The Chemokine CXCL8 in Carcinogenesis and Drug Response

Abstract

Although the functions of chemokines in the regulation of immune processes have been studied in some detail, the role of these biomolecules in cancer is not fully understood. Chemokines mediate migration of immune cells and other functions related to immunity. They are also involved in oncogenesis and in tumor progression, invasion, and metastasis through mechanisms similar to their roles in immune functions. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. Consequently, chemokines and their receptors present potential therapeutic targets for anticancer drugs. The chemokine CXCL8, also known as interleukin-8 (IL8), is a proinflammatory molecule that has functions within the tumor microenvironment. Due to its potent angiogenic effects and the activity of the chemokine and its receptors in the promotion of invasion and metastasis, CXCL8 and its receptors are now considered as attractive targets for cancer therapy. This review relates the current understanding of the regulation, signaling, and functions of CXCL8 that contribute to tumor growth and metastasis, and of its role in drug response.

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

“…High circulating levels of IL6 have been correlated with advancing stage and worse survival in several malignancies (10). Circulating IL8 also reflects tumor burden and stage, and its levels correlate with OS (11,28). We here report not only that IL6 and IL8 levels were prognostic for PFS and OS, but it was also apparent that patients with high IL6 or IL8 levels had no particular benefit from bevacizumab-based therapy.…”

“…The findings regarding IL6 and IL8 have not yet been documented in bevacizumabtreated patients. IL6 and IL8 are particularly well known for their immunomodulating function, but a substantial body of evidence indicates an emerging role in tumor angiogenesis (10,11). IL6 may promote tumor angiogenesis through upregulation of VEGF-A via the STAT3 signaling pathway (27).…”

“…In several tumor models a role of IL6 has been described in tumor angiogenesis as well as in failure with antiangiogenic therapy (10). IL8 promotes an angiogenic response by binding to its receptors CXCR1 and 2 expressed by endothelial cells and may activate VEGFR2 in endothelial cells (11). Another protein to mention is MUC1, a hyperglycosylated transmembrane protein expressed on normal secretory epithelial cells, while 90% of carcinomas show aberrant MUC1 expression (12,13).…”

Formylpeptide receptor 1 mediates the tumorigenicity of human hepatocellular carcinoma cells

“…11 Previous reports have implicated IL-8 in the growth and angiogenesis of malignant tumors. 12 In cancer models of pancreas, colorectum, melanoma and liver, IL-8 functions as an autocrine growth factor.…”

The involvement of the Toll-like receptor signaling and Nrf2-Keap1 pathways in thein vitroregulation of IL-8 and HMOX1 for skin sensitization

“…We hypothesized that targeting Nrf2 would decrease HMOX1 expression, while targeting Keap1, the negative regulator of Nrf2, would increase HMOX1 expression due to the increased availability of Nrf2. As the TLR-signaling cascade is thought to affect IL-8 levels through the activation of NF-B (Gales et al, 2013), knocking down the key proteins in this cascade would limit IL-8 production. In addition, the role of Nrf2 in IL-8 regulation was studied, as was the involvement of TLR signaling in HMOX1 regulation.…”