Demystifying the CXCR4 conundrum in cancer biology: Beyond the surface signaling paradigm

The oncogenic chemokine duo CXCR4-CXCL12/SDF-1 (C-X-C Receptor 4-C-X-C Ligand 12/ Stromal-derived factor 1) has been the topic of intense scientific disquisitions since Muller et al., in her ground-breaking research, described this axis as a critical determinant of organ-specific metastasis in breast cancer. Elevated CXCR4 levels correlate with distant metastases, poor prognosis, and unfavourable outcomes in most solid tumors. Therapeutic impediment of the axis in clinics with Food and Drug Administration (FDA) approved inhibitors like AMD3100 or Plerixafor yield dubious results, contrary to pre-clinical developments. Clinical trials entailing inhibition of CXCR7 (C-X-C Receptor 7), another convicted chemokine receptor that exhibits affinity for CXCL12, reveal outcomes analogous to that of CXCR4-CXCL12 axis blockade. Of note, the cellular CXCR4 knockout phenotype varies largely from that of inhibitor treatments. These shaky findings pique great curiosity to delve further into the realm of this infamous chemokine receptor to provide a probable explanation. A multitude of recent reports suggests the presence of an increased intracellular CXCR4 pool in various cancers, both cytoplasmic and nuclear. This intracellular CXCR4 protein reserve seems active as it correlates with vital tumor attributes, viz. prognosis, aggressiveness, metastasis, and disease-free survival. Diminishing this entire intracellular CXCR4 load apart from the surface signals looks encouraging from a therapeutic point of view. Transcending beyond the classically accepted concept of ligand-mediated surface signaling, this review sheds new light on plausible associations of intracellularly compartmentalised CXCR4 with various aspects of tumorigenesis. Besides, this review also puts forward a comprehensive account of CXCR4 regulation in different cancers.