Gen Thorac Cardiovasc Surg DOI 10.1007/s11748-014-0386-x
CURRENT TOPICS REVIEW ARTICLE
Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment Yasuo Sekine • Atsushi Hata • Eitetsu Koh Kenzo Hiroshima
•
Received: 19 January 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8–1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-jB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-jB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-jB and STAT3 also contribute to epithelial–mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of
This review was submitted at the invitation of the editorial committee. Y. Sekine (&) A. Hata E. Koh Department of Thoracic Surgery, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan e-mail: [email protected] K. Hiroshima Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan
lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy. Keywords Chronic obstructive pulmonary disease Lung cancer Carcinogenesis Cancer stem cells Signal transducers
Introduction Both chronic obstructive pulmonary disease (COPD) and lung cancer are worldwide health problems, and COPD is a major risk factor for lung cancer. In 2011, the World Health Organization (WHO) reported that lower respiratory tract infection was the third most common cause of death (3.2 million deaths), COPD was the fourth most common (3.0 million deaths), and lung cancer was the seventh most common (1.5 million deaths) worldwide [1]. Since COPD is thought to lead to lung cancer and lower respiratory tract infection, this condition should be considered as one of the most critical fatal diseases. Exposure to toxic gases and particulates, particularly those in cigarette smoke, is well known to induce both diseases. COPD has been reported to be a risk factor for lung cancer independent of cigarette smoking [2, 3]. We previously reviewed the epidemiology and etiology of lung cancer associated with COPD and discussed the importance of early detection of COPD for lung cancer surveillance [4]. In this article, we review the characteristics of lung cancer due to COPD and the pathogenesis of the
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progression of COPD to lung cancer, with particular emphasis on the contribution of signal transducers, lung stem cells, and cancer stem cells (CSCs) in the inflammatory microenvironment. The risk of lung cancer from COPD Reports have shown that between 50 and 80 % of patients diagnosed with lung cancer had pre-existing COPD [5, 6] and that the prevalence of COPD in lung cancer ranges from 8 to 50 % [7, 8]. The annual incidence of lung cancer arising from COPD has been reported to be 0.8–1.7 % [9– 11]. Sin et al. summarized several series on the underlying causes of death in COPD patients [12]. These investigators reported that the primary causes of death in those with mild or moderate COPD were lung cancer and cardiovascular diseases, while in those with more advanced COPD (\60 % of predicted FEV1), respiratory failure was the predominant cause. These results suggest that early detection of both COPD and lung cancer is required to improve survival and maintain quality of life (QOL) in patients with COPD [4, 13]. The severity of COPD also influences the incidence of lung cancer. The first National Health and Nutrition Examination Survey (NHANES I) collected data from a 22-year follow-up of 5,402 participants and demonstrated a positive correlation between the degree of airflow obstruction and lung cancer incidence [14]. Multivariate proportional hazards analysis of the data in this survey showed that mild COPD was associated with a relatively higher risk (HR 1.4; 95 % CI 0.8–2.6) and that moderate or severe COPD was associated with a significantly higher risk of lung cancer compared to normal pulmonary function (HR 2.8; 95 % CI 1.8–4.4). Calabro et al. [15] reported that a reduction of as little as 10 % in the predicted FEV1 was associated with a nearly threefold greater lung cancer risk. These authors suggested that recognition of minimal lung function impairment might identify the best candidates for enrollment in lung cancer early detection and screening clinical trials. Because only 15–20 % of smokers are thought to develop lung cancer and/or COPD in their lifetime, individuals appear to have different susceptibilities to these diseases [16]. Cohen first reported on the genetic epidemiology of COPD [17]. Patients whose first-degree relatives had COPD or lung cancer had an increased risk for airflow limitation, independent of smoking history. Furthermore, smokers with a family history of early-onset lung cancer among first-degree relatives had a higher risk of lung cancer development with increasing age compared to smokers without a family history [18]. These findings suggest the presence of susceptibility genes associated with these diseases [19].
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The impact of COPD on lung cancer surgery One-fourth to one-third of lung cancer patients who undergo surgery have COPD [20, 21]. We analyzed various characteristics of lung cancer patients with COPD who underwent surgical resection. Although the most frequent lung cancer histology in patients with non-COPD and mild COPD was adenocarcinoma, those with moderate to severe COPD were more likely to have squamous cell carcinoma [20]. More advanced cancer stage was associated with increasing COPD severity [20]. Postoperative complications, including supraventricular tachycardia [22], pneumonia, prolonged air leak, prolonged oxygen supplementation [23, 24], and need for tracheostomy [24], were more frequent in patients with COPD compared to those without COPD. Long-term survival after lung cancer surgery decreased according to the severity of COPD [20]. Since low-grade malignancy such as well-differentiated adenocarcinoma is frequently observed in patients without COPD, long-term survival in patients with COPD was worse than that in patients without COPD due to frequent tumor recurrence [20, 24]. Furthermore, patients with combined pulmonary fibrosis and emphysema (CPFE) or COPD had a worse prognosis after lung cancer surgery compared to those without fibrosis due to more frequent occurrence of acute lung injury and respiratory insufficiency [25, 26]. However, when COPD can be well managed following lung cancer surgery, postoperative pulmonary function and QOL can be well preserved [27–29]. The most important factors for perioperative management in lung cancer patients with COPD include pulmonary rehabilitation [27] and appropriate use of antibiotics [30] and bronchodilators [28]. Through these careful management strategies, patients with COPD can preserve higher pulmonary function than expected [29]. To overcome lung cancer due to COPD in the future, lung cancer must be detected as early as possible [4, 13], and an appropriate limited resection technique such as segmentectomy [31, 32] or partial resection [32] must be selected. Molecular biological relationship between COPD and lung cancer The biological features of COPD include intense immune inflammation, degradation of extracellular matrix, ineffective tissue repair, increased apoptosis, and limited angiogenesis. In contrast, lung cancer is characterized by DNA damage, ineffective DNA repair, sustained angiogenesis, genetic instability, limited cell replication, apoptosis evasion, and tissue invasion [33]. Several possible pathogenic pathways from COPD to lung cancer have been proposed. First, mucociliary
Gen Thorac Cardiovasc Surg Fig. 1 Cycles of tissue injury and repair and carcinogenesis. Reactive oxygen species (ROS), radiation, toxins, and carcinogens induce cell damage and lead to induction of necrotic cell death and loss of tissue integrity. The cycles of tissue injury and repair progress to carcinogenesis in the inflammatory microenvironment (with permission of modified reproduction from a publisher [36])
Fig. 2 The relationship between putative normal lung stem cell markers and lung cancer stem cell markers in each anatomic location during lung cancer development (with permission of modified reproduction from a publisher [39])
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Fig. 3 Interaction between STAT3 and NF-jB in carcinogenesis in an inflammatory microenvironment (with permission of modified reproduction from a publisher [36])
dysfunction caused by smoking results in the accumulation of toxicants in the airway. Second, an imbalance between oxidants and antioxidants can lead to free radical damage to DNA. Third, genetic mutations and polymorphisms may influence the acceleration or suppression of lung cancer development. Fourth, chronic inflammation can lead to chronic mitogenesis and increase the likelihood of the conversion of endogenous DNA damage into mutations [4]. Many candidate susceptibility genes are involved in these processes, including COX-2, NF-jB, IL-1b, IL-6, STAT3, neutrophil elastase, IL-8 in neutrophils, and MIF in macrophages during inflammation, as well mutation and polymorphisms in Kras, p53, p16, GSTM1, CYP2A6, nAChR, HHIP, and GYPA [4, 34]. Although lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusions respond to treatment by EGFR and ALK inhibition, respectively, few genetic aberrations and therapeutically effective driver oncogenes have yet been identified in patients with lung cancer derived from COPD. Recently, several gene modifications in squamous cell carcinoma, representing possible driver oncogenes, have been reported, including fibroblast growth factor receptor 1 (FGFR1), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), and CDKN2A (p16). Weiss et al. [35] identified frequent and focal FGFR1 amplification in
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squamous cell lung cancer. These potentially strong driver oncogenes have not yet led to new treatment options; therefore, further studies are required to develop appropriate molecularly targeted therapies. Carcinogenesis from COPD and contributions of lung stem cells and CSCs Chronic inflammation has been shown to lead to cancer in many organs. For example, chronic hepatitis due to hepatitis virus C infection contributes to the development of hepatocellular carcinoma, Helicobacter pylori gastric inflammation is associated with gastric cancer, ulcerative colitis leads to colon cancer, asbestosis is associated with malignant mesothelioma, and COPD/interstitial pneumonia causes lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during tissue injury and repair cycles (Fig. 1) [36]. Cellular damage can induce two fundamental processes: necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, in a chronic inflammatory environment, since inflammation generates mediators that are potentially genotoxic, the injury–repair cycle progresses to carcinogenesis. Inflammatory mediators in the microenvironment have been proposed to promote bronchioalveolar stem cells (BASCs) to induce proneoplastic mutations, proliferation,
Gen Thorac Cardiovasc Surg
Fig. 4 Putative mechanism of lung carcinogenesis from COPD. Oxidative stress from cigarette smoke stimulates the NF-jB pathway in lung epithelium and recruits inflammatory cells that release cytokines and chemokines. Released matrix metalloproteinases (MMPs) and ROS induce inflammation, apoptosis, matrix degradation, and ineffective tissue repair, leading to enlarged airspaces.
Bronchioalveolar stem cells may attempt to repair and replace damaged alveolar cells, but enhance carcinogenesis in an inflammatory environment. Persistent activation of the STAT3 signaling pathway and EMT also induce pulmonary inflammation and carcinogenesis and development in the lung (with permission of modified reproduction from a publisher [4])
resistance to apoptosis, angiogenesis, invasion, metastasis, and secretion of immunosuppressive factors [37, 38]. Kratz et al. [39] reviewed the major studies supporting the existence and importance of CSCs in lung tumorigenesis (Fig. 2). These investigators reported that evidence exists to support the presence of adult stem cells in each of the epithelial compartments and that this is caused by the influence of the microenvironment on the transformation and progression of lung CSCs from lung stem cells. Putative CSC surface markers and characteristics of stem cells, representing possible lung CSC phenotypes, have been identified in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): side population (SP), CD133, aldehyde dehydrogenase (ALDH),
CD166, CD44, and nuclear b-catenin have been recognized in NSCLC, and SP and CD133 have been observed in SCLC [40]. CSCs may be responsible for disease recurrence after definitive therapy and therefore represent possible therapeutic targets for maintenance therapy in this patient population. Transcription factors in carcinogenesis and tumor progression Reactive oxygen species (ROS) from cigarette smoke directly induce biological features of both COPD and lung cancer. Furthermore, lung carcinogenesis and tumor growth and progression can be initiated by activation of
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inflammatory cytokine/chemokine production and mutational activation in cancer cells in COPD. Many transcription factors as well as lung stem cells play pivotal roles in this inflammatory environment [41, 42]. Grivennikov et al. [41] reported that the activation of and interaction between signal transducer and activator of transcription 3 (STAT3) and NF-jB play a key role in controlling the dialog between the malignant cell and its microenvironment, particularly with inflammatory/immune cells that infiltrate tumors (Fig. 3). Many of the protumorgenic effects of NF-jB and STAT3 activation in immune cells are mediated through paracrine signaling via a network of pro-inflammatory cytokines that further control NF-jB activity. NF-jB and STAT3 also contribute to epithelial–mesenchymal transition (EMT). In the inflammatory microenvironment, malignant cells progress from an epithelial-like state to a fibroblast-like state, thereby facilitating invasion and metastasis. Many intracellular signaling pathways have been implicated in both COPD and lung cancer, including GTPase signaling pathways and the signaling molecules PI3K, NF-jB, and STAT3. These pathways are probably activated as part of an inflammatory–repair process that promotes EMT and involves embryological pathway components [43]. Based on the reviews discussed above, we proposed a putative mechanism of lung carcinogenesis from COPD in the inflammatory microenvironment (Fig. 4) [4]. However, multiple mechanisms may contribute to carcinogenesis from COPD. Therefore, our proposed mechanism may only be one component of a more complex process.
Conclusion Recent advances in the development of molecularly targeted drugs for lung cancer promise dramatic prolongation of survival in specific gene-mutated patients, primarily those who are non-smokers and have adenocarcinoma. However, the majority of lung cancer patients are smokers and have COPD. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. Further investigation and accurate interpretation of the mechanisms underlying the progression of COPD to lung cancer are critical, and the associated clinical implications with respect to lung cancer prevention, screening, and treatment should be clarified. Acknowledgments This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y. Sekine (No. 23592075). Conflict of interest All authors have declared no conflicts of interest.
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CURRENT TOPICS REVIEW ARTICLE
Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment Yasuo Sekine • Atsushi Hata • Eitetsu Koh Kenzo Hiroshima
•
Received: 19 January 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8–1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-jB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-jB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-jB and STAT3 also contribute to epithelial–mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of
This review was submitted at the invitation of the editorial committee. Y. Sekine (&) A. Hata E. Koh Department of Thoracic Surgery, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan e-mail: [email protected] K. Hiroshima Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba 276-8524, Japan
lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy. Keywords Chronic obstructive pulmonary disease Lung cancer Carcinogenesis Cancer stem cells Signal transducers
Introduction Both chronic obstructive pulmonary disease (COPD) and lung cancer are worldwide health problems, and COPD is a major risk factor for lung cancer. In 2011, the World Health Organization (WHO) reported that lower respiratory tract infection was the third most common cause of death (3.2 million deaths), COPD was the fourth most common (3.0 million deaths), and lung cancer was the seventh most common (1.5 million deaths) worldwide [1]. Since COPD is thought to lead to lung cancer and lower respiratory tract infection, this condition should be considered as one of the most critical fatal diseases. Exposure to toxic gases and particulates, particularly those in cigarette smoke, is well known to induce both diseases. COPD has been reported to be a risk factor for lung cancer independent of cigarette smoking [2, 3]. We previously reviewed the epidemiology and etiology of lung cancer associated with COPD and discussed the importance of early detection of COPD for lung cancer surveillance [4]. In this article, we review the characteristics of lung cancer due to COPD and the pathogenesis of the
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progression of COPD to lung cancer, with particular emphasis on the contribution of signal transducers, lung stem cells, and cancer stem cells (CSCs) in the inflammatory microenvironment. The risk of lung cancer from COPD Reports have shown that between 50 and 80 % of patients diagnosed with lung cancer had pre-existing COPD [5, 6] and that the prevalence of COPD in lung cancer ranges from 8 to 50 % [7, 8]. The annual incidence of lung cancer arising from COPD has been reported to be 0.8–1.7 % [9– 11]. Sin et al. summarized several series on the underlying causes of death in COPD patients [12]. These investigators reported that the primary causes of death in those with mild or moderate COPD were lung cancer and cardiovascular diseases, while in those with more advanced COPD (\60 % of predicted FEV1), respiratory failure was the predominant cause. These results suggest that early detection of both COPD and lung cancer is required to improve survival and maintain quality of life (QOL) in patients with COPD [4, 13]. The severity of COPD also influences the incidence of lung cancer. The first National Health and Nutrition Examination Survey (NHANES I) collected data from a 22-year follow-up of 5,402 participants and demonstrated a positive correlation between the degree of airflow obstruction and lung cancer incidence [14]. Multivariate proportional hazards analysis of the data in this survey showed that mild COPD was associated with a relatively higher risk (HR 1.4; 95 % CI 0.8–2.6) and that moderate or severe COPD was associated with a significantly higher risk of lung cancer compared to normal pulmonary function (HR 2.8; 95 % CI 1.8–4.4). Calabro et al. [15] reported that a reduction of as little as 10 % in the predicted FEV1 was associated with a nearly threefold greater lung cancer risk. These authors suggested that recognition of minimal lung function impairment might identify the best candidates for enrollment in lung cancer early detection and screening clinical trials. Because only 15–20 % of smokers are thought to develop lung cancer and/or COPD in their lifetime, individuals appear to have different susceptibilities to these diseases [16]. Cohen first reported on the genetic epidemiology of COPD [17]. Patients whose first-degree relatives had COPD or lung cancer had an increased risk for airflow limitation, independent of smoking history. Furthermore, smokers with a family history of early-onset lung cancer among first-degree relatives had a higher risk of lung cancer development with increasing age compared to smokers without a family history [18]. These findings suggest the presence of susceptibility genes associated with these diseases [19].
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The impact of COPD on lung cancer surgery One-fourth to one-third of lung cancer patients who undergo surgery have COPD [20, 21]. We analyzed various characteristics of lung cancer patients with COPD who underwent surgical resection. Although the most frequent lung cancer histology in patients with non-COPD and mild COPD was adenocarcinoma, those with moderate to severe COPD were more likely to have squamous cell carcinoma [20]. More advanced cancer stage was associated with increasing COPD severity [20]. Postoperative complications, including supraventricular tachycardia [22], pneumonia, prolonged air leak, prolonged oxygen supplementation [23, 24], and need for tracheostomy [24], were more frequent in patients with COPD compared to those without COPD. Long-term survival after lung cancer surgery decreased according to the severity of COPD [20]. Since low-grade malignancy such as well-differentiated adenocarcinoma is frequently observed in patients without COPD, long-term survival in patients with COPD was worse than that in patients without COPD due to frequent tumor recurrence [20, 24]. Furthermore, patients with combined pulmonary fibrosis and emphysema (CPFE) or COPD had a worse prognosis after lung cancer surgery compared to those without fibrosis due to more frequent occurrence of acute lung injury and respiratory insufficiency [25, 26]. However, when COPD can be well managed following lung cancer surgery, postoperative pulmonary function and QOL can be well preserved [27–29]. The most important factors for perioperative management in lung cancer patients with COPD include pulmonary rehabilitation [27] and appropriate use of antibiotics [30] and bronchodilators [28]. Through these careful management strategies, patients with COPD can preserve higher pulmonary function than expected [29]. To overcome lung cancer due to COPD in the future, lung cancer must be detected as early as possible [4, 13], and an appropriate limited resection technique such as segmentectomy [31, 32] or partial resection [32] must be selected. Molecular biological relationship between COPD and lung cancer The biological features of COPD include intense immune inflammation, degradation of extracellular matrix, ineffective tissue repair, increased apoptosis, and limited angiogenesis. In contrast, lung cancer is characterized by DNA damage, ineffective DNA repair, sustained angiogenesis, genetic instability, limited cell replication, apoptosis evasion, and tissue invasion [33]. Several possible pathogenic pathways from COPD to lung cancer have been proposed. First, mucociliary
Gen Thorac Cardiovasc Surg Fig. 1 Cycles of tissue injury and repair and carcinogenesis. Reactive oxygen species (ROS), radiation, toxins, and carcinogens induce cell damage and lead to induction of necrotic cell death and loss of tissue integrity. The cycles of tissue injury and repair progress to carcinogenesis in the inflammatory microenvironment (with permission of modified reproduction from a publisher [36])
Fig. 2 The relationship between putative normal lung stem cell markers and lung cancer stem cell markers in each anatomic location during lung cancer development (with permission of modified reproduction from a publisher [39])
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Fig. 3 Interaction between STAT3 and NF-jB in carcinogenesis in an inflammatory microenvironment (with permission of modified reproduction from a publisher [36])
dysfunction caused by smoking results in the accumulation of toxicants in the airway. Second, an imbalance between oxidants and antioxidants can lead to free radical damage to DNA. Third, genetic mutations and polymorphisms may influence the acceleration or suppression of lung cancer development. Fourth, chronic inflammation can lead to chronic mitogenesis and increase the likelihood of the conversion of endogenous DNA damage into mutations [4]. Many candidate susceptibility genes are involved in these processes, including COX-2, NF-jB, IL-1b, IL-6, STAT3, neutrophil elastase, IL-8 in neutrophils, and MIF in macrophages during inflammation, as well mutation and polymorphisms in Kras, p53, p16, GSTM1, CYP2A6, nAChR, HHIP, and GYPA [4, 34]. Although lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusions respond to treatment by EGFR and ALK inhibition, respectively, few genetic aberrations and therapeutically effective driver oncogenes have yet been identified in patients with lung cancer derived from COPD. Recently, several gene modifications in squamous cell carcinoma, representing possible driver oncogenes, have been reported, including fibroblast growth factor receptor 1 (FGFR1), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), and CDKN2A (p16). Weiss et al. [35] identified frequent and focal FGFR1 amplification in
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squamous cell lung cancer. These potentially strong driver oncogenes have not yet led to new treatment options; therefore, further studies are required to develop appropriate molecularly targeted therapies. Carcinogenesis from COPD and contributions of lung stem cells and CSCs Chronic inflammation has been shown to lead to cancer in many organs. For example, chronic hepatitis due to hepatitis virus C infection contributes to the development of hepatocellular carcinoma, Helicobacter pylori gastric inflammation is associated with gastric cancer, ulcerative colitis leads to colon cancer, asbestosis is associated with malignant mesothelioma, and COPD/interstitial pneumonia causes lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during tissue injury and repair cycles (Fig. 1) [36]. Cellular damage can induce two fundamental processes: necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, in a chronic inflammatory environment, since inflammation generates mediators that are potentially genotoxic, the injury–repair cycle progresses to carcinogenesis. Inflammatory mediators in the microenvironment have been proposed to promote bronchioalveolar stem cells (BASCs) to induce proneoplastic mutations, proliferation,
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Fig. 4 Putative mechanism of lung carcinogenesis from COPD. Oxidative stress from cigarette smoke stimulates the NF-jB pathway in lung epithelium and recruits inflammatory cells that release cytokines and chemokines. Released matrix metalloproteinases (MMPs) and ROS induce inflammation, apoptosis, matrix degradation, and ineffective tissue repair, leading to enlarged airspaces.
Bronchioalveolar stem cells may attempt to repair and replace damaged alveolar cells, but enhance carcinogenesis in an inflammatory environment. Persistent activation of the STAT3 signaling pathway and EMT also induce pulmonary inflammation and carcinogenesis and development in the lung (with permission of modified reproduction from a publisher [4])
resistance to apoptosis, angiogenesis, invasion, metastasis, and secretion of immunosuppressive factors [37, 38]. Kratz et al. [39] reviewed the major studies supporting the existence and importance of CSCs in lung tumorigenesis (Fig. 2). These investigators reported that evidence exists to support the presence of adult stem cells in each of the epithelial compartments and that this is caused by the influence of the microenvironment on the transformation and progression of lung CSCs from lung stem cells. Putative CSC surface markers and characteristics of stem cells, representing possible lung CSC phenotypes, have been identified in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): side population (SP), CD133, aldehyde dehydrogenase (ALDH),
CD166, CD44, and nuclear b-catenin have been recognized in NSCLC, and SP and CD133 have been observed in SCLC [40]. CSCs may be responsible for disease recurrence after definitive therapy and therefore represent possible therapeutic targets for maintenance therapy in this patient population. Transcription factors in carcinogenesis and tumor progression Reactive oxygen species (ROS) from cigarette smoke directly induce biological features of both COPD and lung cancer. Furthermore, lung carcinogenesis and tumor growth and progression can be initiated by activation of
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inflammatory cytokine/chemokine production and mutational activation in cancer cells in COPD. Many transcription factors as well as lung stem cells play pivotal roles in this inflammatory environment [41, 42]. Grivennikov et al. [41] reported that the activation of and interaction between signal transducer and activator of transcription 3 (STAT3) and NF-jB play a key role in controlling the dialog between the malignant cell and its microenvironment, particularly with inflammatory/immune cells that infiltrate tumors (Fig. 3). Many of the protumorgenic effects of NF-jB and STAT3 activation in immune cells are mediated through paracrine signaling via a network of pro-inflammatory cytokines that further control NF-jB activity. NF-jB and STAT3 also contribute to epithelial–mesenchymal transition (EMT). In the inflammatory microenvironment, malignant cells progress from an epithelial-like state to a fibroblast-like state, thereby facilitating invasion and metastasis. Many intracellular signaling pathways have been implicated in both COPD and lung cancer, including GTPase signaling pathways and the signaling molecules PI3K, NF-jB, and STAT3. These pathways are probably activated as part of an inflammatory–repair process that promotes EMT and involves embryological pathway components [43]. Based on the reviews discussed above, we proposed a putative mechanism of lung carcinogenesis from COPD in the inflammatory microenvironment (Fig. 4) [4]. However, multiple mechanisms may contribute to carcinogenesis from COPD. Therefore, our proposed mechanism may only be one component of a more complex process.
Conclusion Recent advances in the development of molecularly targeted drugs for lung cancer promise dramatic prolongation of survival in specific gene-mutated patients, primarily those who are non-smokers and have adenocarcinoma. However, the majority of lung cancer patients are smokers and have COPD. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. Further investigation and accurate interpretation of the mechanisms underlying the progression of COPD to lung cancer are critical, and the associated clinical implications with respect to lung cancer prevention, screening, and treatment should be clarified. Acknowledgments This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y. Sekine (No. 23592075). Conflict of interest All authors have declared no conflicts of interest.
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