Complement protein holds diagnostic, prognostic promise in lung cancer

By Joanna Lyford, Senior medwireNews Reporter

A complement activation product known as “C4d” may have value as a diagnostic and prognostic biomarker for lung cancer, research suggests.

The study found that C4d is increased in patients with lung cancer, is associated with poor prognosis, and can be detected at an early phase of tumor development.

In a series of experiments, Luis Montuenga (Universidad de Navarra, Pamplona, Spain) and team first assessed complement activation in bronchial epithelial and lung cancer cell lines. There are three pathways of complement activation, they explain, but it is unclear which occurs in lung cancer cells.

They found that lung cancer cells but not bronchial epithelial cells showed activation of the classical complement pathway. Further study showed that activation was mediated by direct binding of C1q and was inhibited by phosphomonoesters in a dose-dependent manner. The team then analyzed 90 non-small-cell lung tumor specimens for C4d, an inactive product of complement activation. Immunohistochemical staining was positive for C4d, therefore confirming that the classical complement pathway is activated in primary lung tumor cells.

C4d levels were higher in adenocarcinomas than squamous cell carcinomas, note the authors, and were significantly associated with both smoking and tumor stage. Furthermore, overall survival significantly inversely correlated with C4d levels, with a hazard ratio (HR) of 3.06 after adjustment for gender, smoking, and stage.

Further study showed that C4d levels were significantly higher in bronchoalveolar lavage fluid from patients with lung cancer as compared with patients with nonmalignant respiratory diseases (mean 0.61 vs 0.16 µg/mL). Also, C4d levels in plasma were higher in patients with advanced lung cancer or early-stage lung cancer than those without cancer.

High plasma C4d levels predicted poor survival in both advanced lung cancer (HR=1.59) and early lung cancer (HR=5.57) and were dramatically reduced after surgical removal of lung tumors.

Finally, C4d levels were associated with incident lung cancer risk in 190 asymptomatic individuals, with an odds ratio of 4.38 and an area under the receiver operating characteristic curve of 0.735, indicating moderately good discriminative ability.

Writing in the Journal of the National Cancer Institute, Montuenga and co-authors say that their results “support the value of C4d quantification, or another method of assessing classical complement activation, for the early diagnostic and prognostic evaluation of lung cancer patients.”

They add: “Further clinical validation of our findings may support the clinical use of this marker.”

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