Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Abstract

As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

Figure 1.

Targets for disruption of TGFβ tumor suppression (dark blue background), initiated by TGFβ binding and TβR-I receptor-mediated C-terminal phosphorylation of Smad2/3 (yellow ovals) and followed by translocation and transcriptional activation/repression.

Figure 2.

Schematic diagram depicting connexins, connexons (hemichannels) and gap junction (GJ) intercellular channels. PM1 and PM2 represent plasma membranes from two adjacent cells. Blue and green represent two different connexin family members.

Figure 3.

Contact growth inhibition and the control of cell proliferation and motility. Cadherins interact with other cadherins on adjacent cells and intracellular proteins including p120 and β-catenin (β), which associates with α-catenin (α) to control the actin cytoskeleton and inhibit cell motility and proliferation. Normally, free β-catenin is phosphorylated by GSKβ and associates with the Axin-APC complex to undergo ubiquitin-mediated proteasomal degradation. However, Wnt signaling can prevent β-catenin degradation and allow it to augment transcription of genes that promote cell migration and proliferation (TF). Contact growth inhibition also promotes the expression of tumor suppressors including Rb to prevent cell cycle progression. Transforming agents exemplified by the Src tyrosine kinase can disrupt intercellular junctions and augment the activity of tumor promoters such as VEGFR2, Crk, Cas and PDPN to promote cancer invasion and metastasis. For example, PDPN associates with ezrin proteins (ERM) to modify the actin cytoskeleton and promote cell migration. Receptors that allow tumor cells to overcome contact growth inhibition may serve as cancer biomarkers and chemotherapeutic targets. For example, bevacizumab inhibits VEGF signaling, whereas monoclonal antibodies (NZ1) or lectins (MASL) target PDPN on malignant cells.