Identification of stromal cell-derived factor 4 as a liquid biopsy-based diagnostic marker in solid cancers

Abstract

There is a need for serum diagnostic biomarkers to improve the prognosis of solid malignant tumors. Here, we conducted a single-institutional study to evaluate the diagnostic performance of serum stromal cell-derived factor 4 (SDF4) levels in cancer patients. Serum samples were collected from a total of 582 patients with solid cancers including gastric cancer (GC) and 80 healthy volunteers. SDF4 protein levels in sera, and conditioned media or lysates of human GC cell lines were measured by enzyme-linked immunosorbent assay, and those in GC tissue by immunohistochemistry. Serum SDF4 levels were higher in patients with cancer than the healthy control in all cancer type. Regarding GC, serum SDF4 levels distinguished healthy controls from GC patients with the area under the curve value of 0.973, sensitivity of 89%, and specificity of 99%. Serum SDF4 levels were significantly elevated in patient with early stage GC. In immunohistochemistry, the frequency of SDF4-positive GC tumors did not vary significantly between GC stages. The ability of human GC cell lines to both produce and secrete SDF4 was confirmed in vitro. In conclusion, serum SDF4 levels could be a promising candidate for a novel diagnostic biomarker for GC and other malignancies.

Figure 1

(a) Serum levels of SDF4 in healthy controls and patients with various cancers. (b) Serum levels of SDF4 in healthy controls and patients with stage I, II, III, and IV GC. (c) Receiver operating characteristic curve analysis to determine the serum SDF4 level able to discriminate between healthy controls and patients with GC. (d) Diagnostic performances of SDF4, CEA, and CA19-9 for identifying patients with GC.

Figure 2

Kaplan–Meier analysis of overall survival in GC patients with high or low serum SDF4 levels based on the median serum level. The number at risk every 12 months is shown at the bottom of the figure.

Figure 3

(a) Production of SDF4 by human GC and normal gastric cell lines measured by ELISA. SDF4 levels in conditioned media were quantified on days 1–3 of culture and cell lysates were prepared and quantified on day 3 of culture. (b) Correlation between SDF4 levels in conditioned medium and cell lysates of all cell lines on day 3.

Figure 4

(a) Representative immunohistochemical staining of SDF4 in normal gastric and GC tissues. The five panels at each stage show normal gastric tissue, negative control GC tissue, positively stained GC tissue, and enlargements showing the mucosal side and invasive front. (b) Proportion of tumors at each stage staining positively for SDF4.

Figure 5

Perioperative changes in serum SDF4 levels in (a) patients undergoing any type of gastrectomy or (b) total gastrectomy.