Elevated Levels of the Complement Activation Product C4d in Bronchial Fluids for the Diagnosis of Lung Cancer

Abstract

Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71–0.94) and 0.67 (95%CI = 0.58–0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56–0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.

Efficacy of multiple anticancer therapies may depend on host immune response

“…Generally, the complement cascade system is activated to defend a host against microbes during an inflammatory response. The activation of complement and its role in tumor progression is evident in studies conducted for different cancer types, including lung adenocarcinoma [44], breast [45] and thyroid cancer [46]. Consequently, we observed similar processes from ClueGO results where genes involved in inflammation, complement activation and defense response were activated in PD alongside genes responsible for positive regulation of leukocyte chemotaxis.…”

Early urinary protein changes in the tumor-forming process of the NuTu-19 lung metastasis

“…It was also reported that the silencing sortilin expression in tumor cells may introduce sortilin as a potential candidate for developing a novel targeted therapy in patients with ovarian carcinoma [63]. (5) Complement C4 (CO4) was reported as a lung cancer biomarker for diagnosis and prognosis [30,64]. (6) Upregulation of Syndecan-4 (SDC4) was reported to contribute to the TGF-β1-induced epithelial to mesenchymal transition in lung adenocarcinoma A549 cells [65].…”

Innate immune mediators in cancer: between defense and resistance

“…C4d, a complement split product derived from the classical pathway activation, is deposited in a wide range of primary tumors, including lung cancer, papillary thyroid carcinoma, astrocytoma, and follicular and MALT lymphoma . Soluble C4d was increased in biological fluids from lung and oropharyngeal cancer patients and may be of value for diagnosis and prognosis . Abnormalities in the activation of the classical pathway have been described in patients with chronic lymphatic leukemia .…”

“…33,[35][36][37] Soluble C4d was increased in biological fluids from lung and oropharyngeal cancer patients and may be of value for diagnosis and prognosis. 33,38,39 Abnormalities in the activation of the classical pathway have been described in patients with chronic lymphatic leukemia. 40,41 Finally, complement components, compatible with classical pathway activation, were abundantly present in endometriosis and ovarian cancer, whereas normal endometrium showed little to no expression of these factors.…”