Searching for New Biomarkers of Neuroendocrine Tumors: A Comparative Analysis of Chromogranin A and Inflammatory Cytokines in Patients with Neuroendocrine Tumors

Abstract

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications.

Keywords: cancer; chromogranin A; cytokines; diagnostic markers; neuroendocrine tumors.

Figure 5

Three-dimensional plot of TNF-β (tumor necrosis factor β) and GRO-α (growth-regulated oncogene) variables. In this plot, the symbol “+” (in red) represents the results for patients classified as sick, while the symbol “o” (in blue) represents the results for healthy people. This visual representation helps in understanding the distribution and relationship of these variables in distinguishing between sick and healthy individuals. The plot demonstrates the clustering of data points, indicating how variations in TNF-β and GRO-α concentrations correlate with the probability of disease presence.

Figure 1

Correlation between chromogranin A (CgA) and selected cytokines in a group of the patients with neuroendocrine tumors. (A)—granulocyte colony-stimulating factor (G-CSF) vs. CgA (r = 0.219; p = 0.045); (B)—granulocyte-macrofage colony-stimulating factor (GM-CSF) vs. CgA (r = 0.267; p = 0.014); (C)—interferone gamma (IFN-γ) vs. CgA (r = 0.248; p = 0.023); (D)—interleukin 2 receptor subunit alpha (IL-2Rα) vs. CgA (r = 0.301; p = 0.005).

Figure 2

Correlation between chromogranin A (CgA) and selected cytokines in a group of the patients with neuroendocrine tumors. (A)—interleukin 2 (IL2) vs. CgA (r = 0.228; p = 0.037); (B)—interleukin 5 (IL-5) vs. CgA (r = 0.254; p = 0.020); (C)—Interleukin 6 (IL-6) vs. CgA (r = 0.221; p = 0.043), (D)—interleukin IL-12 (p40) vs. CgA (r = 0.222; p = 0.042).

Figure 3

Correlation between chromogranin A (CgA) and selected cytokines in a group of patients with neuroendocrine tumors. (A)—interleukin 15 (IL-15) vs. CgA (r = 0.217; p = 0.047); (B)—macrophage colony stimulating factor (M-CSF) vs. CgA (r = 0.293; p = 0.007); (C)—macrophage inflammatory protein 1 beta (MIP-1β) vs. CgA (r = 0.259; p = 0.017); (D)—nerve growth factor β (β-NGF vs. CgA (r = 0.261; p = 0.016); (E)—vascular endothelial growth factor (VEGF) vs. CgA (r = 0.234, p = 0.032).

Figure 4

Receiver operating characteristic (ROC) of serum cytokines of the patients diagnosed with neuroendocrine neoplasms (NENs). (A)—ROC of chromogranin A (CgA); (B)—ROC of stem cell factor (SCF); (C)—ROC of granulocyte colony-stimulating factor (G-CSF); (D)—ROC of nerve growth factor β (β-NGF); (E)—ROC of interleukin 16 (IL-16); (F)—ROC of monocyte chemotactic protein 1 (MCP-1).

Figure 4

Receiver operating characteristic (ROC) of serum cytokines of the patients diagnosed with neuroendocrine neoplasms (NENs). (A)—ROC of chromogranin A (CgA); (B)—ROC of stem cell factor (SCF); (C)—ROC of granulocyte colony-stimulating factor (G-CSF); (D)—ROC of nerve growth factor β (β-NGF); (E)—ROC of interleukin 16 (IL-16); (F)—ROC of monocyte chemotactic protein 1 (MCP-1).