Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis

Abstract

Inflammation is a necessary albeit insufficient component of tumorigenesis in some cancers. Infectious agents directly implicated in tumorigenesis have been shown to induce inflammation. This process involves both the innate and adaptive components of the immune system which contribute to tumor angiogenesis, tumor tolerance and metastatic properties of neoplasms. Recently, heat-shock proteins have been identified as mediators of this inflammatory process and thus may provide a link between infection-mediated inflammation and subsequent cancer development. In this review, the role of heat-shock proteins in infection-induced inflammation and carcinogenesis will be discussed.

Figure 1

Growth and inhibitory effects of free radicals on tumors. The unchecked production of hydroxyl radicals and other reactive oxygen species (ROS) leads to protein and lipid peroxidation as well as DNA damage which increase mutation load resulting in either tumor regression or tumor progression. In response to intracellular protozoa, classically-activated macrophages produce nitric oxide (NO) from arginine (L-arg) using the iNOS enzyme. H.pylori disinhibits iNOS in the gastric mucosa by attenuating the expression of HSP70 and HSP27. Tumor-associated macrophages (TAM) are not toxic to tumor cells because of their limited production of NO.

Figure 2

Heat-shock protein signal cascade. Necrotic tumor-derived mammalian gp96 and HSP70 can signal antigen-presenting cells (APCs) via CD14, and other receptors such as TLRs and CD91 which remain to be fully determined.

Figure 3

Venn diagram demonstrating a model of the tumorigenic relationship between infection, chronic inflammation and microbial- or host-derived heat-shock proteins.