Fine particulate matter and tobacco product exposure exacerbates metabolic syndrome-related colon cancer via regulating oxidative stress and tumor-associated macrophage interactions.

backgroundThe incidence of colorectal cancer (CRC) is closely associated with prolonged exposure to fine particulate matter (PM 2.5) and tobacco carcinogens, 4-methylnitrosamino-l-3-pyridyl-butanone (NNK). However, due to a lack of understanding of its intricate pathological processes, there is currently no approved clinical medication or successful treatment plan. Also, tobacco carcinogens and PM 2.5 are implicated in the progression of CRC by the onset of a metabolic disorder. Nonetheless, direct evidence connecting the metabolic disorder to NNK/PM 2.5-mediated CRC development has yet to be developed.

methodsWe investigated CRC cells treated with NNK/PM 2.5 to investigate the function of metabolic alterations in CRC (NNK/PM 2.5)-induced tumor growth. The results were verified using human CRC cancer samples, cell-derived xenografts, and online survival analysis. To clarify the mechanism of regulation of changes in metabolism, metabolic tracking, western blotting, massarray assay, real-time PCR, and reporter assays were conducted. SPSS version 20.0 or GraphPad Prism version 10.0 were used for all statistical analyses.

resultsOur research indicates that NNK/PM 2.5, elicit characteristics of metabolic syndrome, notably hyperglycemia, decrease in reactive oxygen species (ROS) contents, and a substantial upregulation of anti-oxidative stress-related gene expression, thereby facilitating the progression of colon cancer in a murine model. By increasing the expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1), NNK/PM 2.5 increases the uptake of glucose in tumor-associated macrophages. This leads to the increased expression of insulin-like growth factor 2 (IGF2), which in turn paracrinely hyper-activates the insulin receptor (IR) in colorectal cancer cells, facilitating its nuclear import. Through IR/NPM1 mediation, nuclear IR and nucleophosmin (NPM1) interact to activate the CD274 promoter and produce programmed death ligand-1 (PD-L1). Inhibiting glycolysis, diminishing macrophages, or obstructing PD-L1 impedes NNK/PM 2.5-induced colorectal cancer growth. Analysis of patient samples and public databases reveals elevated expression of tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR), as well as elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, suggesting possible negative prognostic biomarkers for patients with colorectal cancer.

conclusionsOur results provided new insights into the mechanisms of intestinal cancer progresses by paracrine IR-PD-L1 signaling, which is aided by the deregulation of oxidative stress and macrophage communication brought on by smoking carcinogen-induced the metabolic syndrome.