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May 8, 2018

Lung Cancer Biomarker Discovery Raises Hopes for Early Detection

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    Immunoblot analysis using anti-CKAP4 antibody with whole-cell lysates from A549, RERF-LC-AI, N231, and LCN1, and lung tissue samples. (A) CKAP4 protein is detected at approximately 63 kDa in all lung cancer cells. (B) CKAP4 protein is also detected at approximately 63 kDa in culture supernatants of A549 and RERF-LC-AI cells. (C) The CKAP4 protein is expressed only in lung cancer tissues and not in their normal counterparts. (T) Tumor tissue, (N) normal lung tissue. CKAP4 was observed at various intensities in the cytoplasm of lung cancer cells (D, A549; E, RERF LC-AI; F, N231; G, LCN1) and tissues (H, AC; I, SCC), but not in normal lung epithelium (J, alveolar epithelium; K, bronchial epithelium). [The American Journal of Pathology]

    Scientists in Japan report that they have found high levels of cytoskeleton-associated protein 4 (CKAP4) in the blood of patients with lung cancer. In a study (“Cytoskeleton-Associated Protein 4 Is a Novel Serodiagnostic Marker for Lung Cancer”) in The American Journal of Pathology, CKAP4 levels were significantly higher in patients with lung cancer than in healthy individuals. 

    The researchers also determined that CKAP4 levels are already elevated in the blood of patients with stage I disease, making it a potential noninvasive diagnostic marker that could change current practices in the diagnosis and treatment of some types of lung cancer, including non-small-cell lung cancer and squamous cell carcinoma, and improve patient outcomes.

    “Our aim was to develop a serodiagnostic marker for lung cancer. Monoclonal antibodies were generated, and one antibody designated as KU-Lu-1, recognizing cytoskeleton-associated protein 4 (CKAP4), was studied further. To evaluate the utility of KU-Lu-1 antibody as a serodiagnostic marker for lung cancer, reverse-phase protein array analysis was performed with sera of 271 lung cancer patients and 100 healthy controls. CKAP4 was detected in lung cancer cells and tissues, and its secretion into the culture supernatant was also confirmed. The serum CKAP4 levels of lung cancer patients were significantly higher than those of healthy controls (P < 0.0001), and the area under the curve of receiver-operating characteristic curve analysis was 0.890, with 81.1% sensitivity and 86.0% specificity,” wrote the investigators.

    “Furthermore, the serum CKAP4 levels were also higher in patients with stage I adenocarcinoma or squamous cell carcinoma than in healthy controls (P < 0.0001). Serum CKAP4 levels may differentiate lung cancer patients from healthy controls, and they may be detected early even in stage I non–small cell lung cancer. Serum CKAP4 levels were also significantly higher in lung cancer patients than in healthy controls in the validation set (P < 0.0001). The present results provide evidence that CKAP4 may be a novel early serodiagnostic marker for lung cancer.”

    "The identification of patients at an early stage of cancer, when it can be treated surgically, is extremely important to improve prognosis," explained Yuichi Sato, Ph.D., department of molecular diagnostics, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan, who led the study. "We need better biomarkers for early diagnosis."

    Current biomarkers for lung cancer include carcinoma embryonic antigen (CEA), sialyl Lewis X antigen (SLX), squamous cell carcinoma (SCC) antigen, and cytokeratin fragment (CYFRA) 21-1, but these are not sensitive enough to detect tumors early, according to co-investigator Ryo Nagashio, Ph.D., from the Kitasato University School of Allied Health Sciences. "The results of our study provide evidence that the CKAP4 protein may be a novel early serodiagnostic marker for lung cancer."

    Using immunoprecipitation and mass spectrometry, the team confirmed that the KU-Lu-1 antibody recognized CKAP4 in lung cancer cells and tissues, and its secretion into the culture supernatant was also confirmed. In addition, a validation set consisting of samples from 100 patients with lung cancer and 38 healthy controls was also studied. 

    CKAP4 was recently identified as a receptor of Dickkopf1 (DKK1). Expressions of DKK1 and CKAP4 were frequently observed in tumor lesions of human pancreatic and lung cancers, and the simultaneous expression of both proteins in tumor tissues was inversely correlated with prognosis and relapse-free survival. 

    Across disease stages I–IV, the sensitivities of serum CEA, CYFRA, and SCCA are reported with 30% to 52%, 17% to 82%, and 24% to 39%, respectively. In this study, the sensitivity of serum CKAP4 was 81% in the training set and 69% in the validation set. These rates are higher than those of the current serodiagnostic markers. Furthermore, the sensitivity of serum CKAP4 was also high, even in stage I non-small-cell lung cancer and squamous cell carcinoma.

    "The use of CKAP4 as a biomarker could change current practices regarding the treatment of lung cancer patients, and the diagnostic accuracies may be markedly improved by the combination of CKAP4 and conventional markers," noted Dr. Sato. 

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