Elevated lung cancer risk shortly after smoking cessation: Is it due to a reduction of endotoxin exposure?

https://doi.org/10.1016/j.mehy.2005.02.043Get rights and content

Summary

Several reports indicate that the risk of lung cancer increases slightly for a short period of time after cessation of smoking while the risk of adverse cardiovascular events drops immediately. Recent studies on subjects occupationally exposed to organic dust-containing endotoxin have revealed lower than expected rates of lung cancer. There is experimental evidence that stimulation of the immune system by endotoxin has a protective effect against cancer. Tobacco smoke has been shown to contain high levels of endotoxin. We therefore postulate that cessation of smoking eliminates the protective effect of endotoxin. Any benefit conferred by endotoxin does not, however, justify smoking. As the inverse relationship between exposure to endotoxin and the risk of lung cancer is a strong one, endotoxin-like substances could form the basis of vaccination strategies.

Introduction

It has been previously reported in epidemiological studies that there is an almost immediate reduction in the risk of heart disease after cessation of smoking [1]. Several epidemiological studies have focused on the pattern of lung cancer risk in relation to time since cessation of smoking, and have generally found a decline in risk over years after giving up smoking. However, there is an increased risk of lung cancer for a short period of time after cessation [2], [3], [4], [5], [6], [7], [8]. This enhanced effect of smoking for a few years after cessation results in a large number of cases of lung cancer. We here suggest a clue to this unexpected finding.

Several epidemiological studies have revealed lower than expected rates of lung cancer in cotton textile workers and dairy farmers exposed to organic dust. This beneficial effect has been attributed to endotoxin, a biologically active component associated with the outer membrane of gram negative bacteria which are common contaminants of organic dusts and various natural organic products, including tobacco. We postulate that endotoxin contaminating tobacco is responsible for keeping in check some of the carcinogenic effects exerted by cigarette smoke. It is possible that the initiation of cancers presenting in the few years after cessation of smoking commenced while the person still smoked. Many such cancers may develop but the majority is destroyed, directly or indirectly, by the activity of endotoxin. Once the endotoxin is removed, cancers already initiated can then develop and present themselves clinically.

Among studies reviewed in publications by the International Agency for Research on Cancer [9], [10] we selected those reporting lung cancer risk estimates for current smokers and, at the same time, for ex-smokers who quitted less than five years previously. These criteria were met by 5 cohort (Table 1) and nine case-control studies (Table 2). The main characteristics and findings of such studies are summarized in these two tables. The chronology between quitting smoking and occurrence of lung cancer tend to be more precise in case-control rather in cohort studies because the former are based on the actual incidence of lung cancer while the latter are based on mortality. In seven extensive studies, three with a cohort [2], [3], [4], (Table 1), and four with a case-control design [5], [6], [7], [8], (Table 2), risks of lung cancer tend to exceed those in current smokers in the first few years after cessation of smoking. Interestingly, an elevated lung cancer risk shortly after smoking cessation is evident whenever daily consumption of cigarettes and/or duration of smoking were taken into account [2], [3], [5], [6], except for a small case-control study of 123 cases and controls [11]. No increased lung cancer risk shortly after cessation was reported in eight studies comparing former and current smokers without any adjustment for intensity or duration of smoking [4], [11], [12], [13], [14], [15], [16], [17].

According to Hrubec and McLaughlin [18], a temporary rise in lung cancer after cessation of smoking may reflect a substantial lag in the impact of smoking on lung cancer. This lag implies that the ‘effective’ cumulative exposure for current smokers was much smaller than that for ex-smokers with the same intensity but less duration. As it can, however, be seen in Table 2, lung cancer risk was higher in former smokers than in current smokers, after adjustment for duration and daily consumption of cigarettes [5], or pack-years, residence, and age [6] (Table 2).

On the other hand, Hauptmann et al. [19] claims that some patients with early symptoms of lung cancer stopped smoking just before diagnosis, inducing a reverse causality bias. Most investigators have observed that smokers are at a higher risk of developing squamous cell lung carcinoma than adenocarcinoma. The growth rate (doubling time) of lung cancers has been reported to vary between 97 and 533 days depending on the tumor histology; the shortest volume doubling time was noted in small cell carcinoma followed by squamous cell carcinoma, while adenocarcinomas approximately doubled their size in 18 months [20]. Thus, the findings reported by Hammond [2] that lung cancer standardized mortality ratios are higher in ex-smokers within one year since cessation (Table 1), may be the result of bias. By contrast, a reverse causality bias does not explain the elevated lung cancer risks reported after 1–5 years from stopping smoking in either case-control [5], [6], [7], (Table 2), or cohort studies [3], [4], (Table 1).

Mortality from lung cancer in cotton textile industry workers has been shown to decrease in proportion to increasing levels [21] and increasing length [22], [23] of exposure to cotton dust. This protective effect against lung cancer has been attributed to endotoxin (lipopolysaccharide, LPS) released by gram-negative bacteria proliferating on cotton dust [24].

When the epidemiological data on cancer risk in textile industry workers were reviewed in relation to the calendar year of study publication [25], the risk of lung cancer relative to that of the general population was around 0.4 in the first epidemiologic study on cotton workers published in 1936, around 0.7 in subsequent studies (mostly published in the 1970s and 1980s), and around 1.0 in a later study published in 1995. This chronological variation has been attributed to improvements in working conditions over time resulting in a progressive reduction in exposure to dust and therefore to endotoxin. Accordingly, industrial safety measures introduced to prevent respiratory disease may, paradoxically, have increased the lung cancer burden among the textile workers.

Exposure to endotoxin-containing dust is ubiquitous in agriculture [26], [27]. Endotoxin and other microbial products are inherent elements of farm dusts, particularly in cowsheds of dairy farms, where animal faeces containing large numbers of bacteria make a major contribution to organic dusts [28], [29], [30], [31], [32].

Several studies have shown that the risk of lung cancer is lower in dairy/livestock farmers than in crop/orchard farmers [33], [34], [35] (Table 3). In a cohort nested case-control study, the odds ratio for lung cancer adjusted for smoking and age decreased by 19% per head of dairy cattle (OR: 0.81; CI: 0.68, 0.97) [36]. In the study by Lange and colleagues [35] listed in Table 3, based on death certificates collected from 26 states in the USA between 1984 and 1993, a rough adjustment for smoking revealed a reduced risk of lung cancer in both livestock farmers and in crop farmers although the risk was lower in the former. Accordingly, differences in smoking habits do not provide the whole explanation of the reduced risk of lung cancer among livestock/dairy farmers. Measurements of exposure to endotoxin in groups of Californian farmers showed that those engaged in livestock farming were exposed to an average of 132.5 endotoxin units per cubic meter (EU/m3) of air, compared to 19.9 EU/m3 during field crop and fruit farming [30].

Taken together, these findings suggest that, although many harmful effects have been attributed to exposure to endotoxin-containing dust, a beneficial effect is a protection against lung cancer. It appears that this benefit is conferred on other subjects occupationally exposed to endotoxin, including machinists who inhale aerosols of oil containing endotoxin [37].

In the industrialized countries, the number of farmers has progressively declined over the last three decades. People leaving dairy farming and taking employment in industry or services have experienced a lower level of exposure to bacteria and microbial agents. In a cohort of dairy farmers, the downward trend of lung cancer standardized mortality ratios across the tertiles of numbers of dairy cattle was significant (p < 0.05) from 1970 to 1984, but not from 1985 to 1998, when most subjects were no longer dairy farmers. Furthermore, age-smoking-adjusted odds ratios for lung cancer significantly decreased with increasing number of dairy cattle (p for trend = 0.001) in workers with ⩽15, but not in those with >15 years elapsed from end of work to end of follow-up. Therefore, reducing exposure to farm dust exposure increases the risk of lung cancer [38].

Tobacco contains high levels of endotoxin, approximately 1% of which survives combustion as an active component of cigarette smoke, and that smoking 20 cigarettes daily delivers a dose of respirable endotoxin comparable to that associated with byssinosis in cotton textile workers [39]. Larsson et al. [40] identified an endotoxin marker ((R)-3-hydroxytetradecanoic acid) in cigarette smoke particles and found that smoking involves inhalation of 17.4 pmol of endotoxin per each smoked cigarette. Indoor exposure to environmental tobacco smoke entails inhalation of 12.1 pmol of LPS/m3 air, an amount that was 120 times higher than the levels found in smoke-free indoor air [40]. Endotoxin is one of the most potent inflammatory agents known [41], hence these results explain, at least in part, the high prevalence of respiratory disorders in smokers and in susceptible individuals exposed to environmental tobacco smoke.

Since the late 19th century, evidence has accrued that certain bacterial products have anti-cancer properties [42]. In 1882, Coley [43] claimed that extracts of Streptococcus pyogenes and Bacillus prodigiosus (Serratia marcescens) were effective in the treatment of inoperable sarcomas, and more recently endotoxin has been used as an anti-cancer agent in various clinical trials [44]. It has been established that endotoxins are potent activators of the adaptive immune system and that they exert this effect by stimulating toll-like receptors (TLRs) which are evolutionarily primitive receptors that bind to certain conserved microbial components [45]. It has also been established that such activation pathways, particularly those initiated by TLR-4, lead to increased anti-tumor activity of various effector cells of the immune system, including macrophages, cytotoxic T cells and natural killer (NK) cells, enhanced migration of these cells through tissues and changes in the cell surface receptors that confer on them a greater affinity for tumors.

Other immune mechanisms that may be involved in destruction of tumors include the production of cytokines (e.g. tumor necrosis factor) which act directly on intracellular mechanisms in tumor cells resulting in apoptosis [45]. These cytokines and/or TLRs stimulate signal transduction pathways [46], such as nuclear factor kappa B and the mitogen-activated protein kinases (MAPKs), specifically the c-Jun-NH2-terminal protein kinase (JNK) family, which is suggested to result in apoptosis of the tumor [47], [48]. Other anti-neoplastic mechanisms may well be involved, such as an extracellular signal-regulated kinase – ERK, p38 MAP, and as yet poorly understood non-immunological processes [49], [50].

In conclusion, certain microbial products notably endotoxin from gram-negative bacteria may protect against lung cancer, and possibly some other cancers, by exerting a direct anti-neoplastic effect or, through activation of toll-like receptors, by regulating the immune system so that the most effective defense mechanisms are mobilized. Any benefit conferred by endotoxin present in tobacco smoke does not, however, justify smoking.

It has been suggested that endotoxin and other adjuvants could form the basis of vaccination strategies to replace ‘natural’ exposure to such adjuvants, thereby facilitating the maturation of the immune system and preventing the wide range of diseases associated with immune dysregulation [51]. Indeed, the need for the development of vaccination strategies that compensate for the missing natural microbial challenges has been emphasized in a paper entitled ‘Give us this day our daily germs’ [52].

Until recently treated with suspicion, even with derision, the concept that the human body possesses potentially effective surveillance and defense mechanisms for detecting and either repairing or destroying pre-malignant and malignant cells is gaining widespread acceptance. Many strategies for tumor vaccine development are under investigation [53]. In this context, an agent with the beneficial pharmaceutical properties of bacterial endotoxin, without the harmful properties of organic dusts, could be used to make a significant beneficial impact on the high incidence of lung cancer and, possibly, other types of neoplasms.

There is, however, reason for caution because it is well known that high endotoxin exposures can cause adverse respiratory effects [41], although these might not necessarily occur at the same levels required for protection from lung cancer (but instead might occur only at higher levels). It is, moreover, not entirely clear whether endotoxin is solely responsible for the observed protective effects or whether other agents, such as peptidoglycans [26] or mycobacterial antigens [54], could prove to be equally or more important either on their own or synergistically in combination with endotoxin.

Notwithstanding, on the basis of the mainly indirect evidence presented above, we consider that it is plausible that increased levels of endotoxin (or other environmental factors associated with endotoxin) might be protective from lung cancer. Randomized clinical trials exposing subjects for a limited time to endotoxin to test this hypothesis would have considerable ethical implications. Alterative ways for safely eliciting immune responses naturally induced by endotoxin are needed but their development will require a far better understanding of the underlying immunologic mechanisms involved.

References (55)

  • C. Dunn et al.

    Molecular mechanisms and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor

    Cell Signal

    (2002)
  • A.M. Jimenez-Lara et al.

    Retinoic-acid-induced apoptosis in leukemia cells

    Trends Mol Med

    (2004)
  • B. Krone et al.

    Impact of vaccinations and infectious diseases on melanoma risk – evaluation of an EORTC case-control study

    Eur J Cancer

    (2003)
  • G.A. Rook et al.

    Give us this day our daily germs

    Immunol Today

    (1998)
  • S. Mocellin et al.

    Vaccines for solid tumours

    Lancet Oncol

    (2004)
  • J.K. Ockene et al.

    The relationship of smoking cessation to coronary heart disease and lung cancer in the multiple risk factor intervention trial (MRFIT)

    Am J Publ Health

    (1990)
  • E.C. Hammond

    Smoking in relation to the death rates of one million men and women

    Natl Cancer Inst Monograph

    (1966)
  • L. Garfinkel et al.

    Smoking and lung cancer in women: findings in a prospective study

    Cancer Res

    (1988)
  • E. Rogot et al.

    Cancer mortality among nonsmokers in an insured group of US veterans

    J Natl Cancer Inst

    (1980)
  • E. Benhamou et al.

    Changes in patterns of cigarette smoking and lung cancer risk: results of a case-control study

    Br J Cancer

    (1989)
  • Y. Bhurgri et al.

    A case-control study of lung cancer in Karachi, Pakistan

    Int J Cancer

    (2002)
  • Y.T. Gao et al.

    Lung cancer in Shanghai

    Int J Epidemiol

    (1988)
  • International Agency for Research on Cancer. Tobacco and smoking. vol. 38, France: Lyon;...
  • International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. vol 83, France: Lyon;...
  • R. Doll et al.

    Mortality in relation to smoking: 20 years’ of observations on male British doctors

    Br Med J

    (1976)
  • F.E. Speizer et al.

    Prospective study of smoking, antioxidant intake, and lung cancer in middle-aged women (USA)

    Cancer Cause Control

    (1999)
  • S.A. Kuhder et al.

    Effect of cigarette smoking on major histological types of lung cancer in men

    Lung Cancer

    (1998)
  • Cited by (8)

    • The composition of microbial aerosols, PM2.5, and PM10 in a duck house in Shandong province, China

      2019, Poultry Science
      Citation Excerpt :

      Exposure to such high concentrations of microbial aerosols for long periods leads to disease in both animals and humans, including respiratory diseases and immune insults (Crowe et al., 1996; Urbain et al., 1996a,b; Whyte and Williamson, 1993). Long-term exposure to high endotoxin concentrations is also a potential danger for being attacked by various diseases (Lange et al., 2005). Bacteria from animal farms entering the environment is the main cause of occupational lung disease in the livestock industry (Donham et al., 2000).

    • Lung Cancer: Epidemiology, Etiology, and Prevention

      2011, Clinics in Chest Medicine
      Citation Excerpt :

      In the Women’s Health Study of women ages 55 to 69 years, there was a beneficial effect of smoking cessation among recent and distant former smokers. There are some investigators who argue that lung cancers may be triggered by smoking cessation.267,268 The process of lung cancer development, however, takes place over many years.

    • Spontaneous smoking cessation before lung cancer diagnosis

      2011, Journal of Thoracic Oncology
      Citation Excerpt :

      We suggest that there may also be a causal relationship between the presence of lung cancer and smoking cessation and that smoking cessation may itself be a symptom in some lung cancer cases. Two groups have argued that lung cancers may be triggered by smoking cessation.15,16 However, initiation and promotion of lung cancer is a process that develops over many years.

    View all citing articles on Scopus
    View full text