Abstract
Background: Lung cancer is a multifactorial disease with a heterogeneous tumor group that hampers diagnostic and therapeutic approaches, as well as understanding of the processes that underlie its pathogenesis. Current research efforts are focused on examining alterations in the tumor microenvironment, which may affect the pathogenesis and further malignant progression in lung cancer. The aim of this study was to investigate changes in the levels of biomarkers involved in the lung tumor microenvironment and their diagnostic utility in differentiating lung cancer subtypes and stages. Methods: This study comprised 112 lung cancer patients, 50 with adenocarcinoma, 35 with squamous cell carcinoma, 13 with other non-small cell lung carcinoma subtypes, and 14 with other lung neoplasms than non-small cell lung carcinoma. Tumor markers (CEA, CYFRA 21-1, and NSE) were measured in the patients’ sera and plasmas, along with IL-6, TNF-α, SAA1, CRP, MMP-2, MMP-9, glucose, lactate, and LDH, utilizing enzyme-linked immunosorbent assays, enzyme immunoassays, and automated clinical chemistry and turbidimetry systems. The results were statistically analyzed across patient groups based on the subtype and stage of lung cancer. Results: Glucose concentrations showed statistically significant (p < 0.05) differences both between lung cancer subtypes and stages, with the highest levels in patients with other lung neoplasms (me = 130.5 mg/dL) and in patients with stage IIB lung cancer (me = 132.0 mg/dL). In patients with advanced lung cancer, IL-6 and LDH had considerably higher concentration and activity. There was also a significant positive correlation between IL-6 and MMP-9 in adenocarcinoma and SqCC, with correlation coefficients of 0.53 and 0.49, respectively. The ROC analyses showed that the best single biomarkers for distinguishing adenocarcinoma from squamous cell carcinoma are glucose, CRP, and CYFRA 21-1; however, their combination did not significantly improve sensitivity, specificity, and the AUC value. The combinations of IL-6, glucose, LDH and CEA, IL-6, SAA1, MMP-9, and lactate can distinguish patients with stage IIB lung cancer from those with stage IIA with 100% sensitivity, 100% specificity, and with an AUC value of 0.8333 and 1.0000, respectively, whereas the combination of CEA, IL-6, and LDH can identify patients with stage IIIA lung cancer from those with stage IIB with 72.73% sensitivity, 94.44% specificity, and an AUC value of 0.8686. Conclusion: There is a link between biomarkers of tumor microenvironment changes and tumor markers, and combinations of these markers may be clinically useful in the differential diagnosis of adenocarcinoma and squamous cell carcinoma, as well as lung cancer stages IIB and IIA, and IIIA and IIB.
Highlights
Cancer is one of the multifactorial diseases that is thought to be caused by complex interactions between genetic and environmental factors
Tumor (CEA, CYFRA 21-1, and neuron-specific enolase (NSE)), inflammatory markers (IL-6, TNF-α, SAA1, CRP, MMP-2, and MMP-9), and metabolic markers were measured in the sera and plasmas of 112 lung cancer patients, who were classified into four groups based on subtype and seven groups based on stage
We examined serum levels of pro- and anti-inflammatory cytokines (IL-6, TNF-α), which regulate immune responses, cell proliferation, and differentiation; matrix metalloproteinases (MMP-2, MMP-9), which remodel and degrade extracellular matrix (ECM) and mediate cell–cell adhesion; acute-phase proteins (CRP, SAA1 ), which are linked to the expression of pro- and anti-inflammatory cytokines and play a role, among others, in the recruitment of immune cells to inflammatory sites; and metabolic markers, which are associated with glucose metabolism in cancer cells, known as the Warburg effect
Summary
Cancer is one of the multifactorial diseases that is thought to be caused by complex interactions between genetic and environmental factors. Lung neoplasm results from the final stage of multi-stage bronchial cells carcinogenesis, with progressively increasing genetic and epigenetic changes due to exposure to environmental factors and patients’ individual predispositions to lung cancer [4,5]. Lung cancer is a multifactorial disease with a heterogeneous tumor group that hampers diagnostic and therapeutic approaches, as well as understanding of the processes that underlie its pathogenesis. Current research efforts are focused on examining alterations in the tumor microenvironment, which may affect the pathogenesis and further malignant progression in lung cancer. The aim of this study was to investigate changes in the levels of biomarkers involved in the lung tumor microenvironment and their diagnostic utility in differentiating lung cancer subtypes and stages. The results were statistically analyzed across patient groups based on the subtype and stage of lung cancer
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