To many including physicians, the cause or major risk factor to lung cancer is smoking! But global statistics estimate that 15% of all cases of lung cancer in men and 53% in women are not attributable to smoking, and these data indicate that worldwide, approximately 25% of patients with lung cancer are never smokers. Moreover simply quitting smoking has not been sufficient as the primary means

of preventing lung cancer. Although indirect exposure to environmental tobacco smoke or second hand smoking and exposure to workplace carcinogens or industrial air pollutions have been considered, the two most important alternative risk factors, such history is absent in more than a third of such non-smokers population with lung cancers. This has made some researchers in the field to suspect two different pathophysiologic pathways to the causation of lung cancers in smokers than non-smokers with different genetic susceptibilities. Surprisingly the type of lung cancer in never-smokers is adenocarcinoma or small cell carcinoma that is the major type of lung cancer in both smokers and non-smokers!

Moreover despite the decline in smoking at least in the adult population of the developed world such as USA, the rate of lung cancer has not declined. Lung cancer still remains a serious public health problem and is the first cause of cancer death worldwide with an overall maximum 5-year survival rate up to 17%. Clinical and epidemiologic studies have suggested a strong association among chronic infection, inflammation, and cancer, including lung cancer. Immune system plays a critical role in maintaining tissue homeostasis, cell turnover, tissue remodeling, and preventing infection and cell transformation. Cancer-related inflammation affects many aspects of malignancy, including the proliferation and survival of malignant cells, angiogenesis, tumor metastasis, and tumor response to chemotherapeutic drugs and hormones. Moreover, epidemiologic studies and meta-analysis have shown that prolonged use of non-steroid anti-inflammatory (NSAID) drugs reduces the risk of several solid tumor including lung cancer. Strong lines of evidence suggest that the chemopreventive properties of chronic NSAID administration are based on their Cyclooxygenase (COX)-inhibitory activity. Cytokines and inflammatory mediators related to prostaglandins (PGE) that are the therapeutic target of NSAIDs have been recognized as major molecular factors in turning on the cancerous machinery in some cancers such as lung cancer. Clinical trials are underway to evaluate COX-2 inhibitors as adjuvants to chemotherapy in patients with lung cancer as well as breast cancer with the possibility of getting approval by heath regulatory agencies such as FDA that has approved Celebrex for Familial Adenomatous polyposis.

 The role of inflammation in causing lung cancer is now so convincing to the researchers that some attempt to connect the cigarette smoking that is still believed to be the main cause of lung cancer to the inflammatory process described above. These researchers explain that smoking can induce COX-2 expression and activity, increase PGE2 and other inflammatory molecules, e.g.Thromboxane A2 (TxA2) and hence contribute to carcinogenesis and tumor progression. Since previous lung diseases such as Chronic obstructive pulmonary disease (COPD) are frequently preexisted in the lung cancer patients, some researchers attempt to connect the two conditions along with smoking as precipitating factors through fibroblasts, the cells in lung that initiate the above described inflammatory process. But the truth of the matter goes beyond blaming only smoking as the main causative agent in lung cancer, though it is plausible and has shown in molecular studies to cause inflammation in the lung. But the main contention to the existing theory and belief is that inflammation alone is not sufficient to start the cancerous machinery in the lung even through smoking, but precipitatory. In a lay term, smoking is not the main criminal but an associate in the crime!

As discussed in other articles of this website, the microbial invasion to the human bodies are the main causes of cancer in our different organs. Therefore the search to identify the offender in the case of lung cancer has to be looking for previous lower respiratory tract infections in this patient population. This search and fact as early as 1997 have been confirmed somehow by Laurila and colleagues from Finland that Chlamydia pneumoniae infection has been implicated in several chronic lung diseases by serology and direct antigen detection. These researchers, more than a quarter of century ago had confirmed that acute lower respiratory tract infection caused by C. pneumoniae seems often to precede attacks of asthma in

both children and adults and is involved in some exacerbations of chronic bronchitis, COPD and persistently elevated C. pneumoniae antibody titres in sarcoidosis and lung cancer. Chlamydophila pneumonia that is responsible for about 20% of lower respiratory tract infections, has been later on recognized as a major contributor in the pathogenesis and course of bronchial asthma, and responsible for 4-16% of COPD exacerbations. Most recently a suspicious relationship of this lung infection has also been raised with the lung cancer, but not yet explained and detailed.

In this article like the others in this website, through didactic reasoning and weaving the current data from existing research, I present the concept of microbial invasions to our body system and organs as the initiators of different cancers such as lung cancer. More recently COPD that is a chronic lung condition often caused by earlier infections in the lower respiratory tracts, has been correlated with the lung cancer independent of the smoking history. In another recent meta-analytic review of more than 39 studies, previous history of COPD, chronic bronchitis, or emphysema have been shown as major risk factors in developing lung cancer. In another pooled analysis review from the international lung cancer consortium, including 24,607 cases and 81,829 controls, an association with pre-existing lung diseases such as chronic bronchitis, tuberculosis and pneumonia even independent of smoking has been confirmed. While these discoveries seem to be new, there have been earlier reports as early as 1992 by Alavanja and colleagues, then in 1995 by Wu and colleagues of the association of previous lung diseases such as the above and lung cancer in non-smoking women and in 1999 by Mayne and colleagues of such connection in both men and women non-smokers.

As discussed in other articles of this website, e.g. “Trauma and insults”, “autoimmune disorders”, “Viral attacks”, “a new look at infections”, “A new look at cancer”, “ovarian and endometrial cancers:revisited”, “a new look at the prostate cancer”, “breast cnacer:revisited”,  “genetic or viral”, lung cancer does not seem to exempt from causation by microbial invasions. There are many other cancers, autoimmune disorders and other disorders of different categories in medicine that have been caused by viruses and bacterial infections, e.g. gastric cancer by H.Pylor, Salmonella typhi causing gallbladder cancer among many other cancers and disorders that all could not be obviously detailed here.

The research in medicine, now more than ever, needs to wake up and recognize the true impact of the microbial invasion to our existence that could one day soon or later bring us to our demise much earlier than an attack by asteroids, or extra-terrestrial beings, or in a very long term by the heating up or cooling down of the earth! Therefore instead of fooling ourselves that a cancer such as of lung is caused solely by smoking, or calling hemophilia a purely genetic disorder, or calling many carcinomas and autoimmune disorders as “iatrogenic” meaning not knowing the cause, we need to take a new good look into the damages done by the microbial world to our very existence. This new look requires extensive and long-term research into the matter and follow each case of infection for years and decades to recognize the impact! It would be very immature and impatient thinking to expect the impact of any such infections, would be seen right away or in a few years. Some of these infections as discussed in other posts, may have their finger prints not on the infected individual but on his/her genetic make up, infect and pass the infected genes to the next generations and make us believe that some disorders are purely genetic!

Dr.Mostafa Showraki, MD, FRCPC                                                               Lecturer, University of Toronto,School of Medicine,Author: “ADHD:Revisited” Book “adhdrevisited.com”/”medicinerevisited.com”

Refrences:

1. Okazaki I, Ishikawa S, Sohara Y. Genes associated with succeptibility to lung adenocarcinoma among never smokers suggest the mechanism of disease. Anticancer Res. 2014 Oct;34(10):5229-40.
2. Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ. Eur J Cancer. 2012 Jun;48(9):1299-311. Lung cancer in never smokers–a review.
3. Centers for Disease Control and Prevention (CDC) (2009). “Cigarette smoking among adults and trends in smoking cessation-United States, 2008”. Morbidity and mortality weekly report 58 (44): 1227–1232.
4. Gomes M, Teixeira AL, Coelho A, Aravjo A, Medeiros R. The role of inflammation in lung cancer. Adv Exp Med Biol. 2014;816:1-23.
5. Peebles KA, Lee JM, Mao JT, Hazra S, Reckamp KL, Krysan K,   Dohadwala M,Heinrich EL, Walser TC, Cui X, Baratelli FE, Garon E, Sharma S, Dubinett SM. Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther. 2007 Oct;7(10):1405-21.
6. Lee JM, Yanagawa J, Peebles KA, Sharma S, Mao JT, Dubinett SM. Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment. Crit Rev Oncol Hematol. 2008 Jun;66(3):208-17.
7. Huang RY, Chen GG. Cigarette smoking, cyclooxygenase-2 pathway and cancer. Biochim Biophys Acta. 2011 Apr;1815(2):158-69.
8. Martey CA, Pollock SJ, Turner CK, O’Reilly KM, Baglole CJ, Phipps RP, Sime PJ. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L981-91. Epub 2004 Jul 2.
9. Laurila AL, Von Hertzen L, Saikku P. Chlamydia pneumoniae and chronic lung diseases. Scand J Infect Dis Suppl. 1997;104:34-6.
10. Choroszy-K, Frej-Modrzak M, Hober M, Sarowska J, Jama-Kmiecik A. Infections caused by Chlamydophila pneumoniae. Adv Clin Exp Med. 2014 Jan-Feb;23(1):123-6.
11. Takiguchi Y, Sekine I, Iwasawa S(1), Kurimoto R(1), Tatsumi K(1). Chronic obstructive pulmonary disease as a risk factor for lung cancer.World J Clin Oncol. 2014 Oct 10;5(4):660-6.
12. Brenner DR, McLaughlin JR, Hung RJ. Previous lung diseases and lung cancer risk: a systematic review and meta-analysis. PLoS One. 2011 Mar 31;6(3):e17479.
13. Brenner DR, et. al. Previous lung diseases and lung cancer risk: a pooled analysis from the International Lung Cancer Consortium Am J Epidemiol. 2012 Oct 1;176(7):573-85.
14. Alavanja MC, Brownson RC, Boice JD Jr, Hock E. Preexisting lung disease and lung cancer among nonsmoking women. Am J Epidemiol. 1992 Sep 15;136(6):623-32.
15. Wu AH, Fontham ET, Reynolds P, Greenberg RS, Buffler P, Liff J, Boyd P, Henderson BE, Correa P. Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol. 1995 Jun 1;141(11):1023-32.
16. Mayne ST, Buenconsejo J, Janerich DT. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol. 1999 Jan 1;149(1):13-20.
17. Showraki, Mostafa.  “A new look at Cancer”. medicinerevisited.com.
18. Showraki, Mostafa.  “A new look at infections”. medicinerevisited.com.
19. Showraki, Mostafa.  “Trauma and insults”. medicinerevisited.com.
20. Showraki, Mostafa.  “Breast Cancer:Revisited”. medicinerevisited.com.
21. Showraki, Mostafa.  “Ovarian and endometrial Cancers:Revisited”. medicinerevisited.com.
22. Showraki, Mostafa.  “A new look at the prostate cancer”. medicinerevisited.com.
23. Showraki, Mostafa. “Viral attacks”. medicinerevisited.com.
24. Showraki, Mostafa. “Genetic or Viral?!”. medicinerevisited.com.
25. Mager DL. Bacteria and cancer: cause, coincidence or cure? A review.J Transl Med. 2006 Mar 28;4:14.