Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology

Abstract

With the recent addition of anti-angiogenic agents to cancer treatment, the angiogenesis regulators in platelets are gaining importance. Platelet factor 4 (PF-4/CXCL4) and Connective tissue activating peptide III (CTAP-III) are two platelet-associated chemokines that modulate tumor angiogenesis, inflammation within the tumor microenvironment, and in turn tumor growth. Here, we review the role of PF-4 and CTAP-III in the regulation of tumor angiogenesis; the results of clinical trial using recombinant PF-4 (rPF-4); and the use of PF-4 and CTAP-III as cancer biomarkers.

Figure 1

Amino acid sequences of β-thromboglobulin-like proteins [36].

Figure 2

PF-4 and CTAP-III/NAP-2 connection and their role in tumor angiogenesis and progression. The interaction of various components of the wound or tumor stroma depends on the presence or absence of different tissue proteases and on the reciprocal interaction of the various cells. PF-4 inhibits angiogenesis by (1) competitive inhibition of pro-angiogenic growth factors binding to HS sites in the tissues, where HS serve as co-receptor of growth factor receptors, such as VEGFR2 [47,48]; (2) by binding of IL-8 to form PF-4/IL-8 heterodimers [49] (3) and by antagonising of CXCR2, IL-8 receptor, which is involved in regulation inflammation and angiogenesis [50]. (4) IL-8, released by tumor as well as stroma and endothelial cells, induces chemotaxis of inflammatory cells [51] and angiogenesis [52] (5) by signaling through CXCR2 receptor [52]. The CXCL7/CTAP-III acts in a number of different ways: (6) CTAP-III is cleaved by leukocyte proteases to NAP-2 [31,32]; (7) NAP-2 splits HS from glycosaminosulfates (GAG) in the stroma, leading to interruption of extracellular matrix (ECM) protein-protein interactions and release of heparan sulphate-bound growth factors, such as VEGF [40]. (8) The remodeled ECM at the side of inflammation and angiogenesis enables the interaction of the released growth factors (e.g. VEGF) with their respective receptors and leads to modulation of angiogenesis and regulation of tumor spreading [53]; (9) CTAP-III stimulates further GAG synthesis [54] on the surface of endothelial cell injury leading to increased PF-4 production and localization of heparin binding angiogenesis regulators. (10) NAP-2 regulates activity and expression of CXCR2 [51,55].