The effect of environmental chemicals on the tumor microenvironment

Abstract

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

Figure 1.

Carcinogens promote tumorigenesis by targeting multiple components in the tissue, and subsequently, the tumor microenvironment. First, carcinogens may exert preneoplastic influences on various cell types within the tissue, such as stromal cells, fibroblasts and endothelial cells. Carcinogens may also affect the innate (antigen-presenting cells) and adaptive (B, T lymphocytes) immune system, as well as secreted molecules. Carcinogens may encourage angiogenesis and chronic inflammation, which fuel the growth and evolution of the neoplastic cells.

Figure 2.

Environmental pollutant target resident cells and their local environment thus affecting key parameters of tissue homeostasis. Environmental pollutants target tissue resident cells, thus changing their intrinsic properties, and also affect their environment, in particular changing soluble factors available. All these events can lead to modifications of tissue homeostasis and emergence of cancer. During our lifetime, we can be exposed to different types of carcinogens at different times and the consequences of combinatorial exposure remain poorly deciphered. Environmental pollutant seems to induce both short- and long-term effects, which together with our own history (aging, genetic predisposition and/or cancer history) creates a context that may promote the development of cancer, long after the initial parameters. All these complex and person-dependent parameters raise challenging issues for public health to overcome cancer induced by carcinogens.