Association of Serum Proteases and Acute Phase Factors Levels with Survival Outcomes in Patients with Colorectal Cancer

Abstract

Colorectal cancer (CRC) represents a substantial burden on global healthcare, contributing to significant morbidity and mortality worldwide. Despite advances in screening methodologies, its incidence remains high, necessitating continued efforts in early detection and treatment. Neoplastic invasion and metastasis are primary determinants of CRC lethality, emphasizing the urgency of understanding underlying mechanisms to develop effective therapeutic strategies. This study aimed to explore the potential of serum biomarkers in predicting survival outcomes in CRC patients, with a focus on cathepsin B (CB), leukocytic elastase (LE), total sialic acid (TSA), lipid-associated sialic acid (LASA), antitrypsin activity (ATA), C-reactive protein (CRP), and cystatin C (CC). We recruited 185 CRC patients and 35 healthy controls, assessing demographic variables, tumor characteristics, and 7 serum biomarker levels, including (1) CB, (2) LE, (3) TSA, (4) LASA, (5) ATA, (6) CRP, and (7) CC. Statistical analyses included ANOVA with Tukey's post hoc tests and MANOVA for continuous variables. Student's t-test was used for dependent samples, while non-parametric tests like Mann-Whitney U and Wilcoxon signed-rank tests were applied for variables deviating from the normal distribution. Categorical variables were assessed using chi-square and Kruskal-Wallis tests. Spearman's rank correlation coefficient was utilized to examine variable correlations. Survival analysis employed the Kaplan-Meier method with a log-rank test for comparing survival times between groups. Significant associations were observed between CB (p = 0.04), LE (p = 0.01), and TSA (p = 0.008) levels and survival outcomes in CRC patients. Dukes' classification stages also showed a significant correlation with survival (p = 0.001). However, no significant associations were found for LASA, ATA, CRP, and CC. Multivariate analysis of LE, TSA, and ATA demonstrated a notable correlation with survival (p = 0.041), notwithstanding ATA's lack of significance in univariate analysis (p = 0.13). CB, LE, and TSA emerged as promising diagnostic markers with prognostic value in CRC, potentially aiding in early diagnosis and treatment planning. Further research is needed to validate these findings and explore additional prognostic indicators.

Keywords: C-reactive protein; acute phase factors; cathepsin B; colorectal cancer; leukocytic elastase; sialic acid; survival analysis.

Figure 1

The survival analysis of patients with colon adenocarcinoma at serum cathepsin B threshold of 11.2248 mU/L. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; CB: cathepsin B.

Figure 2

The survival analysis of patients with colon adenocarcinoma at serum leukocytic elastase threshold of 534 μg/L. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; LE: leukocytic elastase.

Figure 3

The survival analysis of patients with colon adenocarcinoma at serum total sialic acid threshold of 75.34 mg%. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; TSA: total sialic acid.

Figure 4

The survival analysis of patients with colon adenocarcinoma at serum lipid-associated sialic acid threshold of 0.739 mg%. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; LASA: lipid-associated sialic acid.

Figure 5

The survival analysis of patients with colon adenocarcinoma at serum antitrypsin activity threshold of 2400 U/mL. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; ATA: antitrypsin activity.

Figure 6

The survival analysis of patients with colon adenocarcinoma at serum C-reactive protein threshold of 47.8 mg/L. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; CRP: C-reactive protein.

Figure 7

The survival analysis of patients with colon adenocarcinoma at serum cystatin C threshold of 1.55 mg/L. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance; CC: cystatin C.

Figure 8

The survival analysis of patients with colon adenocarcinoma at combined threshold of −0.113 mg/L for mulitparameter model of leukocytic elastase, total sialic acid, and antitrypsin activity. The Kaplan–Meier test was used to perform the survival analysis. p: statistical significance.

Figure 9

The graphical summary of the association of investigated biochemical factors and survival outcomes in colorectal adenocarcinoma patients. Our study revealed that decreased levels of cathepsin B and leukocytic elastase, along with elevated levels of total sialic acid, were associated with poorer survival outcomes. However, the association of lipid-associated sialic acid, antitrypsin activity, C-reactive protein, and cystatin C with survival outcomes was found to be non-significant. In multivariate survival analysis, only a combination of leukocytic elastase, total sialic acid, and antitrypsin activity showed a correlation with survival outcomes. p: probability; NS: non-significant.