Abstract
Over-activation of the signal transducers and activators of the transcription 3 (Stat3) pathway in lung alveolar type II (AT II) epithelial cells induces chronic inflammation and adenocarcinoma in the lung of CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. One of Stat3 downstream genes products, chitinase 3-like 1 (CHI3L1) protein, showed increased concentration in both bronchioalveolar lavage fluid (BALF) and blood of doxycycline-treated CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. When tested in other inflammation-induced lung cancer mouse models, the CHI3L1 protein concentration was also highly increased in BALF and blood of these models with tumors. Immunohistochemical staining showed strong staining of CHI3L1 protein around tumor areas in these mouse models. Analysis of normal objects and lung cancer patients revealed a significant elevation of CHI3L1 protein concentration in human serum samples from all categories of lung cancers. Furthermore, recombinant CHI3L protein stimulated proliferation and growth of Lewis lung cancer cells. Therefore, secretory CHI3L1 plays an important role in inflammation-induced lung cancer formation and potentially serve as a biomarker for lung cancer prediction. Based on our previous publication and this work, this is the first animal study linking overexpression of CHI3L1 to various lung tumor mouse models. These models will facilitate identification of additional biomarkers to predict and verify lung cancer under various pathogenic conditions, which normally cannot be done in humans.
Highlights
Lung cancer is the most deadly cause in human cancer population
We demonstrated that both lung epithelial cell-initiated regional inflammation and myeloid cell-initiated systemic inflammation can induce spontaneous lung tumorigenesis in multiple lung tumor animal models [1,2,3,4,5], indicating that inflammatory molecules are potentially useful for lung cancer prediction
To test if chitinase 3-like 1 (CHI3L1) is a secretory protein in this mouse model, Western blot analysis was performed in bronchioalveolar lavage fluid (BALF) of CCSP-rtTA/(TetO)7-CMV-Stat3C mice
Summary
Lung cancer is the most deadly cause in human cancer population. The five year survival rate is only about 15%. We demonstrated that both lung epithelial cell-initiated regional inflammation and myeloid cell-initiated systemic inflammation can induce spontaneous lung tumorigenesis in multiple lung tumor animal models [1,2,3,4,5], indicating that inflammatory molecules are potentially useful for lung cancer prediction. These inflammation-induced lung tumor animal models are ideal and valuable systems for identification and verification of lung cancer biomarkers. Persistent presence of these inflammatory cells facilitates spontaneous adenocarcinoma in the lung of CCSP-rtTA/(tetO)7Stat3C bitransgenic mice [1,6]
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