Abstract A25: Arsenic and benzo(a)pyrene coexposure synergizes in inducing cancer stem cell-like property and lung tumorigenesis

Abstract

Abstract Arsenic and benzo(a)pyrene (BaP) are among the most common environmental pollutants that humans are exposed to. Both arsenic and BaP are well-recognized human carcinogens that cause lung cancer. Since millions of people are exposed to arsenic through contaminated drinking water and high levels of BaP are found in cigarette smoke and barbecue cooked meat, arsenic and BaP coexposure is thus very common in humans. However, the combined effect and the underlying mechanism of arsenic and BaP coexposure are poorly understood. Using cell culture and mouse models, we investigated the combined effect of arsenic and BaP coexposure. It was found that arsenic and BaP coexposure acts synergistically in inducing cell malignant transformation as evidenced by forming more than an additive number of soft agar clones compared to arsenic or BaP exposure alone in BEAS-2B cells for 30 weeks. We also determined the combined effect of arsenic and BaP coexposure in inducing cancer stem cell (CSC)-like property by using a well-established assay known as suspension culture sphere formation assay. It was found that BEAS-2B cells transformed by arsenic or BaP exposure alone are capable of forming small numbers of spheres. However, BEAS-2B cells transformed by arsenic and BaP coexposure form more than an additive number of spheres compared to cells transformed by arsenic or BaP exposure alone, indicating that arsenic and BaP coexposure also acts synergistically in inducing CSC-like property. Since CSCs or CSC-like cells are considered tumor-initiating cells, we first compared the tumorigenic effect of BEAS-2B cells transformed by arsenic, BaP alone, or arsenic and BaP coexposure by subcutaneous inoculation of 0.25 × 106 cells into the right flank of 6-week old nu/nu nude mice. It was found that 0 of 5 mice injected with BEAS-2B-Control cells, 0 of 5 mice injected with arsenic exposure alone-transformed cells, 2 of 5 mice injected with BaP exposure alone-transformed cells develop tumors; however, all 5 mice injected with arsenic and BaP coexposure transformed cells develop tumors. These results indicate that cells transformed by arsenic and BaP coexposure have significantly stronger tumor-initiating capability than cells transformed by arsenic or BaP exposure alone. To further investigate whether arsenic and BaP coexposure acts synergistically in inducing mouse lung tumors, male A/J mice were exposed to vehicle control, arsenic, BaP, or arsenic plus BaP for 34 weeks. No lung tumors were found in control and arsenic exposure alone mice. All mice with BaP exposure developed lung tumors. However, mice exposed to arsenic plus BaP developed significantly more (tumor multiplicity) and bigger (tumor burden) lung tumors compared to mice exposed to BaP alone. Together, these results demonstrate a synergism of arsenic and BaP coexposure in inducing lung tumorigenesis. Further mechanistic studies revealed that arsenic and BaP coexposure synergizes in causing epigenetics deregulation to enhance their carcinogenicity. Citation Format: Zhishan Wang, Ping Yang, Yunfei Li, Drew Maddy, Chengfeng Yang. Arsenic and benzo(a)pyrene coexposure synergizes in inducing cancer stem cell-like property and lung tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A25.