Cigarette smoking promotes bladder cancer via increased platelet-activating factor

Abstract

Cigarette smoking is the number one risk factor for bladder cancer development and epidemiological data suggest that nearly half of all bladder cancer patients have a history of smoking. In addition to stimulating the growth of a primary tumor, it has been shown that there is a correlation between smoking and tumor metastasis. Platelet activating factor (PAF) is expressed on the cell surface of the activated endothelium and, through binding with the PAF‐receptor (PAF‐R), facilitates transendothelial migration of cells in the circulation (McHowat et al. Biochemistry 40:14921–14931; 2001). In this study, we show that the exposure of bladder cancer cells to cigarette smoke extract (CSE) results in increased PAF accumulation and increased expression of the PAF‐R. Furthermore, treatment with CSE increases adherence of bladder cancer cells to bladder endothelial cells and could be abrogated by pretreatment with ginkgolide B. Immunohistochemical analysis of tumor biopsy samples from bladder cancer patients who smoked revealed increased PAF and the PAF‐R in tumor regions when compared to normal tissue. These data highlight a pathway in bladder cancer that is influenced by CSE which could facilitate primary tumor growth and increase metastatic potential. Targeting of the PAF‐PAFR interaction could serve as a beneficial therapeutic target for managing further growth of a developing tumor.

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives

“…Interestingly the kidneys are not the only organ in the renal system affected by PAF and its metabolism. In humans, it is thought that cigarette smoking leads to alterations in urethral cells that share similar histology to urethral cells of interstitial cystitis and bladder pain syndrome (IC/BPS) patients through an inflammatory pathway mediated by PAF [287]. Overall it is demonstrated that PAF signalling is upregulated in IC/BPS and that cigarette smoke exposure further upregulated this pathway [287].…”

“…In humans, it is thought that cigarette smoking leads to alterations in urethral cells that share similar histology to urethral cells of interstitial cystitis and bladder pain syndrome (IC/BPS) patients through an inflammatory pathway mediated by PAF [287]. Overall it is demonstrated that PAF signalling is upregulated in IC/BPS and that cigarette smoke exposure further upregulated this pathway [287]. Future research aims to determine the role of PAF in IC/BPS development, whether PAF can act as a marker of IC/BPS, and if PAF antagonists may have therapeutic value in IC/BPS [288].…”

“…Future research aims to determine the role of PAF in IC/BPS development, whether PAF can act as a marker of IC/BPS, and if PAF antagonists may have therapeutic value in IC/BPS [288]. Likewise, PAF seems to be implicated in the development of bladder cancer [287]. This is unsurprising as several lines of research indicate that smoking cigarettes seem to induce the generation of PAF and PAFLL in other cancer pathologies including breast cancer [289,290].…”

Mutational Landscape and Environmental Effects in Bladder Cancer

“…These results suggest that cigarette smoke induces initiation and progression of bladder cancer, mediating EMT and activating ERK1/2 pathway. Kispert S. et al reported that the exposure of bladder cancer cells to cigarette smoke extract results in increased platelet-activating factor accumulation and increased expression of the platelet-activating factor receptor [ 62 ].…”

The benefits of smoking cessation on survival in cancer patients by integrative analysis of multi‐omics data

“…Tobacco smoking is a risk factor for the occurrence and increases the incidence of various cancers, including bladder [1], head and neck [2], lung [3], and pancreatic cancer [4]. Tobacco smoking contains many carcinogenic chemicals that can create a specific mutational signature and increase the somatic mutational burden associated with unrepaired DNA damage [5].…”