Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection

Abstract

BackgroundInflammation-induced endothelial precursor cell recruitment and angiogenesis are thought to be associated with CXCL16-CXCR6 pair activity. This study’s main purpose was to determine plasma CXCL16 levels after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC); an adjunct study assessed wound fluid (WF) and plasma CXCL16 levels in a separate group of CRC patients.MethodsCRC patients who had MICR and for whom plasma was available in a tissue bank were eligible. Plasma samples were collected preoperatively from all patients. Samples were also collected on postoperative days (POD) 1 and 3 and at various late postoperative time points (POD 7–34). In a separate study, blood and intra-abdominal wound fluid (WF) samples were collected from CRC MICR patients (pts). Samples were stored at − 80 °C. CXCL16 levels were determined via ELISA. The Wilcoxon signed-rank and Mann and Whitney tests were used for analysis.ResultsMain study: 86 CRC pts. were included. The mean preoperative plasma CXCL16 level was 2.36 ± 0.57 ng/ml. Elevated mean plasma levels (p < 0.0001 × first 4 time points) were noted on POD 1 (2.82 ± 0.81, n = 86), POD 3 (3.12 ± 0.77, n = 82), POD 7–13 (3.28 ± 0.88, n = 64), POD 14–20 (3.03 ± 0.62, n = 24), POD 21–27 (3.06 ± 0.67, n = 20, p = 0.0003), and POD 28–34 (3.17 ± 0.43, n = 11, p = 0.001) vs. preop levels. WF study: In the adjunct study, plasma and WF CXCL16 levels were determined for 23 CRC MICR pts. WF levels at all time points were significantly elevated over plasma levels.ConclusionPlasma CXCL16 levels were elevated for 4 weeks after minimally invasive colorectal resection for cancer. Also, WF CXCL16 levels were 3–10 times greater than the corresponding plasma concentrations. The source of the late plasma elevations may be the healing wound. Increased plasma CXCL16 levels may promote tumor angiogenesis in the first month after MICR.

Plasma Levels of Keratinocyte Growth Factor Are Significantly Elevated for 5 Weeks After Minimally Invasive Colorectal Resection Which May Promote Cancer Recurrence and Metastasis

“…KGF may follow the concentration gradient from the wound (high KGF levels) to the circulation (low KGF levels). This is in keeping with many of the other proteins, mentioned above, whose plasma levels have been shown to be persistently increased after colorectal resection (11,15,16,18,19,(21)(22)(23)(24)(25)(26). In a study that simultaneously assessed plasma and wound fluid levels of 8 of these "long duration" proteins after colorectal resection, it was demonstrated that the mean wound levels of the proteins were 3 to 40 times higher than their corresponding plasma concentrations which, in turn, were significantly elevated from their pre-operative baseline blood levels (27).…”

“…The majority of plasma protein changes after surgery persist hours or days (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), however, in the last decade, increases in the blood levels of at least 12 proangiogenic proteins have been noted to persist for 3-5 weeks after resection of colorectal cancer (CRC). Included on this list are vascular endothelial growth factor (VEGF), angiopoeitin-2 (Ang-2), placental growth factor (PIGF), soluble vascular adhesion molecule-1 (sVCAM-1), Angiopoietin like 4 (ANPTL4), monocyte chemotactic protein-1 (MCP-1), human chitinase 3-like 1 (Chi3L1), matrix metalloproteinase-2(MMP-2),matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-3 (MMP-7), Chemokine (C-X-C motif) ligand 16 (CXCL 16), and Interleukin 8 (IL-8).…”

“…MMP-2, MMP-3 and MMP-7, as a proteases and regulator of cell matrix interactions, have been proposed to play a role in angiogenesis by paving the way for budding vessels and migrating cells (22,55). CXCL16 is express on leukocytes, endothelial cells, and other tissues and its receptor CXCL6 found on cells at sites of inflammation (24). Endothelial precursor cell recruitment and angiogenesis induced by pro-inflammatory stimuli are thought to be associated with transmembrane chemokine CXCL16 and CXCR6 pair activity (56)(57)(58).…”

“…The vast majority of plasma protein changes after surgery last hours or days (IL-1, TNF, IL-6, CRP, etc.) (12)(13)(14), however, in the last decade, increases in blood levels of at least 12 progangiogenic proteins have been noted to persist for 3 to 5 weeks after resection of colorectal cancer (CRC) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In vitro studies utilizing endothelial cells (EC's), critical to angiogenesis, suggest the net effect of plasma compositional changes is proangiogenic.…”

CXC chemokine ligand 16: a Swiss army knife chemokine in cancer

“…Therefore, elevated plasma levels of CXCL16 may encourage tumour angiogenesis in the first month after MICR and could be a useful marker for screening tumour recurrence after resection (Ref. 65). Also, Shibata et al .…”