Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis

Abstract

The lack of therapy and the failure of existing therapy has been a challenge for clinicians in treating various cancers. Doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel are the first-line therapy in various cancers; however, toxicity, resistance, and treatment failure limit their clinical use. Their status leads us to discover and investigate more targeted therapy with more efficacy. In this article, we dissect literature from the patient perspective, the tumor biology perspective, therapy-induced metastasis, and cell data generated in the laboratory.

Keywords: cancer; chemotherapy; inflammation.

Figure 1

Cisplatin-induced inflammation is mediated through multiple effectors including activation of NFkB, TNF-α, and PARP. NFkB is a focal point for downstream cell survival and proliferation signaling that involves IL-6 and IL-8 upregulation. Cisplatin also induces the MAPK/ERK pathway and EMT acquisition. The ERK signaling cascade is suggested as an upstream signal for TNF-α activation. Abbreviations: ADP-ribose, poly; COX-2, cyclooxygenase; EMT, epithelial–mesenchymal transition; ERK, mitogen-activated protein kinase; HGF, hepatocyte growth factor; HIF-α, hypoxia-inducible factor; ICAM-1, intercellular adhesion molecule; IL, interleukin; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa B; PARP, polymerase; STAT-3, signal transducer and activator of transcription; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.

Figure 2

Paclitaxel-induced inflammation is mediated by upregulation of IL-8 via NFκB signaling. In some cancers, paclitaxel has been shown to activate ERK through Toll-like receptor 4 (TLR4)-myeloid differentiation gene 88 (MyD88) signaling. TLR-4 phosphorylates c-Jun (component of activator protein 1 transcription complex), thereby inducing NFκB activation and upregulation of IL-6, IL-8 and VEGF. Paclitaxel also upregulates metastatic markers consistent with EMT acquisition, including fibronectin, vimentin, Snail, and Twist. Abbreviations: COX-2, cyclooxygenase; EMT, epithelial–mesenchymal transition; ERK, mitogen-activated protein kinase; HGF, hepatocyte growth factor; HIF-α, hypoxia-inducible factor; IL, interleukin; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa B; STAT-3, signal transducer and activator of transcription; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.

Figure 3

In HNSCC, 5-FU activates G-CSF and IL-6. In breast cancer, 5-FU induces NFκB as well as the mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway. Hepatocellular carcinoma cells treated with 5-FU have phenotypes consistent with epithelial-to-mesenchymal transition (EMT) acquisition, including down-regulation of E-cadherin, spindle-shaped morphology, increased pseudopodia formation and upregulation of Twist. Abbreviations: 5-FU, 5-Fluorouracil, c-Jun, component of the activator protein 1 transcription complex; EMT, epithelial–mesenchymal transition; ERK, mitogen-activated protein kinase; G-CSF, granulocyte colony-stimulating-factor; HGF, hepatocyte growth factor; HIF-α, hypoxia-inducible factor; HNSCC, Head and Neck Squamous Cell Carcinoma; IL, interleukin; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa B; STAT-3, signal transducer and activator of transcription; TNF-α, tumor necrosis factor alpha; TWIST, oncogene protein TWIST; VEGF, vascular endothelial growth factor.

Figure 4

Doxorubicin-induced inflammation in a variety of cancers includes upregulation of NFκB, IL-1β, IL-6, IL-8, TNF-α and monocyte chemoattractant protein 1 (MCP-1). In neuroblastoma cells, p533 is required for doxorubicin to activate NFκB. In Lewis lung carcinoma, IL-1β and IL-6 are upregulated by the p38/MAPK pathway. Doxorubicin induces EMT acquisition in breast cancer. Abbreviations: EMT, epithelial–mesenchymal transition; ERK, mitogen-activated protein kinase; HGF, hepatocyte growth factor; HIF-α, hypoxia-inducible factor; IL, interleukin; MAPK, mitogen activated protein kinase; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa B; STAT-3, signal transducer and activator of transcription; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.