Abstract:

Objective:

To describe the epidemiological studies about the relationship between lung cancer (LC) and pulmonary tuberculosis (Tb) and its possible molecular mechanisms.

Materials and methods:

We reviewed research databases in search of publications that included keywords LC and Tb.

Results:

It has been proposed that chronic inflammation in the lungs due to Tb could cause clastogenic activity in the DNA of bronchial epithelium. Another possibility is lateral gene transfer; since Mycobacterium tuberculosis (MTb) is an intracellular organism, bacterial DNA could integrate to bronchial epithelial cells inducing neoplastic transformation.

Conclusions:

There are epidemiological reports, particularly from Asian countries, which confirm a relationship between LC and Tb. MTb could play an active role in cellular transformation and it is important to elucidate the mechanism involved.

Keywords:
tuberculosis; lung cancer; inflammation; EGFR; epidemiology

Resumen:

Objetivo:

Describir los estudios que documentan la relación entre el cáncer de pulmón (CP) y la tuberculosis pulmonar (Tb) y sus posibles mecanismos moleculares.

Material y métodos:

Se revisaron bases de datos de publicaciones, usando como palabras clave CP y Tb.

Resultados:

Se ha propuesto que la inflamación crónica en el pulmón provocada por la Tb podría producir actividad clastogénica. Otra posibilidad es la transferencia lateral de genes; Mycobacterium tuberculosis (MTb) es un organismo intracelular facultativo cuyo DNA podría integrarse al material genético del epitelio bronquial induciendo transformación neoplásica.

Conclusión:

Existen evidencias epidemiológicas, particularmente en países asiáticos, que documentan la relación entre CP y Tb. MTb podría desempeñar un papel activo en la transformación neoplásica cuyo mecanismo debe de ser elucidado.

Palabras clave:
tuberculosis; cáncer de pulmón; inflamación; EGFR; epidemiología

Introduction

Tuberculosis epidemiology and epidemiology link with lung cancer

Tuberculosis (Tb), caused by Mycobacterium tuberculosis (Mtb), is the main cause of death by an infectious agent with more than 1.8 million deaths per year, which makes Tb an important public health issue worldwide. It has been estimated that one third of the world population is a healthy carrier of Mtb (latent infection), from which approximately 10% will eventually develop active disease.¹1. Organización Mundial de la Salud ENT#091;internetENT#093;. OMS; c2018 ENT#091;cited 2018 NovENT#093;. Tuberculosis; ENT#091;about 6 screensENT#093;. Available from:http://www.who.int/mediacentre/factsheets/fs104/es/index.html
http://www.who.int/mediacentre/factsheet... In México, there are more than 19 000 new cases per year, and in 2015 the incidence was three to 58.8 cases per 100 000 inhabitants, depending on the state.²2. Organización Panamericana de la Salud ENT#091;internetENT#093;. Washington: PAHO; c2017. Informe país: México. Salud en las Américas 2017; ;about 4 screen;cited November, 2018;. Available from:Available from:https://www.paho.org/salud-en-las-americas-2017/?post_t_es=mexico&lang=es
https://www.paho.org/salud-en-las-americ... Particularly in Asia there is strong epidemiological evidence indicating that Tb is associated with the development of lung cancer, particularly non-small cell adenocarcinoma, which is one of the most aggressive subtypes.

Lung cancer (LC) is the leading cause of cancer-related deaths in the world, in México most cases are diagnosed at a late stage and survival with traditional first-line chemotherapy platinum-based regimens is usually poor.³3. Arrieta O, Guzman-de Alba E, Alba-Lopez LF, Acosta-Espinoza A, Alatorre-Alexander J, Alexander-Meza JF, et al. Consenso nacional de diagnóstico y tratamiento del cáncer de pulmón de células no pequeñas. Rev Invest Clin. 2013;65(suppl 1):S5-84.^,44. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. https://doi.org/10.1002/ijc.29210
https://doi.org/10.1002/ijc.29210... Non-small cellular lung cancer (NSCLC) accounts for approximately 85% of cases. The main subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma; cigarette smoking is causally related to lung cancer, accounting for approximately 85% of all patients in the United States and Europe, but only between 50-60% in México, particularly in terms of gender, the proportion decreases almost to 30% in women.⁵5. Arrieta O, Campos-Parra AD, Zuloaga C, Aviles A, Sanchez-Reyes R, Manriquez ME, et al. Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure. J Thorac Oncol. 2012;7(8):1228-34. https://doi.org/10.1097/JTO.0b013e3182582a93
https://doi.org/10.1097/JTO.0b013e318258... ^,66. Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e1S-29S. https://doi.org/10.1378/chest.12-2345
https://doi.org/10.1378/chest.12-2345...

There are several factors that participate in neoplastic transformation; being infected by a certain type of pathogen agent is one of these factors. The prevention and treatment of infectious agents have had a substantial effect on cancer prevention.⁷7. Chang MH, You SL, ChenCJ, Liu CJ, Lee CM, Lin SM, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348-55. https://doi.org/10.1093/jnci/djp288
https://doi.org/10.1093/jnci/djp288... In 2008, about 16%, (around two million) of the new cancer cases that occurred worldwide were attributable to infectious agents. This percentage was even higher in less developed regions (22.9%) in comparison with more developed ones (7.4%).⁸8. Martel C de, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13(6):607-15. https://doi.org/10.1016/S1470-2045(12)70137-7
https://doi.org/10.1016/S1470-2045(12)70... The International Agency for Research on Cancer Monographs considered Infection as a significant contributor to cancer development and identified eleven biological agents as group 1 carcinogens, however Mtb was not included.^9,9. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al. A review of human carcinogens--Part B: biological agents. Lancet Oncol. 2009;10(4):321-2. https://doi.org/10.1016/S1470-2045(09)70096-8
https://doi.org/10.1016/S1470-2045(09)70... ¹⁰10. International Agency for Research on Cancer. A review of carcinogen-Part B: Biological Agents. Monographs on the evaluation of carcinogenic risks to humans. Lyon: IARC, 2012. ENT# 091;cited November, 2018ENT# 093; Available from:Available from:https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100B.pdf
https://monographs.iarc.fr/wp-content/up...

The coexistence of pulmonary Tb and lung cancer is not an uncommon clinical observation.¹¹11. Liang HY, Li XL, Yu XS, Guan P, Yin ZH, He QC, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer. 2009;125(12):2936-44. https://doi.org/10.1002/ijc.24636
https://doi.org/10.1002/ijc.24636... There are several studies that have attempted to reveal the exact relationship between Tb and LC.¹¹11. Liang HY, Li XL, Yu XS, Guan P, Yin ZH, He QC, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer. 2009;125(12):2936-44. https://doi.org/10.1002/ijc.24636
https://doi.org/10.1002/ijc.24636... ^,1212. Cicenas S, Vencevicius V. Lung cancer in patients with tuberculosis. World J Surg Oncol. 2007;5:22. https://doi.org/10.1186/1477-7819-5-22
https://doi.org/10.1186/1477-7819-5-22... ^,1313. Littman AJ, Thornquist MD, White E, Jackson LA, Goodman GE, Vaughan TL. Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes Control. 2004;15(8):819-27. https://doi.org/10.1023/B:CACO.0000043432.71626.45
https://doi.org/10.1023/B:CACO.000004343... ^,1414. Wu CY, Hu HY, Pu CY, Huang N, Shen HC, Li CP, et al. Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study. Cancer. 2011;117(3):618-24. https://doi.org/10.1002/cncr.25616
https://doi.org/10.1002/cncr.25616... ^,1515. Zheng W, Blot WJ, Liao ML, Wang ZX, Levin LI, Zhao JJ, et al. Lung cancer and prior tuberculosis infection in Shanghai. Br JCancer . 1987;56(4):501-4. https://doi.org/10.1038/bjc.1987.233
https://doi.org/10.1038/bjc.1987.233... ^,1616. Shiels MS, Albanes D, Virtamo J, Engels EA. Increased risk of lung cancer in men with tuberculosis in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev. 2011;20(4):672-8. https://doi.org/10.1158/1055-9965.EPI-10-1166
https://doi.org/10.1158/1055-9965.EPI-10... ^,1717. Brenner DR, McLaughlin JR, Hung RJ. Previous lung diseases and lung cancer risk: a systematic review and meta-analysis. PLoS One. 2011;6(3):e17479. https://doi.org/10.1371/journal.pone.0017479
https://doi.org/10.1371/journal.pone.001... ^,1818. Everatt R, Kuzmickiene I, Davidaviciene E, Cicenas S. Incidence of lung cancer among patients with tuberculosis: a nationwide cohort study in Lithuania. Int J Tuberc Lung Dis. 2016;20(6):757-63. https://doi.org/10.5588/ijtld.15.0783
https://doi.org/10.5588/ijtld.15.0783... ^,1919. Engels EA, Shen M, Chapman RS, Pfeiffer RM, Yu YY, He X, et al. Tuberculosis and subsequent risk of lung cancer in Xuanwei, China. Int J Cancer . 2009;124(5):1183-7. https://doi.org/10.1002/ijc.24042
https://doi.org/10.1002/ijc.24042... ^,2020. Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol. 2011;6(1):32-7. https://doi.org/10.1097/JTO.0b013e3181fb4fcc
https://doi.org/10.1097/JTO.0b013e3181fb... Some of their findings are summarized in table I . A prospective study evaluating the association between a history of respiratory diseases (asthma, chronic obstructive pulmonary disease ENT#091;COPDENT#093;, Tb) and the development of LC found that there was no relationship between Tb infection and the development of lung cancer. The study does not take in account for confounding factors. The participants of the study came from the Carotene and Retinol Efficacy Trial (CARET), a randomized, double-blind, placebo-controlled prevention trial with a eligibility criteria that includes two high-risk groups: heavy smokers and asbestos-exposed workers.¹³13. Littman AJ, Thornquist MD, White E, Jackson LA, Goodman GE, Vaughan TL. Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes Control. 2004;15(8):819-27. https://doi.org/10.1023/B:CACO.0000043432.71626.45
https://doi.org/10.1023/B:CACO.000004343... Everatt and colleagues examined the risk of LC in a Lithuanian cohort of 21 968 Tb patients and took in to account for different confounding factors. They observed a more than three-fold increase risk of lung cancer in individuals with a history of Tb, but the risk declined substantially >3 years after Tb diagnosis in non-smokers therefore concluding that most of the observed risk possibly reflects the confounding effects of reverse causation, closer medical surveillance and shared risk factors.¹⁸18. Everatt R, Kuzmickiene I, Davidaviciene E, Cicenas S. Incidence of lung cancer among patients with tuberculosis: a nationwide cohort study in Lithuania. Int J Tuberc Lung Dis. 2016;20(6):757-63. https://doi.org/10.5588/ijtld.15.0783
https://doi.org/10.5588/ijtld.15.0783... In contrast, in a cohort study in a rural population in China that included 42 422 subjects, reported that the risk of LC increases up to eight times in patients who have a history of Tb infection (25 vs 3.1 per 10 000 person-year). The adjustment for confounding factors such as demographic characteristics, lung disease, and tobacco consumption did not affect the results.¹⁹19. Engels EA, Shen M, Chapman RS, Pfeiffer RM, Yu YY, He X, et al. Tuberculosis and subsequent risk of lung cancer in Xuanwei, China. Int J Cancer . 2009;124(5):1183-7. https://doi.org/10.1002/ijc.24042
https://doi.org/10.1002/ijc.24042...

Other reports with an experimental design in Asian population, successfully demonstrated that there is an increased risk of developing LC after Tb infection. Yu and colleagues conducted a prospective cohort study with 716 872 individuals and the results from this study showed that the incidence of LC in patients with Tb is approximately 11 fold higher (26.3 vs 2.41 per 10 000 person-years). Worth mentioning are the hazard ratios of other risk factors that were further increased in the presence of a positive history of Tb infection, such as COPD and Tb (HR 6.22 (95%CI: 4.87-7.94) and smoking and Tb (HR 15.5 (95%CI: 2.17-110).²⁰20. Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol. 2011;6(1):32-7. https://doi.org/10.1097/JTO.0b013e3181fb4fcc
https://doi.org/10.1097/JTO.0b013e3181fb... Furthermore, a recent meta-analysis that included 41 studies (37 case-control and four cohort studies) and was adjusted for confounding factors such as passive and active smoking, reported that the risk of developing LC was increased among patients with a history of Tb (2-fold higher over the 20 years following a Tb diagnosis). Interestingly, the histological subtype of LC more frequently associated with a history of Tb was adenocarcinoma (RR 1.6, 95%CI: 1.2-2.1), while the other histological types (squamous and small cells carcinomas) did not show significant association with Tb.11 It is important to note that having a history of Tb not only increases the risk of developing LC, but it can also negatively affect the prognosis of LC patients. In a cohort study conducted in the Netherlands with about 8 000 subjects and a follow-up of 18 years, a total of 214 cases of LC were found, of which 13 had a history of Tb. The overall survival of patients with LC and a history of Tb was lower compared to those without a history of Tb (HR = 2.36, 95%CI: 1.1-4.9), with an average difference in results between the two groups of 311 days (10 months).²¹21. Heuvers ME, Aerts JG, Hegmans JP, Veltman JD, Uitterlinden AG, Ruiter R, et al. History of tuberculosis as an independent prognostic factor for lung cancer survival. LungCancer . 2012;76(3):452-6. https://doi.org/10.1016/j.lungcan.2011.12.008
https://doi.org/10.1016/j.lungcan.2011.1...

Mechanism of MTb infection

Host macrophages (MQ) are the first ones to encounter MTb following the inhalation into the alveolar spaces. During this first stage, MQ will phagocyte the bacteria that may be exposed to toxic agents such as reactive oxygen species (ROS) and nitric oxide (NO). Afterwards, the bacterium will reside within the phagosome, where they are exposed to more cytotoxic factors such as lysosomal hydrolases, antimicrobial peptides and glutathione.²²22. Stokes RW, Waddell SJ. Adjusting to a new home: Mycobacterium tuberculosis gene expression in response to an intracellular lifestyle. Future Microbiol. 2009;4(10):1317-35. https://doi.org/10.2217/fmb.09.94
https://doi.org/10.2217/fmb.09.94... Meanwhile, this encounter also triggers the production of cytokines and chemokines by the MQ, which play pivotal roles in the induction of innate immunity, adaptive immunity and apoptosis. MTb is capable of blocking phago-lysosomal fusion and acidification, partially inhibiting the activation of MQ by Interferon Gamma (INF-γ) a major effector of the Th1 CD4 cell response.²³23. Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol. 2007;85(2):103-11. https://doi.org/10.1038/sj.icb.7100027
https://doi.org/10.1038/sj.icb.7100027... The result is bacterial killing and the persistence of some mycobacteria, leading to chronic antigenic stimulation and T-cell accumulation around MQ. The close apposition of MQ and lymphocytes is necessary to activate more MQ that will try to kill MTb. Thus, these cells congregate producing nodular structures called granulomas. The beginning of the granuloma takes part when MQ differentiate into epithelioid cells or activated MQ; some of them fuse forming giant cells. Within the resulting granuloma, there is a balance between killing and survival of MTb that leads to latent Tb infection. This process controls the infection in 95% of subjects, while the remainder progress to active Tb disease. It is estimated that 5-7% of the two billion subjects with latent Tb will have reactivation of the infection, and almost 30% of them will be co-infected with HIV.²³23. Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol. 2007;85(2):103-11. https://doi.org/10.1038/sj.icb.7100027
https://doi.org/10.1038/sj.icb.7100027... ^,2424. Marks GB, Bai J, Simpson SE, Sullivan EA, Stewart GJ. Incidence of tuberculosis among a cohort of tuberculin-positive refugees in Australia: reappraising the estimates of risk. Am J Respir Crit Care Med. 2000;162(5):1851-4. https://doi.org/10.1164/ajrccm.162.5.2004154
https://doi.org/10.1164/ajrccm.162.5.200...

Chronic inflammation and cancer

The pathophysiological mechanisms of this relationship have not been fully elucidated. However, there is vast preclinical and clinical evidence suggesting that strong and chronic inflammatory responses promote cancer development and progression through different mechanisms. Some hypothesis link lung epithelium DNA damage with the involvement of both free-radical-induced DNA damage and the maintenance of a pro-inflammatory and immunosuppressive cytokine network.²⁵25. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7. https://doi.org/10.1038/nature01322
https://doi.org/10.1038/nature01322... ^,2626. Engels EA. Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther. 2008;8(4):605-15. https://doi.org/10.1586/14737140.8.4.605
https://doi.org/10.1586/14737140.8.4.605...

In granulomas during active Tb, the intense inflammatory response against mycobacteria has the ability to generate tissue damage. Respiratory symptoms can last months before clinical diagnosis and treatment entails at least 6-9 months of multidrug treatment. During this extended time, it has been shown that MTb induces the release of inflammatory mediators such as tumor necrosis factor (TNF), INF-γ, IL-1, IL-2 and IL-12 causing inflammation of lung tissue,²⁷27. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201-9. https://doi.org/10.1086/444545
https://doi.org/10.1086/444545... ^,2828. Cooper AM, Khader SA. The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Immunol Rev. 2008;226(1):191-204. https://doi.org/10.1111/j.1600-065X. 2008 .00702.x
https://doi.org/https://doi.org/10.1111/... framing how inflammation might be conceived to be a cancer initiator or promoter. In addition, the tissue repair process characterized by high activity levels of fibroblasts, which synthesize extra-cellular matrix (ECM) components and eventually produce fibrosis, that may also be involved in the development of LC, related to the production of TGF-β, IL-4, IL-10, IL-3 and IL-13.²⁶26. Engels EA. Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther. 2008;8(4):605-15. https://doi.org/10.1586/14737140.8.4.605
https://doi.org/10.1586/14737140.8.4.605... ^,2727. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201-9. https://doi.org/10.1086/444545
https://doi.org/10.1086/444545... ^,2828. Cooper AM, Khader SA. The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Immunol Rev. 2008;226(1):191-204. https://doi.org/10.1111/j.1600-065X. 2008 .00702.x
https://doi.org/https://doi.org/10.1111/... The role that scarring may play in the pathogenesis of the neoplastic process is obscure; Tb-induced scars have been hypothesized to play an etiologic part in lung cancer for more than 70 years.¹¹11. Liang HY, Li XL, Yu XS, Guan P, Yin ZH, He QC, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer. 2009;125(12):2936-44. https://doi.org/10.1002/ijc.24636
https://doi.org/10.1002/ijc.24636... ^,2929. Auerbach O, Garfinkel L, Parks VR. Scar cancer of the lung: increase over a 21 year period. Cancer . 1979;43(2):636-42. https://doi.org/10.1002/1097-0142(197902)43:2<636::AID-CNCR2820430234>3.0.CO;2-7
https://doi.org/10.1002/1097-0142(197902... Tissue repair is associated with cellular proliferation, during which errors in chromosomal replication might lead to further DNA mutations. Some pro-inflammatory cytokines, such as TNF and IL-6, may also act directly on epithelial cells to up regulate the expression of anti-apoptotic genes through the NF-kB pathway.²⁷27. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201-9. https://doi.org/10.1086/444545
https://doi.org/10.1086/444545... Moreover, angiogenesis, the process of new blood vessel formation is a common feature of tissue repair and is also crucial for tumor growth. By creating an environment conducive to DNA mutation, cellular proliferation and angiogenesis, inflammation may thus initiate or promote cancer development.³⁰30. Ardies CM. Inflammation as cause for scar cancers of the lung. Integr Cancer Ther. 2003;2(3):238-46. https://doi.org/10.1177/153473540325633
https://doi.org/10.1177/153473540325633...

Gene transfer as a mechanism of neoplastic transformation

Lateral gene transfer (LGT) occurs most frequently between bacteria and their eukaryotic endosymbionts. Many pathogens, particularly viruses, promote cancer through well-described genetic disruption mechanisms,³¹31. Moore PS, Chang Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat RevCancer . 2010;10(12):878-89. https://doi.org/10.1038/nrc2961
https://doi.org/10.1038/nrc2961... but the only bacteria classified as a biological agent in the group 1 carcinogen is Helicobacter pylori which promotes the development of gastric cancer through epithelial injury and inflammation.³²32. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539-45. https://doi.org/10.1016/S0140-6736(00)04046-0
https://doi.org/10.1016/S0140-6736(00)04... ^,3333. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012;30:677-706. https://doi.org/10.1146/annurev-immunol-020711-075008
https://doi.org/10.1146/annurev-immunol-... ^,3434. Schwabe RF, Jobin C. The microbiome and cancer. Nat RevCancer . 2013;13(11):800-12. https://doi.org/10.1038/nrc3610
https://doi.org/10.1038/nrc3610... LGT is less common in mammals but in vitro experiments demonstrated that Bartonella henselae and Bartonella quintana are able to integrate their plasmid DNA into the human genome, making them one the few bacteria that could cause tumor formation in humans.³⁵35. Schroder G, Schuelein R, Quebatte M, Dehio C. Conjugative DNA transfer into human cells by the VirB/VirD4 type IV secretion system of the bacterial pathogen Bartonella henselae. Proc Natl Acad Sci USA. 2011;108(35):14643-8. https://doi.org/10.1073/pnas.1019074108
https://doi.org/10.1073/pnas.1019074108... ^,3636. Koehler JE, Sanchez MA, Garrido CS, Whitfeld MJ, Chen FM, Berger TG, et al. Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med. 1997;337(26):1876-83. https://doi.org/10.1056/NEJM199712253372603
https://doi.org/10.1056/NEJM199712253372... Riley and colleagues performed a bioinformatic analysis of the nuclear and mitochondrial genome in normal and tumor tissue from public available sequence data. They found frequent incidences of LGT involving Acinetobacter- and Pseudomonas-like DNA integrated via RNA intermediates in the human genomes from samples of acute myeloid leukemia with a higher rate of integration in cancer cells being more frequently integrated in the mitochondrial genome than in the nuclear genome. The cancer samples had a 210-fold higher frequency of integration of bacterial DNA than the normal tissue.³⁷37. Riley DR, Sieber KB, Robinson KM, White JR, Ganesan A, Nourbakhsh S, et al. Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples. PLoS Comput Biol. 2013;9(6):e1003107. https://doi.org/10.1371/journal.pcbi.1003107
https://doi.org/10.1371/journal.pcbi.100... Taking this in account and considering that mycobacteria is an intracellular bacteria, it will be interesting to explore if MTb can play an active role in the cellular transformation that promotes LC by LGT. In fact, we have recently found through DNA massive sequencing in some cases of adenocarcinoma, diverse mycobacterial genes integrated in the DNA of neoplastic cells (unpublished results).

EGFR mutations and their relation with tuberculosis

Improved treatment has been achieved with the development of targeted drugs for patients with actionable mutations.³⁸38. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. https://doi.org/10.1146/annurev-pathol-011110-130206
https://doi.org/10.1146/annurev-pathol-0... ^,3939. Campos-Parra AD, Zuloaga C, Manriquez ME, Aviles A, Borbolla-Escoboza J, Cardona A, et al. KRAS mutation as the biomarker of response to chemotherapy and EGFR-TKIs in patients with advanced non-small cell lung cancer: clues for its potential use in second-line therapy decision making. Am J Clin Oncol. 2015;38(1):33-40. https://doi.org/10.1097/COC.0b013e318287bb23
https://doi.org/10.1097/COC.0b013e318287... For instance, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are superior to chemotherapy in terms of objective response rate (ORR), progression free survival (PFS) and quality of life. The median overall survival (OS) for patients with advanced-stage NSCLC treated with TKIs is approximately 12 months and up to 18 months for patients with adenocarcinoma. It has been found that 70% of patients with increased response to TKI treatment harbour somatic EGFR gene mutations in the kinase domain.⁴⁰40. Arrieta O, Cardona AF, Martin C, Mas-Lopez L, Corrales-Rodriguez L, Bramuglia G, et al. Updated frequency of EGFR and KRAS mutations in nonsmall-cell lung cancer in Latin America: The Latin-American consortium for the Investigation of lung cancer (CLICaP). J Thorac Oncol. 2015;10(5):838-43. https://doi.org/10.1097/JTO.0000000000000481
https://doi.org/10.1097/JTO.000000000000... The most common EGFR mutations in patients with NSCLC include short in-frame deletions in exon 19 (Del19) and a specific point mutation in exon 21 at codon 858 (L858R).⁴¹41. Sakurada A, Shepherd FA, Tsao MS. Epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer: impact of primary or secondary mutations. Clinical lung cancer. 2006;7(Suppl 4):S138-44. https://doi.org/10.3816/CLC. 2006 .s.005
https://doi.org/10.3816/CLC. 2006 .s.005...

Reports regarding the impact on the incidence and the outcome of patients with a history of Tb with LC and EGFR mutations are scarce. A report from Taiwan observed a higher incidence (OR: 1.83 ENT#091;0.92-3.62ENT#093;) of EGFR mutations in patients with lung adenocarcinoma who had radiographic evidence compatible with old Tb pulmonary lesions.⁴²42. Luo YH, Wu CH, Wu WS, Huang CY, Su WJ, Tsai CM, et al. Association between tumor epidermal growth factor receptor mutation and pulmonary tuberculosis in patients with adenocarcinoma of the lungs. Journal Thorac Oncol. 2012;7(2):299-305. https://doi.org/10.1097/JTO.0b013e31823c588d
https://doi.org/10.1097/JTO.0b013e31823c... Another retrospective study that analyzed the National Health Insurance Research Database of Taiwan, included 8 265 patients with LC who received EGFR-TKIs between 1996 and 2000 reported that a history of pulmonary Tb is associated with poor clinical response to EGFR-TKIs in male patients but better response in female patients.⁴³43. Chang CH, Lee CH, Ho CC, Wang JY, Yu CJ. Gender-based impact of epidermal growth factor receptor mutation in patients with nonsmall cell lung cancer and previous tuberculosis. Medicine (Baltimore). 2015;94(4):e444. https://doi.org/10.1097/MD.0000000000000444
https://doi.org/10.1097/MD.0000000000000... Tb is one of the most common chronic pulmonary infections leading to chronic inflammation, which has been related to EGFR mutation. Some examples are Nitric oxide-induced (iNOS) EGFR-dependent phosphorylation in A431 tumor cells⁴⁴44. Ruano MJ, Hernandez-Hernando S, Jimenez A, Estrada C, Villalobo A. Nitric oxide-induced epidermal growth factor-dependent phosphorylations in A431 tumour cells. Eur J Biochem. 2003;270(8):1828-37. https://doi.org/10.1046/j.1432-1033.2003.03546.x
https://doi.org/10.1046/j.1432-1033.2003... or the increased expression of epiregulin in invasive EGFR-mutant cells with high invasive properties⁴⁵45. Zhang J, Iwanaga K, Choi KC, Wislez M, Raso MG, Wei W, et al. Intratumoral epiregulin is a marker of advanced disease in non-small cell lung cancer patients and confers invasive properties on EGFR-mutant cells. Cancer Prev Res (Phila). 2008;1(3):201-7. https://doi.org/10.1158/1940-6207.CAPR-08-0014
https://doi.org/10.1158/1940-6207.CAPR-0... have been reported before, both (iNOS and epiregulin) of them showed an increased expression during the course of chronic inflammation in animal models.⁴³43. Chang CH, Lee CH, Ho CC, Wang JY, Yu CJ. Gender-based impact of epidermal growth factor receptor mutation in patients with nonsmall cell lung cancer and previous tuberculosis. Medicine (Baltimore). 2015;94(4):e444. https://doi.org/10.1097/MD.0000000000000444
https://doi.org/10.1097/MD.0000000000000... ^,4646. Nalbandian A, Yan BS, Pichugin A, Bronson RT, Kramnik I. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene. 2009;28(17):1928-38. https://doi.org/10.1038/onc.2009.32
https://doi.org/10.1038/onc.2009.32... These observations suggested the existence of a relationship between pulmonary Tb and EGFR mutations in patients with lung adenocarcinoma. However, the detailed pathophysiology remains to be studied.

Conclusions

The epidemiological association between Tb infection and LC is well documented. Nevertheless, the molecular mechanisms by which TB promotes the development and progression of LC remains unknown.

The main hypothesis for the association between LC and Tb suggests strong and chronic inflammatory responses during the chronic infection, promote cancer development and progression creating an environment favorable to DNA mutation, cellular proliferation and angiogenesis. Furthermore, there is evidence describing how MTb is capable of partially inhibiting the activation of the immune response on its favor,²³23. Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol. 2007;85(2):103-11. https://doi.org/10.1038/sj.icb.7100027
https://doi.org/10.1038/sj.icb.7100027... therefore, it is not unreasonable to explore the new hypothesis where MTb participates actively in the cellular transformation that leads to cancer. Many pathogens promote cancer through well-described genetic disruption mechanisms like LGT, and there is increasing evidence of the presence of genetic material in different types of cancer.³⁵35. Schroder G, Schuelein R, Quebatte M, Dehio C. Conjugative DNA transfer into human cells by the VirB/VirD4 type IV secretion system of the bacterial pathogen Bartonella henselae. Proc Natl Acad Sci USA. 2011;108(35):14643-8. https://doi.org/10.1073/pnas.1019074108
https://doi.org/10.1073/pnas.1019074108... ^,3636. Koehler JE, Sanchez MA, Garrido CS, Whitfeld MJ, Chen FM, Berger TG, et al. Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med. 1997;337(26):1876-83. https://doi.org/10.1056/NEJM199712253372603
https://doi.org/10.1056/NEJM199712253372... ^,3737. Riley DR, Sieber KB, Robinson KM, White JR, Ganesan A, Nourbakhsh S, et al. Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples. PLoS Comput Biol. 2013;9(6):e1003107. https://doi.org/10.1371/journal.pcbi.1003107
https://doi.org/10.1371/journal.pcbi.100... Further work will uncover the mechanistic relationship between Tb and LC, and will determine the relevance of the possible active participation of MTb in the development of LC.

References

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