Role of CXC group chemokines in lung cancer development and progression

Abstract

Background: Clinical and translational research on lung cancer patients undergoing surgical treatment can provide valuable scientific data and unique opportunity to study tumor microenvironment. CXC chemokines, which are members of a big family of cytokines, are undoubtedly involved in tumor growth regulation and metastasizing pathways. For better understanding of CXC chemokine involvement in the process of carcinogenesis we have studied the cohort of early stage non-small cell lung cancer patients undergoing surgery with curative intent. Our aim was to assess CXC chemokine ligand (CXCL) levels in patient blood samples representing systemic circulation and tumor microenvironment; assess CXC chemokine receptor (CXCR) expression in tumor tissue; and measure tumor infiltrating immune cell subpopulations.Methods: A total of 54 patients with NSCLC had radical lung resection were enrolled in a single center prospective study and were followed-up annually for up to six years. During surgical procedure peripheral and tumor draining blood samples were taken. CXCL1, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11 and CXCL12 levels were determined by ELISA, and chemokine concentration gradient was calculated. Tumor infiltrating immune cells (T helper cells, T cytotoxic cells, macrophages, B cells, plasma cells) and expression of CXCR1, CXCR2, CXCR3 and CXCR4 in tumor tissue were assessed by immunohistochemistry. Results: Statistically significant decrease in chemokine concentration was found for CXCL4 (P=0.002) and CXCL5 (P=0.011), and statistically significant concentration increase was found for CXCL7 (P=0.001) in total cohort. We have found statistically significant CXC chemokine concentration change for majority of chemokines-CXCL1 (P=0.002), CXCL4 (P=0.001), CXCL5 (P=0.013), CXCL7 (P=0.036), CXCL8 (P=0.026), CXCL9 (P=0.034) and CXCL10 (P=0.032) in a group of patients who had good clinical result after surgery with no evidence of relapse, on the other hand patients with cancer recurrence including local and systemic cancer spread did not show any change of chemokine concentration in blood except for CXCL1 (P=0.041). We have also found that chemokine levels and gradients correlate with CXC receptor expression and number of tumor infiltrating immune cell subpopulations Conclusions: Assessment of tumor microcirculation is useful for evaluation of different types of circulating biomarkers and application of our method can be very wide, integrating thoracic surgeons into translational cancer research.

Plasma exo-hsa_circRNA_0056616: A potential biomarker for lymph node metastasis in lung adenocarcinoma

“…However, it has been observed by Li et al (12) that the expression of circRNAs in exosomes was higher than in normal cells. Levels of circRNAs in serum exosomes of colon cancer patients were higher than in healthy individuals, and the expression levels in the exosomes correlated with the expression levels in cells (R = 0.43) [15]. The results of the present study regarding the detection of circRNAs in exosomes isolated from the peripheral blood of patients with lung adenocarcinoma are consistent with these results.…”

“…It was previously reported that high levels of CXCR4 are expressed in lung adenocarcinoma (14,15). In addition, high levels of CXCR4 have been closely related to lymph node metastasis, a high T stage, and patient prognosis (16).…”

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

“…But not all patients had high CXCL5 levels in their blood or tumor tissues. The content of CXCL5 in the peripheral circulation of patients with laryngeal squamous cell carcinoma or lung cancer has been reported to be significantly lower than that in the blood surrounding the tumor [6,67]. Some researchers hypothesized that the main source of CXCL5 in the blood were the monocytes and platelets that are recruited to the tumor area and leading to decreased levels of CXCL5 in the blood.…”

The paradoxical role of tumor-infiltrating immune cells in lung cancer

“…MDSCs can be recruited by CCL2 in several types of mouse cancers, such as Lewis lung cancer, meth A sarcoma, melanoma, and lymphoma (83). MDSCs express CXCR2 and are detected in abundance in NSCLC (84). CXCR2 ligands, including CXCL1, CXCL2, and CXCL5, are abundant in lung cancer tissue and tumorigenesis can be markedly inhibited by a deficiency in CXCR2 as a result of inhibiting infiltration of MDSCs (Figure 2).…”