A role for G-CSF and GM-CSF in nonmyeloid cancers

Abstract

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) modulate progression of certain solid tumors. The G-CSF- or GM-CSF-secreting cancers, albeit not very common are, however, among the most rapidly advancing ones due to a cytokine-mediated immune suppression and angiogenesis. Similarly, de novo angiogenesis and vasculogenesis may complicate adjuvant use of recombinant G-CSF or GM-CSF thus possibly contributing to a cancer relapse. Rapid diagnostic tools to differentiate G-CSF- or GM-CSF-secreting cancers are not well developed therefore hindering efforts to individualize treatments for these patients. Given an increasing utilization of adjuvant G-/GM-CSF in cancer therapy, we aimed to summarize recent studies exploring their roles in pathophysiology of solid tumors and to provide insights into some complexities of their therapeutic applications.

Keywords: Bladder; G-CSF; GM-SF; bone; cancer; colorectal; glioma; lung; melanoma; metastasis; prostate.

Figure 1

(A) The G-GSF receptor monomers (green and blue) consist of an extracellular Ig-like domain (Ig), a cytokine receptor homologous (CRH) domain, and three fibronectin-type III-like domains followed by a transmembrane region and a cytoplasmic domain. Upon the G-CSF (red) binding, receptors polymerize via Ig-like domains to form an active signaling complex. (Modified from 6). (B) The GM-CSF receptor is a complex of two α-subunits (yellow) and the two βc-subunits (maroon and green). The α-subunits ensure specificity of GM-CSF (purple) binding, whereas βc-subunits which are shared among GM-CSFR, IL-3R, and IL-5R provide high-affinity binding sites. The GM-CSFR localize extracellularly with domains of both α- and βc-subunits tethering them to the cell membranes (Modified from 7).

Figure 2

MetaCore™ pathways analysis has been utilized to generate a map of putative signal transduction pathways for G-CSF or GM-CSF to regulate epithelial to mesenchymal transition in cancer. The green arrows indicate activated signaling pathways, whereas red arrows depict inhibited pathways.