Ribeiro, Ricardo MSc*†; Araújo, António MD†‡; Lopes, Carlos MD, PhD*†; Medeiros, Rui PhD*†
IMMUNOINFLAMMATORY RESPONSE AND LUNG CANCER
Immune cells constitute a critical component of host response to cancer,1 although their role in cancer pathogenesis remains incompletely established. Epidemiological data indicate that chronic inflammation increases the risk of malignant transformation2 and, therefore, that unresolved host immune reactivity may promote tumor development.3 In fact, persistent or recurrent immunoinflammatory up-regulation may induce or influence susceptibility to carcinogenesis by some known mechanisms (Fig. 1).4
Most lung cancer patients are smokers,5 and tobacco consumption is a well-established risk factor.6 A chronic inflammatory state is known to correlate with the decline in lung function among smokers7,8 and with lung cancer etiopathogenesis.9 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.10–12 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.13,14 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.15
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).16 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.17–19 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,20 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.21 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,22 increases phagocytosis by monocytes/macrophages, and activates and promotes macrophage cell chemotaxis.23 Cumulatively, it was shown that recombinant human leptin administration increased both C-reactive protein and P-selectin,24 whereas an association was observed between the concentration of VCAM-1 and ICAM-1 and circulating leptin levels.25,26 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.27,28 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,29 and are associated with the induction of leukocyte recruitment and activating-adhesion molecules, P-selectin, E-selectin, VCAM and ICAM.28,30 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.31,32 Reactive oxygen species derived from inflammation is an important endogenous carcinogenic factor, which is increased by long-term chronic inflammation.
Santos-Alvarez et al.33 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,34 inducing a pattern of cytokine release compatible with the induction of a T-helper 1 immune response,35 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.36 Simultaneously, leptin up-regulates the secretion of IL-1, IL-6, IL-12, TNF, and MIP-1α by dendritic cells.36
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-6.37 The up-regulation of immunomodulators TNF, IL-1, IL-6, and prostaglandin E2 through leptin via the nuclear factor-κB pathway38 further strengthens the up-regulated pro-inflammatory profile in the tumor microenvironment. Furthermore, TNF and IL-1 stimulate leptin production by adipocytes,39,40 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.41,42 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.43 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.44,45 Raso et al42 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.46 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-6,47 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.37 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.48 Leptin orients naive T-cell proliferation and differentiation to TH1 phenotype36 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.49 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.50
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.
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).
1. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4:11–22.
2. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci USA 1995;92:5258–5265.
3. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–867.
4. Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin 2006;56:69–83.
5. Boyle P, Autier P, Bartelink H, et al. European Code Against Cancer and scientific justification: third version (2003). Ann Oncol 2003;14:973–1005.
6. Crispo A, Brennan P, Jockel KH, et al. The cumulative risk of lung cancer among current, ex- and never-smokers in European men. Br J Cancer 2004;91:1280–1286.
7. Burchfiel CM, Marcus EB, Curb JD, et al. Effects of smoking and smoking cessation on longitudinal decline in pulmonary function. Am J Respir Crit Care Med 1995;151:1778–1785.
8. Chinn S, Jarvis D, Melotti R, et al. Smoking cessation, lung function, and weight gain: a follow-up study. Lancet 2005;365:1629–1635.
9. Ballaz S, Mulshine JL. The potential contributions of chronic inflammation to lung carcinogenesis. Clin Lung Cancer 2003;5:46–62.
10. Wanner A, Salathe M, O’Riordan TG. Mucociliary clearance in the airways. Am J Respir Crit Care Med 1996;154:1868–1902.
11. Matsumoto K, Aizawa H, Inoue H, et al. Eosinophilic airway inflammation induced by repeated exposure to cigarette smoke. Eur Respir J 1998;12:387–394.
12. Castro P, Legora-Machado A, Cardilo-Reis L, et al. Inhibition of interleukin-1beta reduces mouse lung inflammation induced by exposure to cigarette smoke. Eur J Pharmacol 2004;498:279–286.
13. 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? Cancer Immunol Immunother 2006;55:639–643.
14. 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. Lung Cancer 2005;50:285–290.
15. Arenberg D. Chemokines in the biology of lung cancer. J Thorac Oncol 2006;1:287–288.
16. 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. Eur J Cancer 2006;42:1188–1193.
17. 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. Proc Natl Acad Sci USA 1997;94:11073–11078.
18. Tsuchiya T, Shimizu H, Horie T, Mori M. Expression of leptin receptor in lung: leptin as a growth factor. Eur J Pharmacol 1999;365:273–279.
19. 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. Endocrinology 2005;146:215–220.
20. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol 2004;4:371–379.
21. Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 2004;14:433–439.
22. Caldefie-Chezet F, Poulin A, Vasson MP. Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic Res 2003;37:809–814.
23. 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. Carcinogenesis 2006 Aug 4 [Epub ahead of print].
24. 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. J Clin Endocrinol Metab 2005;90:5779–5785.
25. 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. Diabetes 2004;53:2691–2695.
26. 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. Atherosclerosis 2004;172:175–180.
27. Mastronardi CA, Yu WH, Rettori V, McCann S. Lipopolysaccharide-induced leptin release is not mediated by nitric oxide, but is blocked by dexamethasone. Neuroimmunomodulation 2000;8:91–97.
28. Rahman A, Anwar KN, Malik AB. Protein kinase C-zeta mediates TNF-alpha-induced ICAM-1 gene transcription in endothelial cells. Am J Physiol Cell Physiol 2000;279:C906–C914.
29. 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. J Clin Invest 1995;95:1669–1675.
30. 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. J Inflamm 1995;45:283–296.
31. Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J 1999;13:1231–1238.
32. 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. J Biol Chem 2001;276:25096–25100.
33. Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol 1999;194:6–11.
34. 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. Clin Exp Immunol 2003;133:11–19.
35. Zarkesh-Esfahani H, Pockley G, Metcalfe RA, et al. High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol 2001;167:4593–4599.
36. 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. J Immunol 2005;174:6820–6828.
37. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5:749–759.
38. 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. Endocrinology 2005;146:3334–3342.
39. Janik JE, Curti BD, Considine RV, et al. Interleukin 1 alpha increases serum leptin concentrations in humans. J Clin Endocrinol Metab 1997;82:3084–3086.
40. Zhang HH, Kumar S, Barnett AH, Eggo MC. Tumour necrosis factor-alpha exerts dual effects on human adipose leptin synthesis and release. Mol Cell Endocrinol 2000;159:79–88.
41. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000;68:437–446.
42. 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. Br J Pharmacol 2002;137:799–804.
43. Goodman JE, Hofseth LJ, Hussain SP, Harris CC. Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease. Environ Mol Mutagen 2004;44:3–9.
44. Mastronardi CA, Yu WH, McCann SM. Resting and circadian release of nitric oxide is controlled by leptin in male rats. Proc Natl Acad Sci USA 2002;99:5721–5726.
45. Vecchione C, Maffei A, Colella S, et al. Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes 2002;51:168–173.
46. Fosslien E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000;37:431–502.
47. Becker C, Fantini MC, Schramm C, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004;21:491–501.
48. Howard JK, Lord GM, Matarese G, et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 1999;104:1051–1059.
49. Martin-Romero C, Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin enhances activation and proliferation of human circulating T lymphocytes. Cell Immunol 2000;199:15–24.
50. 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. Anticancer Res 2005;25:2027–2031.