Chemokine signaling in cancer: one hump or two?

Abstract

Chemokines and their receptors play essential roles in the development and function of multiple tissues. Chemokine expression, particularly CXCL12 and its receptor CXCR4, has prognostic significance in several cancers apparently due to chemokine mediated growth and metastatic spread. These observations provide the rationale for pursuing CXCR4 inhibition for cancer chemotherapy. However, the multiple homeostatic functions of CXCR4 may preclude global inhibition as a therapeutic strategy. Here I review CXCR4 signaling and how it might differ in normal and transformed cells with special emphasis on the role that altered CXCR4 counter-regulation might play in tumor biology. I propose that CXCR4 mediates unique signals in cancer cells as a consequence of abnormal counter-regulation and that this results in novel biological responses. The importance of testing this hypothesis lies in the possibility that targeting abnormal CXCR4 signaling might provide an anti-tumor effect without disturbing normal CXCR4 functions.

Figure 1. Ligand-Bound CXCR4 Dimers Signal Through Diverse Mediators

A hypothetical dimer of CXCR4 is shown engaging Gα_i and Gα_q as well as Gβγ and β-arrestin (βAR). Each of these proteins transduce major components of CXCR4 signaling including: Gα_I inhibition of adenylyl cyclase (AC) and suppression of cAMP levels, Gα_q - activation of phospholipase-β (PLC) and calcium flux, Gβγ - activation of PI3 kinase, MAP kinase (MAPK) as well as Src kinase and the monomeric G protein Rho. βAR – activation of MAPK, ASK1, Src and JNK.

Figure 2. Altered CXCR4 Signaling Results in Novel cellular Response

In normal cells CXCR4 signaling can be considered as occurring in two phases or humps; the heterotrimeric G protein dependent and β-arrestin dependent phases. Cellular responses are determined by whether signal strength exceeds a threshold (white line). Under normal circumstances the two phases of CXCR4 signaling are temporarily distinguishable as the rapid desensitization of AC inhibition or calcium flux is coincident with the onset of β-arrestin dependent signals. I propose that altered desensitization results in greater overlap between these phases of signaling as the heterotrimeric G protein dependent component is extended into the β-arrestin dependent component. The resultant merge of the two phases into one phase or hump results in an entirely novel signal and cellular response such as the abnormal survival response in astrocytoma cells.