Abstract
ObjectiveChronic respiratory inflammation has been associated with lung cancer. Tumor-associated macrophages (TAMs) play a critical role in the formation of inflammation microenvironment. We sought to characterize the role of TAMs in coal tar pitch extract (CTPE)-induced tumorigenic transformation of human bronchial epithelial cells and the underlying mechanisms.MethodsThe expression of TAMs-specific CD68 in lung cancer tissues and paired adjacent tissues from cancer patients was determined using immunostaining. Co-culture of human bronchial epithelial cells (BEAS-2B) and macrophage-like THP-1 cells were conducted to evaluate the promotive effect of macrophages on CTPE-induced tumorigenic transformation of BEAS-2B cells. BEAS-2B cells were first treated with 2.4 µg/mL CTPE for 72 hours. After removal of CTPE, the cells were continuously cultured either with or without THP-1 cells and passaged using trypsin-EDTA. Alterations of cell cycle, karyotype, colony formation in soft agar and tumor xenograft growth in nude mice of BEAS-2B cells at passages 10, 20 and 30, indicative of tumorigenecity, were determined, respectively. In addition, mRNA and protein levels of NF-κB in BEAS-2B cells were measured with RT-PCR and western blot, respectively. B(a)P was used as the positive control.ResultsThe over-expression of TAMs-specific CD68 around lung tumor tissues was detected and associated with lung cancer progression. The tumorigenic alterations of BEAS-2B cells including increase in cell growth rate, number of cells with aneuploidy, clonogenicity in soft agar, and tumor size in nude mice in vivo occurred at passage 10, becoming significant at passages 20 and 30 of the co-culture following CTPE removal in compared to BEAS-2B cells alone. In addition, the expression levels of NF-κB in BEAS-2B cells were positively correlated to the malignancy of BEAS-2B cells under different conditions of treatment.ConclusionThe presence of macrophages facilitated CTPE-induced tumorigenic transformation of BEAS-2B cells, which may be mediated by NF-κB.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide [1], with 1.2 million deaths each year
It was shown that the number of CD68 positive staining macrophages was closely associated with TNM stage (P = 0.001), metastasis to lymph node (P = 0.001) and tumor invasion to pleura (P = 0.001)
Tumorigenic Transformation of BEAS-2B Cells Treated by Coal tar pitch extract (CTPE)
Summary
Lung cancer is the leading cause of cancer mortality worldwide [1], with 1.2 million deaths each year. In China, it is predicted from current epidemiological data that 10 million of people may be diagnosed of lung cancer in 2025. Individuals with chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease resulted from smoking exposure [8], and chronic hypersensitivity pneumonitis [9] were at higher risk for subsequent development of lung cancer. The regular use of aspirin and other nonsteroidal anti-inflammatory drugs can reduce the risk of lung cancer, in animal, and in human [10,11,12,13]. The mechanisms of inflammation-promoted initiation of lung cancer have not been fully understood
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