What is the role of nonalcoholic fatty liver disease in pulmonary carcinoma development?

Abstract

This article summarizes the epidemiological characteristics and clinical manifestations of nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD has been increased dramatically and become the leading cause of chronic liver disease worldwide. In addition to its adverse outcomes of liver fibrosis, cirrhosis, and hepatocellular carcinoma, and related complications, NAFLD has recently been found to be associated with the high-risk extrahepatic carcinomas, such as various types of lung cancer (i.e., lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer). The presence of hepatic steatosis also predisposes lung cancer to liver metastasis, but has better response to immune checkpoint inhibitors. Whether other factors (i.e., gender, smoking, etc.) are associated with NAFLD and lung cancer remains controversial. We also comment on the reciprocal relationships between NAFLD and components of metabolic syndrome. Most metabolic syndrome components are suggested to facilitate lung cancer development via activating insulin/insulin-like growth factor axis. In addition, suppressed anti-tumor immunity and accelerated tumor progression could be attributed to the cell-specific metabolic reprogramming in condition of high-fat diet and related obesity. These findings may reveal the role of NAFLD in pulmonary carcinoma and help develop new treatment strategies for this disease.

Key Words: Nonalcoholic fatty liver disease; Lung; Cancer; Adenocarcinoma; Metabolic syndrome; Component

Core Tip: The increasing incidence of nonalcoholic fatty liver disease (NAFLD) has led to a public health burden, which is even worse due to its close association with lung cancer. Limited understanding of this phenomenon hinders the prevention, diagnosis, and treatment of NAFLD-related lung cancer. This article presents the effects of NAFLD on the progression, pathological subtypes, metastasis, and treatment response of lung cancer. Moreover, the mechanisms underlying the NAFLD-related metabolic disorders, metabolic syndrome-dependent immune impairment and tumor growth are discussed. These findings may provide insights into the role of NAFLD in pulmonary carcinoma, and highlights new treatment strategies for this disease.

INTRODUCTION

With the exclusion of nonmetabolic etiologies (i.e., alcoholic abuse, chronic hepatitis C, and chemical toxication), nonalcoholic fatty liver disease (NAFLD) reflects the pathological manifestation of hepatocyte steatosis based on metabolic stress[1]. It has been described to range from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), resulting in liver fibrosis/cirrhosis, hepatocellular carcinoma (HCC), and related death[2]. In contrast to the simple steatosis in NAFLD, NASH patients display pathological characteristics of hepatocyte steatosis, ballooning, and lobular inflammation according to the NAFLD activity score or Steatosis, Activity, Fibrosis score, with or without liver fibrosis[1-3]. Over the past several decades, the pooled, ultrasound-confirmed prevalence of NAFLD has increased to 30.69% worldwide (44.37% in Latin America, 36.53% in Middle East and North Africa, 33.83% in South Asia, 33.07% in South-East Asia, 31.20% in North America, 29.71% in East Asia, 28.02% in Asia Pacific, 25.10% in Western Europe), although the precise rate varies with factors such as gender, age, occupation, and region[4]. Nowadays, the incidence of NAFLD has already exceeded chronic viral hepatitis (i.e., chronic hepatitis B and chronic hepatitis C) and become the leading cause of chronic liver diseases in China, responsible for approximately 49.3% of the total[5]. Nevertheless, metabolic dysfunction-associated fatty liver disease or metabolic dysfunction-associated steatotic liver disease is recently proposed with definitions similar to those of NAFLD[6-9].

EFFECTS OF NAFLD ON LUNG CANCER

Except for its impact on hepatic injury, fibrosis/cirrhosis, HCC, and related complications, NAFLD demonstrates close association with extrahepatic carcinoma in multiple organs, such as lung, uterine, gallbladder, kidney, thyroid, esophagus, pancreas, bladder, colorectum, breast, prostate, and anus[10-15]. The total incidence of extrahepatic cancers is over 8 times higher than that of HCC in NAFLD patients[11]. Furthermore, accumulating evidence has revealed primary bronchogenic carcinoma (lung cancer), comprising subtype of small cell lung cancer and non-small cell lung cancer (lung squamous cell carcinoma, lung adenocarcinoma, etc.), to be one of the frequent types of cancers affected by NAFLD[10-15]. Being characterized by the gland and/or duct formation and the mucus production, pulmonary adenocarcinoma among these ones exhibits derivation of airways and the location in the periphery of the lung[15]. Pulmonary adenocarcinoma, characterized by gland and/or duct formation and mucus production, is derived from airways and located in the periphery of the lung[15]. In contrast, small cell lung cancer and lung squamous cell carcinoma tend to originate centrally[15].

Systematic review and meta-analysis shed light on the high incidence rate of lung cancer (1.35 per 1000 person-years) in patients with NAFLD[11]. A meta-analysis of 5 cohort studies included 837 cases of lung cancer in a total of 140014 individuals, with the rate of NAFLD of 26.8%, in a median of 8.5 years[12]. Of 2844 Chinese cases, the ratio of NAFLD in patients with lung adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and other types of lung cancer is 24.4%, 16.1%, 18.1%, and 20.4%, respectively[15]. The association between NAFLD and various types of lung cancer shows statistical significance. By pooled random-effects, NAFLD patients have a 30% increase in the risk of developing lung cancer[12]. In addition, a community-based, large cohort study highlights the intimate association of NAFLD and prominent risk of lung cancer [hazard ratio (HR) = 1.23][13].

Stratified analyses based on the United Kingdom Biobank study identify that the association between metabolic dysfunction-associated fatty liver disease and lung cancer is more prominent in women (HR = 1.21), with a much higher risk ratio in menopausal women than in their premenopausal counterparts (HR = 1.24 vs 0.80)[10]. In contrast, men with NAFLD display a higher risk of extrahepatic cancers (thyroid and lung cancer) than others in a Chinese cohort study[13]. When compared to those in other subtypes of lung cancer, proportions of multiple parameters, including female, nonsmoker, obesity, NAFLD, and serum lipid, seem to be significantly higher in patients with lung adenocarcinoma[15]. However, Wang et al[13] have reported that NAFLD only increases the risk of lung cancer in smokers (HR = 1.38). In addition, liver metastasis-free survival of non-small cell lung cancer seems to be poorer in the presence of hepatic steatosis[16]. Multivariate regression analysis further verifies hepatic steatosis as an independent risk factor for liver metastasis (HR = 1.43)[16]. But liver metastasis of non-small cell lung cancer responds better to immune checkpoint inhibitor-based treatment in the NASH-affected liver[17]. Thus, NAFLD is suggested to exert great impact on the susceptibility, natural history, and therapeutic effects of lung cancer regardless of its histopathological subtypes.

ASSOCIATION OF NAFLD AND METABOLIC SYNDROME

NAFLD has already been well described to affect the glycolipid metabolism[18]. There are substantial proofs highlighting the causative relationship, sometimes reciprocal causative relationship between NAFLD and metabolic disorders, such as metabolic syndrome (MetS) components (i.e., hypertriglyceridemia, hyperinsulinemia, type 2 diabetes), polycystic ovary syndrome, sarcopenia, and hypothyroidism[1,18-22]. Because of the capacity of the insulin in suppressing endogenous glucose production, the hepatic insulin sensitivity decreases upon abnormal deposition of intrahepatic glyceride (over 1.5%), and subsequently gives rise to compensatory hyperinsulinemia[18]. Impairment of insulin sensitivity to skeletal muscle and adipose (suppression of free fatty acid by insulin) also occurs at the intrahepatic glyceride level lower than 6% ± 2%[18]. Similar pattern to other metabolic changes, such as low high-density lipoprotein cholesterol and hypertriglyceridemia, is observed in NAFLD patients[18]. Interestingly, a community-based study in 2836 middle-aged residents shows that both fasting blood glucose and two-hour glucose increase across the quintiles of liver fat content (LFC) after adjustment for age and gender[19]. Mild LFC augment (1%) predicts the prediabetes and type 2 diabetes, while participants with LFC over 10% exhibit higher odds ratio (OR) of impaired glucose regulation in comparison to those with LFC below 10%[19].

Recent research suggests that MetS plays a promoting role in pulmonary carcinogenesis[23-25]. By assessing new cases of lung cancer in the Korean health screening program (45635/9586753), the adjusted HR for lung cancer is much higher in participants with type 2 diabetes than in non-diabetic ones. Similarly, the presence of MetS and all 5 components positively associate with the risk of lung cancer in men (HR = 1.15). Only low-level high density lipoprotein and high-level triglyceride increase the risk of lung cancer in women. Moreover, the risk of lung cancer upregulates with the number of MetS components[23]. Mendelian randomization analyses uncover the causal relationships between obesity, which often results in NAFLD, and other MetS components, and lung cancer[15,24,25]. Each standard deviation increment in body mass index increases the susceptibility to lung cancer, with statistical significance in subtypes of squamous cell carcinoma (OR = 1.20) and small cell lung cancer (OR = 1.52)[24,25]. However, Zhu et al[15] found an increased risk of lung adenocarcinoma in the obese individuals, especially nonsmoking females. These phenomena may preliminarily indicate the link of NAFLD and lung cancer, and to some extent, metabolic abnormality.

MetS-RELATED MECHANISMS UNDERLYING NAFLD’S EFFECT ON LUNG CANCER

In spite of their interactions and subtle regulation, multiple mechanisms are recognized to underlie the effects of NAFLD on lung cancer. With its causative role in the development of MetS, NAFLD usually predisposes patients to insulin resistance and, successively, the hyperinsulinemia in compensation. The insulin/insulin-like growth factor (IGF) axis, including insulin, insulin receptor, IGF-1, IGF-2, IGF-1 receptor (IGF-1R), IGF-2R, and IGF-binding protein (IGFBP), is concomitantly activated[26]. As a result, the mitotic property of insulin/IGF axis may facilitate the pulmonary carcinogenesis[27]. Despite the malignant potential of insulin/IGF axis, its exact actions in NAFLD-related lung cancer remains controversial. Some existing data document the elevated serum or plasma levels of IGF-I in patients with primary lung cancer, but no significant difference could be discovered between IGF-I concentration and lung cancer regarding its development and histological subtype[28,29]. There is no consensus concerning the role of IGF-binding protein-3 in lung cancer[29].

NAFLD confers high risk of type 2 diabetes, which gives rise to impaired innate and adaptive immune relating to an increase in neutrophil-to-lymphocyte ratio[30]. Additionally, tumor cells instead of tumor-infiltrating CD8+ T increase the fat uptake after high-fat diet[31]. This difference in metabolic adaptation accelerates tumor growth and limits the anti-tumor functions of CD8+ T cells in human and obese mice. Blocking the metabolic reprogramming improves the anti-tumor immunity[31].

CONCLUSION

NAFLD has now predominated the cause of chronic liver diseases worldwide, and contributes to liver fibrosis/cirrhosis, HCC and related complications. The association of NAFLD and extrahepatic carcinoma, especially lung cancer, poses an impact on the public health. According to epidemiological evidences, NAFLD predisposes patients to lung cancer and liver metastasis, yet it has better response to the immune checkpoint inhibitors. Furthermore, there are causative relationships between NAFLD and MetS components, most of which are suggested to facilitate the pulmonary carcinogenesis via activation of insulin/IGF axis. In addition, high-fat diet-induced obesity exhibits lipotoxicity to immune system on the basis of metabolic reprogramming. Consequently, both suppressed anti-tumor immunity and deteriorated tumor progression take place. In summary, NAFLD may confer a higher risk of lung cancer development, partly due to its causative effect on MetS components, which consequently disrupt both tumor growth regulation and anti-tumor immunity.