How do chemokine/chemokine receptor activations affect tumorigenesis?

Ann Richmond, Huang Fan Guo, Punita Dhawan, Jinming Yang

Research output: Chapter in Book/Report/Conference proceedingConference contribution

28 Scopus citations

Abstract

Cells that display chemokine receptors are capable of responding to a gradient of chemokine with a motility response that can translate into a chemotactic response. This continuous response to the chemokine sometimes requires that the chemokine receptor be internalized and recycled back to the membrane. We have shown that ligand activation of the CXC chemokine receptor, CXCR2, results in movement of the receptor into clathrin coated pits, followed by movement into the early endosome, the sorting endosome, then on to the recycling endosome prior to trafficking back into the plasma membrane compartment. Prolonged exposure to saturating concentrations of the ligand results in movement of a large percentage of the receptor into the late endosome and on to the lysosome for degradation. Mutation of the receptor in a manner which impairs receptor internalization by altering the binding of adaptor proteins AP-2 or β arrestin to CXCR2, results in a marked reduction in the chemotactic response. Chemokine receptors also activate multiple intracellular signals that lead to the activation of the transcription factor, nuclear factor κ beta (NF-κB). Transformation is often associated with a constitutive activation of NF-κB, leading to endogenous expression of chemokines and their receptors. This creates an autocrine loop with NF-κB in the activated state, and altered expression of factors that promote tumour angiogenesis and escape from apoptosis. We have shown that the constitutive activation of NF-κB in human melanoma tumours is accompanied by constitutive activation of the NF-κB inducing kinase (NIK) as well as the constitutive activation of AKT. As these factors that modulate the expression of anti-apoptotic factors work together, the tumour cells exhibit enhanced survival and growth. This never ending cycle of activation of NF-κB, leading to enhanced production of chemokines, enhanced activation of AKT and NF-κB, and enhanced transcription of inhibitors of apoptosis and chemokines, is one that has been used to foster the growth of the tumour to the disadvantage of the host. Thus we propose that blocking CXCR2 and/or NF-κB offers potential therapeutic promise for a number of chronic inflammatory conditions and cancers, including malignant melanoma.

Original languageEnglish (US)
Title of host publicationCancer and Inflammation
Pages74-89
Number of pages16
StatePublished - 2004

Publication series

NameNovartis Foundation Symposium
Volume256
ISSN (Print)1528-2511

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'How do chemokine/chemokine receptor activations affect tumorigenesis?'. Together they form a unique fingerprint.

  • Cite this

    Richmond, A., Guo, H. F., Dhawan, P., & Yang, J. (2004). How do chemokine/chemokine receptor activations affect tumorigenesis? In Cancer and Inflammation (pp. 74-89). (Novartis Foundation Symposium; Vol. 256).