The COOH-Terminal Peptide of Platelet Factor-4 Variant (CXCL4L1/PF-4var47-70) Strongly Inhibits Angiogenesis and Suppresses B16 Melanoma Growth In vivo

Abstract

Chemokines influence tumor growth directly or indirectly via both angiogenesis and tumor-leukocyte interactions. Platelet factor-4 (CXCL4/PF-4), which is released from α-granules of activated platelets, is the first described angiostatic chemokine. Recently, it was found that the variant of CXCL4/PF-4 (CXCL4L1/PF4var) could exert a more pronounced angiostatic and antitumoral effect than CXCL4/PF-4. However, the molecular mechanisms of the angiostatic activities of the PF-4 forms remain partially elusive. Here, we studied the biological properties of the chemically synthesized COOH-terminal peptides of CXCL4/PF-4 (CXCL4/PF-4 47-70 ) and CXCL4L1/PF-4var (CXCL4L1/PF-4var ). Both PF-4 peptides lacked monocyte and lymphocyte chemotactic activity but equally well inhibited (25 nmol/L) endothelial cell motility and proliferation in the presence of a single stimulus (i.e., exogenous recombinant fibroblast growth factor-2). In contrast, when assayed in more complex angiogenesis test systems characterized by the presence of multiple mediators, including in vitro wound-healing (2.5 nmol/L versus 12.5 nmol/L), Matrigel (60 nmol/L versus 300 nmol/L), and chorioallantoic membrane assays, CXCL4L1/PF-4var 47-70 was found to be significantly (5-fold) more angiostatic than CXCL4/PF-4 47-70 . In addition, low (7 μg total) doses of intratumoral CXCL4L1/ PF-4var 47-70 inhibited B16 melanoma growth in mice more extensively than CXCL4/PF-4 47-70 . This antitumoral activity was predominantly mediated through inhibition of angiogenesis (without affecting blood vessel stability) and induction of apoptosis, as evidenced by immunohistochemical and fluorescent staining of B16 tumor tissue. In conclusion, CXCL4L1/PF-4var 47-70 is a potent antitumoral and antiangiogenic peptide. These results may represent the basis for the design of CXCL4L1/PF-4var COOH-terminal-derived peptidomimetic anticancer drugs. Mol Cancer Res; 8(3); 322-34. ©2010 AACR.

The Role of Chemokines in Fibrotic Wound Healing

“…Long before the term chemokine was introduced, PF-4 was mentioned as platelet anti-heparin factor 5 and later named CXCL4. It has weak chemotactic potency but strongly involves angiostasis, [13][14][15][16][17] hematopoiesis suppression, 18 inhibition of collagenase activity, 19 and accumulation of deleterious lipoproteins at sites of vascular injury. 20 PF-4 appears to function by neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin III activity and promoting coagulation.…”

Chemokines and Their Receptors Are Key Players in the Orchestra That Regulates Wound Healing

“…In addition, CXCL4L1, a nonallelic gene variant of CXCL4 inhibits angiogenesis during wound healing that is more potent than CXCL4 itself and is very effective in inhibiting tumor growth of melanomas and lung carcinomas. 101 When the platelets are released, they degranulate and discharge a plethora of cytokines that, along with thrombin, activate resident macrophages, keratinocytes, and fibroblasts (Fig. 6).…”

Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer

“…Although some data have been published on the effect of exogenous full-length CXCL4L1 or of a CXCL4L1 C-terminal fragment in subcutaneous tumor models (1,6,(10)(11)(12), nothing is known about its precise role in controlling tumor growth and invasion. We provide herein the first study, to our knowledge, of the regulation of CXCL4L1 expression and the role of endogenous CXCL4L1 in tumor development using pancreatic ductal adenocarcinoma (PDAC) as a tumor model.…”