Lung cancer causes the most cancer deaths worldwide. For decades, people have known that lung cancer is associated with environmental factors, and both cigarette smoke and air pollution are known to cause cancers in humans. Smoke and air pollution both contain chemicals called polycyclic aromatic hydrocarbons (or PAHs). These chemicals cause chronic inflammation of the lung, which in turn is a major risk factor for developing lung cancer.

However, it is unclear exactly how PAHs trigger inflammation and cancer. Xuanwei City in China is suited to the study of this question because until the 1970s its inhabitants used 'smoky coal' for cooking in unventilated indoor spaces; this produced high levels of small particles that contain high concentrations of PAHs. Women from this region, who traditionally do most of the cooking, have rates of lung cancer comparable to those of men. In other parts of China a woman’s chance of getting lung cancer is approximately half that of a man’s. Therefore, Xuanwei City provides a setting in which air pollution is a main contributor to lung cancer risk.

Wang, Cheng et al. have now compared the levels of certain proteins (which are linked to inflammation) in lung cancer patients from Xuanwei City with those in control regions of China. The level of one such protein marker, called CXCL13, was particularly high in almost all patients from Xuanwei City, but only highly expressed in half of the patients from the control regions. Moreover, there was also a clear link between cigarette smoke and CXCL13 expression because, in control regions, smokers were much more likely to have high levels of CXCL13 than non-smokers. To test whether PAHs cause CXCL13 expression, Wang, Cheng et al. first exposed normal lung epithelial cells, cancer cells and then mice to a PAH. These experiments showed that CXCL13 levels did indeed increase and the mice developed lung tumours. However, when the genes for CXCL13 or its binding partner were deleted, the mice no longer got cancer when exposed to the PAH. This shows that CXCL13 signalling is an important mechanism by which PAHs cause lung cancer. Lastly, further experiments showed that CXCL13’s binding partner is highly expressed on some immune cells that can promote lung cancer.

Importantly, the over-expression of CXCL13 occurred before the lung tumours developed. This might provide a new treatment strategy in which CXCL13 signalling could be inhibited after the exposure to PAHs. Future studies may now focus on discovering new drugs, or modifying existing drugs, to achieve this goal.

Air pollution is a diverse mixture of pollutants that originated from anthropogenic and natural sources, is comprised of particulate matter (PM), gases (e.g., sulfur oxides, carbon monoxide, ozone), organic compounds (e.g., polycyclic aromatic hydrocarbons, PAHs), metals (e.g., lead, vanadium, and nickel), and others, such as microbes (Akimoto, 2003; Huang et al., 2014). Air pollution is a global environmental health risk that affects the populations in developed and developing countries alike, and satellite observations suggest that 80% of the global population resides in locations where the ambient pollutant concentrations exceed the World Health Organization (WHO) Air Quality Guideline (van Donkelaar et al., 2010). Outdoor air pollution in cities and rural areas was estimated to cause 3.7 million premature deaths annually worldwide in 2012, including 220,000 deaths due to lung cancer (WHO, 2014). Recently, outdoor (Loomis et al., 2013) and indoor (WHO, 2010) air pollution has been classified as a Group 1 carcinogen in humans by the International Agency for Research on Cancer (IARC) of WHO. Indeed, the risk of lung cancer rises by 18% for every increase of 5 μg/m³ of PM smaller than 2.5 μm in diameter (PM_2.5) in the environment; the risk increases by 22% for every increase of 10 μg/m³ in PM smaller than 10 μm (PM₁₀) (Raaschou-Nielsen et al., 2013). There have been efforts to investigate how air pollution causes human cancers by exposing cells and animals to PM or related chemicals (Straif et al., 2012), but the carcinogenic mechanism remains elusive, at least in part, due to the difficulty of identifying human lung cancers that are causally associated with air pollution.

Xuanwei City of the Yunnan Province in China provides a significant association between air pollution and lung cancer (Lan et al., 2002; Sinton et al., 1995; Mumford et al., 1987). Until the 1970s, residents of this region used smoky coal in unvented indoor fire pits for domestic cooking and heating, which are processes that release high concentrations of PM_2.5/PM₁₀ that contain high concentration PAHs (Mumford et al., 1987). Indoor air pollution in Xuanwei is associated with a significant increase in the absolute lifetime risk of developing lung cancer (Xiao et al., 2012), and the lung cancer incidence in this region is among the highest in China (Mumford, et al., 1987; Xiao et al., 2012; Li et al., 2011). In particular, nearly all women in this region are non-smokers and cook food on the household stove, and the lung cancer incidence in women is high. In Xuanwei, the male-to-female ratio of lung cancer incidences is 1.09:1, while that of China’s national average reaches 2.08:1 (Xiao et al., 2012). Tobacco smoke was weakly and non-significantly associated with lung cancer risk in this region (Kim et al., 2014). In the 1990s, a reduction in the lung cancer incidence was noted after stove improvement, supporting the association between indoor air pollution and lung cancer (Lan et al., 2002). These findings had been cited by the IARC monograph to classify indoor emissions from household coal combustion as ‘carcinogenic to humans (Group 1) (WHO, 2010). However, lung cancer incidence in Xuanwei is still increasing (Li et al., 2011), possibly due to pollutants generated by coal-burning industrial plants that have moved into the area (Cao and Gao, 2012). Therefore, the population in this highly polluted region (HPR) provides a unique opportunity to dissect air pollution-related lung carcinogenesis. Furthermore, the key carcinogens of smoky coal combustion are PAHs (Lv et al., 2009), which are also the key carcinogens of tobacco smoke that causes more than 85% of global lung cancer deaths (Hecht, 2012). Xuanwei lung cancer is, therefore, applicable to elucidate tobacco smoke-induced lung carcinogenesis.

Chronic inflammation can promote cancer formation, progression and metastasis by inducing oncogenic mutations, genomic instability, and enhanced angiogenesis (Grivennikov et al., 2010). Studies show that PAHs can cause immune suppression (Zaccaria and McClure, 2013) and induce the secretion of cytokines/chemokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, CC chemokine ligand 1 (CCL1), chemokine (C-X-C motif) ligand 1 (CXCL1), and CXCL5 (N'Diaye et al., 2006; Umannová et al., 2011; Chen et al., 2012; Dreij et al., 2010). These factors may facilitate cancer initiation and progression. However, most of these factors were identified in cellular and animal PAH exposure models. Clinically relevant inflammation factors should be identified to shed insights into PAH-related carcinogenesis and provide novel therapeutic targets for lung cancer.

To systematically investigate air pollution-induced lung carcinogenesis, we used Xuanwei lung cancers to analyze the abnormalities in the cancer genomes (Yu et al., 2015), genome-wide DNA methylation, non-coding RNAs (miRNAs [Pan et al., 2015] and lncRNAs), and inflammation factors. The abnormalities found in the HPR lung cancers were tested in patients from control regions (CRs) where smoky coal was not used, to compare the difference between HPR and control region (CR) lung cancers. In this study, we explored the abnormal inflammatory factors in HPR non-small cell lung cancers (NSCLCs).

In this study, we took the advantage of the epidemiology profile of Xuanwei lung cancer to systematically explore the abnormalities in inflammatory factors that are critical to air pollution-induced lung cancer, and reported that CXCL13 was up-regulated in 63/70 (90%) HPR NSCLCs (Table 1). BaP induced lung epithelial cells to secret CXCL13 (Figure 2), which recruited tumor-associated macrophages (TAMs) and induced SPP1 production (Figure 5, 6). SPP1 activated β-catenin by facilitating its translocation to the nucleus and promoted an EMT, leading to the progression of lung cancer (Figure 6—figure supplement 1). CXCL13-CXCR5 signaling was required for PAH-induced lung cancer, because knockdown of Cxcl13 or Cxcr5 attenuated BaP-induced lung cancer in mice (Figure 4). These results suggest that the ubiquitous carcinogen BaP may induce tumor-promoting inflammation to facilitate the invasive growth and metastasis of lung cancer, shedding new insights into the carcinogenic mechanisms of air pollution.

CXCL13 may be associated with lung cancer risk in smokers (Shiels et al., 2013). We showed that in HPR, smoker and non-smoker NSCLCs had approximately equal expression levels of CXCL13, suggesting a carcinogenic effect of air pollution. In CR, however, smoker patients had higher CXCL13 expression than non-smoker cases (Figure 1 and Table 1). Moreover, high CXCL13 expression was associated with advanced stage cancer and poor prognosis (Figure 2). These results indicate that CXCL13 is a common and critical factor in air pollution-induced and tobacco smoke-induced lung carcinogenesis. Furthermore, the serum concentration of CXCL13 was elevated in mice before the emergence of detectable lung tumor by microCT (Figure 2 and Figure 2—figure supplement 1), suggesting that this chemokine may represent a biomarker for early diagnosis, which warrants further investigation.

PAHs are key carcinogens in air pollution and tobacco smoke (Huang et al., 2014; Hecht, 2012), and cause mutations in TP53 and K-RAS, resulting in uncontrolled cell growth (Hecht, 2012). PAHs also perturb the immune system and induce production of the inflammatory factors to facilitate cancer progression in cellular and animal models (Zaccaria and McClure, 2013; N'Diaye et al., 2006; Umannová et al., 2011; Chen et al., 2012; Dreij et al., 2010). By treating 16HBE cells with a relatively low concentration (1 μM) of BaP for a long time course (30 days) to mimic BaP-induced lung cancer in humans, we showed that CXCL13 was the most significantly up-regulated gene among the 84 cytokines/chemokines (Figure 2). Furthermore, CXCL13 was increased in 134/201 (66.7%) NSCLCs (Table 1), suggesting the clinical relevance of CXCL13 in BaP-induced lung cancer. AhR is critical for the carcinogenic action of BaP (Shimizu et al., 2000). We found that CXCL13 was a direct target of AhR (Figure 3), and deficiency in CXCL13 or its receptor, CXCR5, abrogated BaP-induced lung cancer (Figure 4), while an anti-CXCR5 antibody significantly inhibited lung cancer cell migration (Figure 5). These results further demonstrate CXCL13’s critical role in environmental pollutant-induced lung cancer, but its role in pre-malignancy and cell transformation remains to be addressed.

Cross-talk between cancer cells and cells of the neoplastic stroma is involved in the acquired ability for invasive growth and metastasis (Hanahan and Weinberg, 2011). Using a whole -genome gene expression array (Figure 6), we discovered that TAMs secreted SPP1, which activates β–catenin and is regulated by this transcription factor (Robertson and Chellaiah, 2010; El-Tanani et al., 2001). SPP1 induced the nuclear localization and activation of β–catenin in epithelial and cancer cells, resulting in an EMT phenotype (Figure 6—figure supplement 1H–K). At this stage, the detailed mechanisms of CXCL13-CXCR5-induced SPP1 production were unclear. However, our results suggested that SPP1-β–catenin could form a positive feedback loop to promote EMT and lung cancer progression. CXCL13 was shown to be able to induce an EMT in breast cancer via RANKL and Src activation (Biswas et al., 2014). We found that BaP or CXCL13 treatment or SPP1 overexpression in lung epithelial or cancer cells did not up-regulate RANKL or Src (data not shown), but did activate β–catenin (Figure 6—figure supplement 1), suggesting that CXCL13 may induce an EMT via different mechanisms in different settings.

Chemokines can modulate tumor cell proliferation, survival, angiogenesis, senescence and metastasis (Wang et al., 2015). For example, CCL20 is induced by another important carcinogen in tobacco smoke, nicotine-derived nitrosaminoketone, and is overexpressed in smoker lung cancers and inversely associated with prognosis. CCL20 promotes lung cancer cell proliferation and migration (Wang et al., 2015). CXCL12 and CCR7 regulate the metastasis of breast cancers and NSCLCs (Phillips et al., 2003; Müller et al., 2001; Takanami, 2003), while CXCL1/2 enhance cell survival and promote chemoresistance (Acharyya et al., 2012). CXCL13 is overexpressed in breast cancer (Panse et al., 2008) and mediates prostate cancer cell proliferation (El-Haibi et al., 2011). Given their critical roles in cancer, pharmaceutical development pipelines are filled with new chemokine-targeting drugs to treat malignancies (Klarenbeek et al., 2012). DEX is a synthetic glucocorticoid used to counteract certain side effects of chemotherapies or as a direct chemotherapeutic agent in certain malignancies. It reduces lung tumor multiplicities in the tobacco smoke-exposed and non-exposed mice (Witschi et al., 2005). We showed that DEX inhibited CXCL13 production by epithelial cells and SPP1 production by TAMs (Figure 3 and Figure 6—figure supplement 1), inhibited the EMT (Figure 6—figure supplement 1), reduced the tumor burden and prolonged the life span of the mice (Figure 2), revealing a new mechanism for this existing drug. Because DEX is a wide-spectrum anti-inflammatory drug that may cause severe side effects, more specific, CXCL13/CXCR5-targeting antibodies or small molecules should be developed to combat lung cancer, the leading cause of cancer-related mortality accounting for 1.59 million deaths worldwide in 2012 (WHO, 2012).

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Author details

1. Gui-Zhen Wang

   State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

   Contribution

   G-ZW, Acquisition of data

   Contributed equally with

   Xin Cheng

   Competing interests

   The authors declare that no competing interests exist.

2. Xin Cheng

   State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

   Contribution

   XC, Acquisition of data

   Contributed equally with

   Gui-Zhen Wang

   Competing interests

   The authors declare that no competing interests exist.

3. Bo Zhou

   State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

   Contribution

   BZ, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Zhe-Sheng Wen

   Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China

   Contribution

   Z-SW, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Yun-Chao Huang

   Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China

   Contribution

   Y-CH, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

6. Hao-Bin Chen

   Department of Pathology, The First People’s Hospital of Qu Jing City, Qu Jing, China

   Contribution

   H-BC, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

7. Gao-Feng Li

   Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China

   Contribution

   G-FL, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

8. Zhi-Liang Huang

   Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China

   Contribution

   Z-LH, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

9. Yong-Chun Zhou

   Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China

   Contribution

   Y-CZ, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

10. Lin Feng

    Department of Pathology, Chinese PLA General Hospital, Beijing, China

    Contribution

    LF, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

11. Ming-Ming Wei

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Contribution

    M-MW, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

12. Li-Wei Qu

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Contribution

    L-WQ, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

13. Yi Cao

    Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Contribution

    YC, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

14. Guang-Biao Zhou

    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Contribution

    G-BZ, Conception and design, Analysis and interpretation of data, Drafting and revising the article

    For correspondence

    gbzhou@ioz.ac.cn

    Competing interests

    The authors declare that no competing interests exist.

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