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Immunoinflammatory Mechanisms in Lung Cancer Development: Is Leptin a Mediator?

  • Ricardo Ribeiro
    Affiliations
    Molecular Oncology—CI, Portuguese Institute of Oncology, Porto, Portugal

    ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal
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  • António Araújo
    Affiliations
    ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal

    Department of Medical Oncology, Portuguese Institiute of Oncology, Porto, Portugal
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  • Carlos Lopes
    Affiliations
    Molecular Oncology—CI, Portuguese Institute of Oncology, Porto, Portugal

    ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal
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  • Rui Medeiros
    Correspondence
    Address for correspondence: Dr. Rui Medeiros, Ph.D., Molecular Oncology, CI, Instituto Português de Oncologia, Porto, Edifício Laboratórios - PISO 4, R. Dr. Ant. Bernardino Almeida, 4200-072 Porto, Portugal
    Affiliations
    Molecular Oncology—CI, Portuguese Institute of Oncology, Porto, Portugal

    ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal
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      Abstract:

      This is a short review focusing on leptin immunoinflammatory mechanisms that ultimately may contribute to lung cancer development. We explored the complex and intricate interaction of leptin with immune cells to propose a pathway of inflammation-associated lung cancer development.

      Key Words

      IMMUNOINFLAMMATORY RESPONSE AND LUNG CANCER

      Immune cells constitute a critical component of host response to cancer,
      • Dranoff G
      Cytokines in cancer pathogenesis and cancer therapy.
      although their role in cancer pathogenesis remains incompletely established. Epidemiological data indicate that chronic inflammation increases the risk of malignant transformation
      • Ames BN
      • Gold LS
      • Willett WC
      The causes and prevention of cancer.
      and, therefore, that unresolved host immune reactivity may promote tumor development.
      • Coussens LM
      • Werb Z
      Inflammation and cancer.
      In fact, persistent or recurrent immunoinflammatory up-regulation may induce or influence susceptibility to carcinogenesis by some known mechanisms (Fig. 1).
      • Schottenfeld D
      • Beebe-Dimmer J
      Chronic inflammation: a common and important factor in the pathogenesis of neoplasia.
      Figure thumbnail gr1
      FIGURE 1Leptin's role in immunoinflamatory-mediated lung cancer development. After exposure to inhaled antigens (e.g., smoke particles) follows acute inflammation that under normal circumstances is self-limited. However, depending on the magnitude and duration of exposure to pro-inflammatory inhaled antigens and on the individual's genetic background (polymorphisms in genes that express pro-inflammatory molecules), the inflammatory reaction may last longer and/or may be increased. Leptin may have a central role in chronic inflammation development and maintenance of chronic inflammation, through autocrine, paracrine, and endocrine mechanisms. There is a broad range of action for leptin in immune cells. Leptin stimulates and activates neutrophils, macrophages, peripheral blood mononuclear cells, dendritic cells, and T cells, whose products, ultimately, may induce chronic inflammation and lung cancer carcinogenesis. Th0 = naive T cell, Th1 = T helper 1, Th2 = T helper 2, NF-κB = nuclear factor κB, TNF = tumor necrosis factor-α, VEGF = vascular endothelial growth factor, PLA2 = phospholipase A2, LKTs = leukotrienes, PGs = prostaglandins, IFNg = interferon-γ, COX-2 = cyclooxygenase 2, iNOS = inducible nitric oxide synthase, NO = nitric oxide, CSF = colony stimulating factor, ROS = reactive oxygen species, RNS = reactive nitrogen species, PBMCs = peripheral blood mononuclear cells.
      Most lung cancer patients are smokers,
      • Boyle P
      • Autier P
      • Bartelink H
      • et al.
      European Code Against Cancer and scientific justification: third version (2003).
      and tobacco consumption is a well-established risk factor.
      • Crispo A
      • Brennan P
      • Jockel KH
      • et al.
      The cumulative risk of lung cancer among current, ex- and never-smokers in European men.
      A chronic inflammatory state is known to correlate with the decline in lung function among smokers
      • Burchfiel CM
      • Marcus EB
      • Curb JD
      • et al.
      Effects of smoking and smoking cessation on longitudinal decline in pulmonary function.
      • Chinn S
      • Jarvis D
      • Melotti R
      • et al.
      Smoking cessation, lung function, and weight gain: a follow-up study.
      and with lung cancer etiopathogenesis.
      • Ballaz S
      • Mulshine JL
      The potential contributions of chronic inflammation to lung carcinogenesis.
      Chronic cigarette smoking retards mucociliary clearance of foreign particulates and secretions that favor a persistent inflammation, whereas the inhaled particles evoke vigorous lung and airway inflammatory responses.
      • Wanner A
      • Salathe M
      • O'Riordan TG
      Mucociliary clearance in the airways.
      • Matsumoto K
      • Aizawa H
      • Inoue H
      • et al.
      Eosinophilic airway inflammation induced by repeated exposure to cigarette smoke.
      • Castro P
      • Legora-Machado A
      • Cardilo-Reis L
      • et al.
      Inhibition of interleukin-1beta reduces mouse lung inflammation induced by exposure to cigarette smoke.
      Initiation of the immunoinflammatory lung response is induced by exposure to inhaled antigenic particles and is followed by an expression pattern of chemokines and cytokines that may be influenced by the individual genetic background.
      • Coelho A
      • Calcada C
      • Catarino R
      • Pinto D
      • Fonseca G
      • Medeiros R
      CXCL12-3′ A polymorphism and lung cancer metastases protection: new perspectives in immunotherapy?.
      • Lind H
      • Zienolddiny S
      • Ryberg D
      • Skaug V
      • Phillips DH
      • Haugen A
      Interleukin 1 receptor antagonist gene polymorphism and risk of lung cancer: a possible interaction with polymorphisms in the interleukin 1 beta gene.
      This mechanism may predispose a patient to an amplified and longer immune response. The role of chemokines in lung cancer biology has been highlighted in a previous review.
      • Arenberg D
      Chemokines in the biology of lung cancer.

      LEPTIN, INFLAMMATION, AND LUNG CANCER

      Investigators have found that a functional polymorphism in the leptin gene (LEP-2548 G/A) was associated with increased risk for developing non-small cell lung cancer (odds ratio, 1.97; 95% confidence interval, 1.13–3.43) and to earlier onset of disease, and that carriers of the risk genotype simultaneously smokers had even higher risk for developing cancer of the lung (odds ratio, 4.82; 95% confidence interval, 1.05–22.17).
      • Ribeiro R
      • Araujo AP
      • Coelho A
      • et al.
      A functional polymorphism in the promoter region of leptin gene increases susceptibility for non-small cell lung cancer.
      These results support leptin's role in exacerbating existing cigarette smoke-induced lung inflammation that may lead to increased amplitude and duration of reaction, which has a major role in lung cancer pathogenesis.
      Leptin is an adipocytokine that has been consistently implicated in lung physiology and pathophysiology. It is involved in fetal lung development and in adult normal lung cells’ physiology or malignant proliferation.
      • Hoggard N
      • Hunter L
      • Duncan JS
      • Williams LM
      • Trayhurn P
      • Mercer JG
      Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta.
      • Tsuchiya T
      • Shimizu H
      • Horie T
      • Mori M
      Expression of leptin receptor in lung: leptin as a growth factor.
      • Meissner U
      • Hanisch C
      • Ostreicher I
      • et al.
      Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation.
      Besides a possible direct effect of leptin in normal and tumor lung cells, most importantly, there is strong evidence of leptin's up-regulatory role in the immunoinflammatory system,
      • La Cava A
      • Matarese G
      The weight of leptin in immunity.
      supporting its role as a prominent interplay between inflammation and lung cancer (Figure 1). It is now well established that fat depots’ function goes beyond structural, metabolic, and heat-insulating properties because of cytokines, growth factors, and hormone production that may prolong the pro-inflammatory microenvironment.

      LEPTIN, INNATE IMMUNITY, AND CANCER

      Although the immune surveillance hypothesis has received some experimental support, the net effect of inflammation and/or innate immune system activation is stimulation of tumor growth in most cases.
      • Philip M
      • Rowley DA
      • Schreiber H
      Inflammation as a tumor promoter in cancer induction.
      Leptin affects both innate and adaptive immunity. In innate immunity, leptin directly and indirectly modulates the activity and function of neutrophils by increasing chemotaxis and production of oxygen radicals,
      • Caldefie-Chezet F
      • Poulin A
      • Vasson MP
      Leptin regulates functional capacities of polymorphonuclear neutrophils.
      increases phagocytosis by monocytes/macrophages, and activates and promotes macrophage cell chemotaxis.
      • Fenton JI
      • Hursting SD
      • Perkins SN
      • Hord NG
      Leptin induces an Apc genotype-associated colon epithelial cell chemokine production pattern associated with macrophage chemotaxis and activation.
      Cumulatively, it was shown that recombinant human leptin administration increased both C-reactive protein and P-selectin,
      • Canavan B
      • Salem RO
      • Schurgin S
      • et al.
      Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation.
      whereas an association was observed between the concentration of VCAM-1 and ICAM-1 and circulating leptin levels.
      • Kent JW
      • Comuzzie AG
      • Mahaney MC
      • et al.
      Intercellular adhesion molecule-1 concentration is genetically correlated with insulin resistance, obesity, and HDL concentration in Mexican Americans.
      • Porreca E
      • Di Febbo C
      • Fusco L
      • Moretta V
      • Di Nisio M
      • Cuccurullo F
      Soluble thrombomodulin and vascular adhesion molecule-1 are associated to leptin plasma levels in obese women.
      These evidences support an indirect role for leptin in chemotaxis and, consequently, in attraction of inflammatory cells through an action in adhesion molecules, further increasing the magnitude of inflammation.
      The inflammatory process initiated by infection, cellular damage, tumor cells, reactive oxygen species production, inhaled particles from tobacco, or environment pollutants stimulates the synthesis of interleukin (IL)-1, IL-6, leptin, and tumor necrosis factor (TNF) by macrophages and stromal and endothelial cells.
      • Mastronardi CA
      • Yu WH
      • Rettori V
      • McCann S
      Lipopolysaccharide-induced leptin release is not mediated by nitric oxide, but is blocked by dexamethasone.
      • Rahman A
      • Anwar KN
      • Malik AB
      Protein kinase C-zeta mediates TNF-alpha-induced ICAM-1 gene transcription in endothelial cells.
      These molecules are partially responsible for the expression of acute-phase inflammatory response elements, such as cyclooxygenase-2, nuclear factor κB, and C-reactive protein,
      • Feng L
      • Xia Y
      • Garcia GE
      • Hwang D
      • Wilson CB
      Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide.
      and are associated with the induction of leukocyte recruitment and activating-adhesion molecules, P-selectin, E-selectin, VCAM and ICAM.
      • Rahman A
      • Anwar KN
      • Malik AB
      Protein kinase C-zeta mediates TNF-alpha-induced ICAM-1 gene transcription in endothelial cells.
      • Manning AM
      • Bell FP
      • Rosenbloom CL
      • et al.
      NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment.
      Activated leukocytes produce large quantities of reactive oxygen species that will cause oxidative damage to surrounding cells and enhance risk for inflammation-mediated cytotoxicity and DNA damage in normal cells. The role of leptin in up-regulating reactive oxygen species production through an effect in monocytes or indirectly in endothelial cells by an increase in monocyte-chemoattractant protein 1 is well known.
      • Bouloumie A
      • Marumo T
      • Lafontan M
      • Busse R
      Leptin induces oxidative stress in human endothelial cells.
      • Yamagishi SI
      • Edelstein D
      • Du XL
      • Kaneda Y
      • Guzman M
      • Brownlee M
      Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A.
      Reactive oxygen species derived from inflammation is an important endogenous carcinogenic factor, which is increased by long-term chronic inflammation.
      Santos-Alvarez et al.
      • Santos-Alvarez J
      • Goberna R
      • Sanchez-Margalet V
      Human leptin stimulates proliferation and activation of human circulating monocytes.
      observed a stimulatory effect of leptin on peripheral blood mononuclear cell production of TNF and IL-6. Furthermore, leptin's role in peripheral blood mononuclear cell proliferation and activation is mediated by activation of the leptin receptor in these cells,
      • Sanchez-Margalet V
      • Martin-Romero C
      • Santos-Alvarez J
      • Goberna R
      • Najib S
      • Gonzalez-Yanes C
      Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action.
      inducing a pattern of cytokine release compatible with the induction of a T-helper 1 immune response,
      • Zarkesh-Esfahani H
      • Pockley G
      • Metcalfe RA
      • et al.
      High-dose leptin activates human leukocytes via receptor expression on monocytes.
      which is associated with a negative prognostic factor in patients with non-small cell lung cancer. Leptin mediates the up-regulation of dendritic cells’ function and survival and decreases production of IL-10, which further contributes further to T-helper 1 immune phenotype.
      • Mattioli B
      • Straface E
      • Quaranta MG
      • Giordani L
      • Viora M
      Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming.
      Simultaneously, leptin up-regulates the secretion of IL-1, IL-6, IL-12, TNF, and MIP-1α by dendritic cells.
      • Mattioli B
      • Straface E
      • Quaranta MG
      • Giordani L
      • Viora M
      Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming.
      Activation of the inhibitor of nuclear factor-κB kinase β-dependent nuclear factor-κB molecular pathway is a molecular mechanism that connects inflammation and cancer. Its activation increases tumor growth and progression in different cell types through activation of gene targets of pro-inflammatory cytokines and chemokines, such as TNF, IL-1, and IL-6.
      • Karin M
      • Greten FR
      NF-kappaB: linking inflammation and immunity to cancer development and progression.
      The up-regulation of immunomodulators TNF, IL-1, IL-6, and prostaglandin E2 through leptin via the nuclear factor-κB pathway
      • Lappas M
      • Permezel M
      • Rice GE
      Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-kappaB, peroxisomal proliferator-activated receptor-gamma and extracellularly regulated kinase 1/2.
      further strengthens the up-regulated pro-inflammatory profile in the tumor microenvironment. Furthermore, TNF and IL-1 stimulate leptin production by adipocytes,
      • Janik JE
      • Curti BD
      • Considine RV
      • et al.
      Interleukin 1 alpha increases serum leptin concentrations in humans.
      • Zhang HH
      • Kumar S
      • Barnett AH
      • Eggo MC
      Tumour necrosis factor-alpha exerts dual effects on human adipose leptin synthesis and release.
      further contributing to prolonged leptin-induced inflammation.
      After leptin's stimulatory effect, macrophages also increase the production of the pro-inflammatory enzyme cyclooxygenase 2 and their products leukotriene (LKT) B4 and prostaglandin (PG) E2, and augments inducible nitric oxide synthase (iNOS) activity.
      • Fantuzzi G
      • Faggioni R
      Leptin in the regulation of immunity, inflammation, and hematopoiesis.
      • Raso GM
      • Pacilio M
      • Esposito E
      • Coppola A
      • Di Carlo R
      • Meli R
      Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A. 1.
      Production of reactive nitrogen species (RNS) in response to inflammation-induced iNOS overexpression might induce generation and accumulation of additional mutations that drive tumor progression.
      • Goodman JE
      • Hofseth LJ
      • Hussain SP
      • Harris CC
      Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease.
      Several studies support a stimulatory action of leptin in endothelial NOS (eNOS) and inducible NOS (iNOS) activities, which results in increased NO production by adipocitic and endothelial cells.
      • Mastronardi CA
      • Yu WH
      • McCann SM
      Resting and circadian release of nitric oxide is controlled by leptin in male rats.
      • Vecchione C
      • Maffei A
      • Colella S
      • et al.
      Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway.
      Raso et al
      • Raso GM
      • Pacilio M
      • Esposito E
      • Coppola A
      • Di Carlo R
      • Meli R
      Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A. 1.
      showed that leptin is a potent synergistic factor that cooperates with IFN-γ to increase the expression of iNOS and cyclooxygenase 2. The cyclooxygenase-2 enzyme up-regulates the production of the vasoactive prostaglandins (PGs) and leukotrienes (LKTs) responsible for increasing the amount of local vasodilation and vasopermeability, and cumulatively, for enhanced inflammation through leukocytes accumulation. The PGs also inhibit apoptosis and stimulate angiogenesis and invasiveness.
      • Fosslien E
      Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.
      As a result of chronic inflammation, constant exposure to cyclooxygenase 2-derived prostaglandins may also enhance carcinogenic risk by reducing apoptosis and increasing the likelihood of mutant cell survival and cancer development.

      LEPTIN, ADAPTIVE IMMUNITY, AND CANCER

      Apparently, T cells may also contribute to tumor growth because, in the progression phase, they are the main source of IL-6,
      • Becker C
      • Fantini MC
      • Schramm C
      • et al.
      TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.
      and their overall contribution might depend on the balance between tumor-promoting cytokines, such as IL-6, and tumor-suppressor cytokines, such as IL-10 and TGF-β.
      • Karin M
      • Greten FR
      NF-kappaB: linking inflammation and immunity to cancer development and progression.
      Leptin, which increases IL-6 production and decreases IL-10 secretion, provides an interesting clue to the understanding of leptin's association with inflammation and cancer, although much research in inflammatory cancer models is required to clarify this issue.
      In adaptive immunity, leptin affects the generation, maturation, and survival of thymic T cells by reducing their rate of apoptosis.
      • Howard JK
      • Lord GM
      • Matarese G
      • et al.
      Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.
      Leptin orients naive T-cell proliferation and differentiation to TH1 phenotype
      • Mattioli B
      • Straface E
      • Quaranta MG
      • Giordani L
      • Viora M
      Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming.
      and promotes the switch toward TH1 immune responses on memory T cells by increasing IFNγ and TNF secretion and stimulating the production of IgG2α by B cells.
      • Martin-Romero C
      • Santos-Alvarez J
      • Goberna R
      • Sanchez-Margalet V
      Human leptin enhances activation and proliferation of human circulating T lymphocytes.
      The TH1/TH2 cytokine balance is preserved in normal individuals, but during inflammation, the imbalance in the TH1/TH2 cytokine response overcomes. In patients with non-small cell lung cancer, a high TH1/TH2 ratio in peripheral blood is a negative prognostic factor.
      • Ito N
      • Suzuki Y
      • Taniguchi Y
      • Ishiguro K
      • Nakamura H
      • Ohgi S
      Prognostic significance of T helper 1 and 2 and T cytotoxic 1 and 2 cells in patients with non-small cell lung cancer.

      SUMMARY

      Recent developments in leptin immunological pathways suggest a previously unappreciated complexity of cancer cell-normal cell-immunoinflammatory cell cross-talk. This interaction found in the inflammatory medium may deregulate and increase the magnitude and duration of inflammation, promoting tumor development. Leptin, a pleiotrophic hormone synthesized mainly by adipocytes, may be an important interplay between immunoinflammatory up-regulation and lung cancer development, warranting further studies in this field.

      ACKNOWLEDGMENTS

      The authors acknowledge the Portuguese League Against Cancer – North Centre, Astra Zeneca Foundation, Yamanouchi European Foundation and Minister of Health of Portugal (Comissão de Fomento da Investigação em Cuidados de Saúde: CFICS- 226/01), for their support. RR is a research fellow of Fundação para a Ciência e a Tecnologia (grant SFRH/BD/30021/2006).

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