Elsevier

Cellular Signalling

Volume 21, Issue 3, March 2009, Pages 378-383
Cellular Signalling

Review
Inflammatory signaling and cellular senescence

https://doi.org/10.1016/j.cellsig.2008.10.011Get rights and content

Abstract

Inflammation acts as a double-edged sword in the pathogenesis of cancer. Inflammatory responses play a key role in eliminating potentially cancerous cells; however, an inflammatory microenvironment also promotes the development of cancer. Proinflammatory cytokines, the key mediators of inflammation, also play a dual role in oncogenesis. While they can promote neoplastic progression, recent studies have revealed an unexpected function of the inflammatory pathways in inhibiting cancer development. These studies demonstrate that cells undergoing senescence, a cellular program serving as a barrier to cancer development, produce increased amount of inflammatory cytokines. These inflammatory cytokines play an essential role in the initiation and maintenance of cellular senescence, and are responsible for triggering an innate immune response that clears the senescent tumor cells in vivo. The purpose of the present review is to discuss the dual roles of the inflammatory cytokines produced by senescent cells in the pathogenesis of cancer, and the signaling pathway mediating their role in cellular senescence.

Introduction

The function of the immune system is to protect against foreign substances, such as bacteria and viruses, and to eliminate endogenous damaged cells. Based on this classic concept of immunosurveillance, the immune system should play a key role in preventing tumor initiation and development. Indeed, many studies have demonstrated the existence of the cancer immunosurveillance processes that protect the host against the development of primary cancer [1], [2]. The adaptive immune system reacts to tumors in a similar manner as to foreign pathogens, by stimulating immune cells to recognize tumor-specific antigens and to activate the functions of immune effectors, leading to eradication of cancerous cells. However, the effect of the immune system on cancer is paradoxical. Substantial evidence shows that inflammation, the major innate immune response to infectious pathogens and to endogenous dangerous cells, can promote the development of many types of cancers. In contrast to the role of cancer immunosurveillance, chronic inflammation provides a microenvironment that promotes cancer development in many cases [3], [4]. Immune cells recruited into the tumor microenvironment produce growth factors for epithelial and endothelial cells; inflammatory cytokines and chemokines that enhance cell proliferation and survival; and angiogenesis and immunosuppressive mediators that inhibit cancer immunosurveillance of the host [5], [6]. Collectively, these factors facilitate the malignant progression of tumors. The role of inflammation in the initiation of tumors has also been suggested. For example, chronic inflammation is linked to oxidative stress, which can cause DNA damage and thus contribute to the accumulation of cancer-initiating genetic alternations in cells.

Adding to the complexity of the effect of the immune system on cancer development, recent studies have revealed the involvement of inflammation in cellular senescence, a tumor suppressing mechanism that is equally important as apoptosis in restricting tumor development in vivo. These studies show that the gene expression patterns in senescent cells mimic the inflammatory response and wound repair process. The inflammatory state of cellular senescence again displays dual effects on tumor development. Production of inflammatory cytokines and chemokines is essential for the induction and maintenance of senescence, which prevents premalignant tumor cells from progressing into malignancies, and is responsible for the clearance of the senescent, premalignant tumor cells in vivo. Meanwhile, these inflammatory cytokines and chemokines produced by the senescent cells also provide a cancer-promoting microenvironment for their neighboring tumor cells. As a result, the net effect of the inflammatory state of senescence on cancer development will greatly depend on the tissue context, the genetic makeup of the tumor cells as well as the stromal cells, and the extracellular stimuli present in the tumor microenvironment.

Section snippets

Cellular senescence and cancer

Cellular senescence is a permanent cell cycle arrest initially described as the terminal phase of primary human cell populations when passaged in cell culture. This type of cellular senescence is thus termed replicative senescence, in reference to the exhaustion of replicative potential of the primary cells cultured in vitro as the cause of senescence. In human cells, replicative senescence usually occurs as a result of telomere attrition caused by the failure of the DNA replication machinery

The inflammatory state of senescent cells

The connection between inflammation and cellular senescence was initially suggested by studies on the gene expression profiles of senescent cells. These studies demonstrate that senescence is associated with gene expression patterns similar to those observed in inflammatory responses and wound healing processes. Increased expression of inflammation-associated genes, including the chemokines monocyte chemotactic protein-1 (MCP-1) and Gro-α, cytokines IL-15 and IL-1β, Toll-like receptor 4 (TLR4)

Perspective

It has been well established that inflammation plays a crucial role in the pathogenesis of cancer. Mounting evidence has indicated that tumors can take advantage of some of the molecular mechanism underlying inflammation for their growth and metastasis. Inflammatory cells are recruited to and activated in the microenvironment of a developing tumor, where they promote neoplastic progression of the tumor by producing a myriad of soluble growth factors, cytokines, and chemokines, as well as

Acknowledgement

This work was supported by National Basic Research Program of China (973 program) 2009CB522200.

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