promoting activity at least in part through upregulation of survival genes. However, many cancers develop in response to chronic tissue injury, in which the resulting cell death increases the tumorigenic potential of the neighboring cells. In this review, we discuss a resolution to this paradox based on cell death-mediated induction of tumor promoting inflammatory cytokines, which enhance cell survival and trigger compensatory proliferation in response to tissue injury.

Conflict of interest statement

The authors also apologize to those whose papers were not cited due to space restrictions and declare no competing financial interests.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. Tumorigenesis in response to chronic tissue injury of different types

Tissue injury and cell death lead to activation of various inflammatory cells that secrete cytokines that promote wound healing. However, if this process is reiterated several times or inflammation fails to resolve, tissue regeneration may be dysregulated and, when combined with carcinogen exposure, can lead to malignant transformation.

Figure 2. Cell death and inflammation

While normal apoptotic cell death inhibits inflammation, apoptotic death of infected cells, necrotic cell death or factors released by stressed cells lead to activation of different types of immune cells, including T and B lymphocytes, macrophages (mΦ) and dendritic cells (DC). The latter produce cytokines that have either positive (red) or negative (blue) influences on cell survival and proliferation and regulate different steps of tumorigenesis, including tumor growth and progression. In addition, mΦ and DC may recruit other immune cells into the tumor microenvironment. Damaged or neighboring epithelial cells can also release various cytokines, which further modulate cell survival and growth.

Figure 3. The critical pro-tumorigenic function of cell death

Sentinel immune cells are present in normal tissue, but they do not produce inflammatory cytokines and do not promote tumorigenesis. (A) Injury and cell death induce inflammation which precedes or accompanies tumor development, while immune cells and epithelial cell mutations without injury do not cause cancer (1) Normal tissue (2). Inflammation results in robust tissue infiltration by immune cells, but without extensive tissue injury and cell death, tumor promotion does not take place. (3) Tissue injury and epithelial cell death in combination with inflammation result in an enhanced regenerative response, leading to the proliferation of stem cells that may harbor oncogenic mutations. Immune cells, in turn, maintain chronic inflammation and cause additional tissue injury. This leads to tumor initiation and promotion and further enhancement of tumor progression and metastasis and modulation of anti-tumor therapy response by inflammation (4). (B) NB Inflammation can regulate tumor promotion, progression and metastasis by other mechanisms, which do not invoke tissue damage and cell death. These mechanisms rely on cancer cells recruiting immune cells to the tumor microenvironment as a part of tumor-elicited inflammation.