The role of inflammation in the pathogenesis of lung cancer

INTRODUCTION: It is reported that cancer may arise in chronically inflamed tissue. There is mounting evidence suggesting that the connection between inflammation and lung cancer is not coincidental but may indeed be causal. The inflammatory molecules may be responsible for augmented macrophage recruitment, delayed neutrophil clearance and an increase in reactive oxygen species. The cytokines and growth factors unusually produced in chronic pulmonary disorders have been found to have harmful properties that pave the way for epithelial-to-mesenchymal transition and tumor microenvironment. However, the role of inflammation in lung cancer is not yet fully understood. AREAS COVERED: The role of chronic inflammation in the pathogenesis of lung cancer and some of the possible mechanisms involved, with particular focus on inflammatory mediators, genetic and epigenetic alterations, inflammatory markers, tumor microenvironment and anti-inflammatory drugs are discussed. A framework for understanding the connection between inflammation and lung cancer is provided, which may afford the opportunity to intercede in specific inflammatory damage mediating lung carcinogenesis and therapeutic resistance. EXPERT OPINION: Advances in tumor immunology support the clinical implementation of immunotherapies for lung cancer. Along with therapeutic benefits, immunotherapy presents the challenges of drug-related toxicities. Gene modification of immunocytokine may lower the associated toxic effects.     

Refined fructose and cancer

Introduction: Caloric excess, including increased refined carbohydrate intake, is associated with higher cancer risk emphasizing the importance of improved understanding of cancer cell metabolism in tumor survival and metastasis.

Areas covered: This article reviews the relationship between increased dietary refined sugar and cancer risk, with specific emphasis on the monosaccharide fructose. Cancer cell metabolism is reviewed, and the potential mechanisms by which dietary sugars contribute to the tumor microenvironment are discussed. Recent observations indicate that cancer cells readily utilize fructose to support proliferation and preferentially use fructose for nucleic acid synthesis. This review discusses the potential role of how dietary fructose can promote cancer growth by a variety of mechanisms, including altered cellular metabolism, increased reactive oxygen species, DNA damage and inflammation. Preliminary insights into potential therapeutic strategies by which fructose-mediated cancer effects may be abrogated are presented.

Expert opinion: Other sugars (particularly fructose, given its abundance in the modern diet) must be considered with reference to cancer cell metabolism. Cancer cells utilize similar sugars in distinct ways, which may present important new therapeutic avenues of targeting cancer.     

Ron receptor tyrosine kinase signaling as a therapeutic target

Introduction: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis.

Areas covered: This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer.

Expert opinion: The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients.     

Targeting IL-8 in colorectal cancer

Introduction: Colorectal cancer is the leading cause of death from gastrointestinal malignancy in the US. Chemokines and their receptors are being recognized as key regulators of cancers and increasingly as therapeutic targets for metastatic cancers, including colorectal cancer. Several studies have demonstrated that IL-8 and its receptor CXCR2 are two of the most significantly upregulated chemokines in colorectal cancer. IL-8 through binding to its receptors can act not only on inflammatory responses and infectious diseases, but also on cancer cells via their receptors to promote migration, invasion and proliferation, and in vivo angiogenesis. Therefore, IL-8 and CXCR2 may be important therapeutic targets against colorectal cancer.

Areas covered: This review provides an update on the roles of IL-8 and its receptors in colorectal cancer preclinical models and translational relevance: i) Increased expression of IL-8 and/or its receptors has been characterized in colon cancer cells; ii) IL-8 signaling pathway in colorectal cancer cells; iii) targeting IL-8 expression, or receptor-targeted strategies in colorectal cancer, eliminates the redundant function of IL-8 signaling and determines the effects of suppressing IL-8 signaling on tumor progression and development.

Expert opinion: IL-8 and its receptor CXCR2 may function as significant regulatory factors within the tumor microenvironment and be important therapeutic targets in colorectal cancers. Not only may they lead to antitumor properties, but also they may chemosensitize the tumor toward the current chemotherapy.     

PPARα as a therapeutic target in inflammation-associated diseases

Introduction: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) plays a major regulatory function of genes involved in energy metabolism and is a therapeutic target for dyslipidemia. The last decade provided a constellation of findings demonstrating that PPARα behaves as a modulator of both acute and chronic inflammation. PPARα became a rational potential therapeutic target for the treatment of inflammatory disorders.

Aeras covered: The ability of PPARα to control inflammatory signaling pathways via a diversity of molecular mechanisms is discussed. This review is especially focused on the global action of PPARα on inflammation in several tissues from data obtained in numerous cell types and in vivo models exposed to inflammatory stimuli.

Expert opinion: Available PPARα agonists currently used in clinic belong to the class of hypolipidemic drugs but were not expected and not designed to act as anti-inflammatory drugs. To date, accumulating preclinical suggest evidence promising benefits when considering PPARα as a drug target to treat inflammatory disorders. However, clinical studies are needed to validate this concept. Drug design should also be directed toward the elaboration of PPARα agonists more specifically active in the control inflammatory signaling.     

The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune,neuroimmune and bone diseases

Introduction: Semaphorin 4D (Sema4D), also known as CD100, has been implicated in physiologic roles in the immune and nervous systems. However, the interaction of Sema4D with its high affinity receptor, Plexin-B1, reveals a novel role for Sema4D produced by the tumor microenvironment in tumor angiogenesis and metastasis.

Areas covered: The ligation of Sema4D/CD100 with CD72 on immune and inflammatory cells is known to stimulate immune responses and regulation. Because CD100 and CD72 are expressed on lung immune and nonimmune cells, as well as on mast cells, the CD100/CD72 interaction plays another important role in allergic airway inflammation and mast cell functions. A better understanding of Sema4D-mediated cell signaling in physiological and pathological processes may be crucial for crafting new Sema4D-based therapeutics for human disease and tumor microenvironments. Strategies to achieve effective management through treatment with Sema4D include special siRNAs, neutralizing antibodies and knockdown.

Expert opinion: This review focuses on the links between Sema4D and human diseases such as cancer, bone metabolism, immune responses and organ development. The current knowledge regarding the expression of Sema4D and its receptors and its functional roles is systemically reviewed to explore Sema4D as both a target and a therapeutic in human diseases.     

Targeting chronic inflammation in cerebral aneurysms: focusing on NF-κB as a putative target of medical therapy

Importance of the field: Cerebral aneurysms (CAs) are the main cause of life-threatening subarachnoid hemorrhage. Given its prevalence and endpoint, CA treatment is a public health issue. Effective medical treatment of CAs is lacking because the detailed mechanisms of CA formation are incompletely understood.

Areas covered in this review: The aim of this contribution is to review recent articles about CA formation, to suggest the underlying mechanisms of CA formation, and to discuss potential therapeutic targets for treatment. Articles were collected by an internet search of PubMed using the keywords ‘intracranial’ or ‘cerebral aneurysm’.

What the readers will gain: A review of articles about the pathogenesis of CA formation focusing on inflammation. Recent articles demonstrate that inflammation-related-molecule induction and inflammatory cell infiltration in CA walls and the close relationship between inflammatory responses and CA formation. From studies in experimental models, chronic inflammation triggered primarily by NF-κB activation in endothelial cells and subsequent macrophage infiltration have critical roles in CA formation. Inhibition of inflammation-related molecules in CA walls results in the decreased incidence of CA formation.

Take-home message: Agents with anti-inflammatory activity (particularly anti- NF-κB effects) have potential as therapeutic drugs for CAs.     

Therapeutic targeting of tumor–stroma interactions

Introduction: Cancers exist within a complex microenvironment populated by diverse cell types within a protein-rich extracellular matrix. It is becoming increasingly apparent that molecular interactions between epithelial cells and cells in the surrounding stroma promote growth, invasion and spread of the tumor itself and thus represents a crucial underlying driving force in tumorigenesis.

Areas covered: This article reviews how key interactions between tumor epithelial cells and surrounding mesenchymal and immune cells can promote tumor progression and highlights molecular elements that might represent novel therapeutic targets.

Expert opinion: The tumor microenvironment is increasingly being viewed as a potential therapeutic target with a number of strategies being developed to disrupt tumor–stroma interactions, in order to delay or circumvent tumor progression. Targeting elements of the tumor microenvironment, or signaling pathways in tumor cells activated as a consequence of stromal interactions, may prove a useful therapeutic strategy to prevent tumor development and progression. However, given the tumor cells' ability to circumvent various therapeutic agents when given as monotherapy, the success of these agents is likely to be seen when used in combination with existing treatments.     

ROCKs as immunomodulators of stroke

Introduction: Stroke is the third leading cause of death and a major cause of long-term disability in the adult population. Growing evidence suggests that inflammation may play an important role in the evolution of stroke. Because Rho-associated coiled-coil containing kinases (ROCKs) are important mediators of inflammation, they may contribute to stroke and stroke recovery.

Areas covered: The pathophysiological role of ROCKs in mediating inflammation at different phases of stroke, and the therapeutic opportunities for stroke prevention and stroke treatment with ROCK inhibitors will be discussed.

Expert opinion: Inflammation is a double-edged sword during the evolution of stroke. Immunomodulation might provide a novel therapeutic approach for stroke prevention and stroke treatment. ROCK plays an important role in mediating the inflammatory response following vascular injury as well as platelet activation and thrombus formation. ROCK inhibitors have been shown to be beneficial in stroke prevention, acute neuroprotection and chronic stroke recovery by affecting inflammatory-mediated platelet and endothelial function, smooth muscle contraction and neuronal regeneration. Thus, ROCK-mediated inflammation could be a potential therapeutic target for stroke prevention and stroke treatment. However, the mechanism by which ROCKs regulate the inflammatory response is unclear, and the role of the two ROCK isoforms in stroke and stroke recovery remains to be determined.     

Common pathogenic mechanisms and pathways in the development of COPD and lung cancer

Introduction: Lung cancer and COPD commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer. In addition to smoking cessation and preventing smoking initiation, understanding the shared mechanisms of these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD.

Areas covered: This review discusses the common mechanisms for susceptibility to lung cancer and COPD, which in addition to cigarette smoke, may involve inflammation, epithelial–mesenchymal transition, abnormal repair, oxidative stress, and cell proliferation. Furthermore, we discuss the underlying genomic and epigenomic changes (single nucleotide polymorphisms (SNPs), copy number variation, promoter hypermethylation and microRNAs) that are likely to alter biological pathways, leading to susceptibility to lung cancer and COPD (e.g., altered nicotine receptor biology).

Expert opinion: Strategies to study genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities.     

Progression of chronic obstructive pulmonary disease: impact of inflammation,comorbidities and therapeutic intervention

ABSTRACT

Background and aim: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and through under-diagnosis, is often inappropriately treated. This multicomponent disease involves both airway and systemic inflammation at all stages and may influence the progression of disease and the pathophysiology of comorbidities. This review examines evidence linking inflammation, disease progression and comorbidities in COPD, and the potential role of anti-inflammatory therapies.

Methods: Systematic searches of Medline and Cochrane Reviews databases from 1976 to March 2008 using the terms: chronic obstructive pulmonary disease, disease progression, inflammation, inflammatory, comorbid condition, comorbidity, treatment, therapy, bronchodilator, inhaled corticosteroid.

Findings: Increased levels of interleukin-8, tumour necrosis factor-alpha and systemic C-reactive protein correlate with worse disease severity, exacerbation rates and lung function decline. Increased systemic C-reactive protein is also associated with poorer health status and comorbidities (e.g. cardiovascular disease, cancer and skeletal muscle dysfunction). The pivotal role of inflammation in the pathogenesis of COPD and its comorbidities suggests anti-inflammatory therapies will be important in the overall management of COPD. Long-term studies indicate that combination therapies consisting of a long-acting beta-agonist plus an inhaled corticosteroid in one inhaler have the potential to modify disease progression through positive effects on lung function, exacerbations, symptoms and health status. The TOwards a Revolution in COPD Health (TORCH) study is the first to demonstrate that a COPD pharmacotherapy (combination salmeterol plus fluticasone propionate) significantly decreased the rate of lung function decline versus placebo.

Conclusion: Better understanding of the specific inflammatory mechanisms underlying COPD disease progression and associated comorbidities will likely lead to more effective management of the disease.     

Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors

Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer.

Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examined. A discussion of Axl and/or Mer inhibitors in development is provided.

What the reader will gain: Potential toxicities associated with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression.

Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with standard cytotoxic therapies.     

Therapeutic targeting of B7-H1 in breast cancer

Introduction: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer.

Areas covered: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer.

Expert opinion: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

Respiratory effects of sulfur mustard exposure,similarities and differences with asthma and COPD

Abstract

Context: Previous research has found relationships between sulfur mustard (SM) toxicity and its adverse effects.

Objective: SM is highly toxic to the respiratory system, leading to hacking cough, rhinorrheachest tightness, acute pharyngitis and laryngitis, chronic bronchitis and lung fibrosis. In this review, based on the scientific literature, we provide an updated summary of information on SM exposures and their differences with asthma and COPD.

Method: Information of this review was obtained by searching Medline/PubMed, ScienceDirect, Scopus, Google Scholar, ISI Web of Knowledge and Chemical Abstracts.

Results: SM exposure can decrease pulmonary function tests (PFTs) values. In addition, inflammatory cell accumulation in the respiratory tract and increased expression of some pro-inflammatory cytokines including tumor necrosis factor-α (TNFα), IL-1a, IL-1β, and reactive oxygen radicals due to SM exposure have been shown. Matrix metalloproteinase (MMP) which degrade extracellular matrix proteins, contributing to inflammatory cell recruitment, tissue injury and fibrosis are also up-regulated in the lung after SM exposure. In the lung, SM exposure also can cause serious pathological changes including airway inflammation, parenchymal tissue destruction and airway obstruction which can lead to asthma or chronic obstructive pulmonary disease (COPD). Following SM poisoning, DNA damage, apoptosis and autophagy are observed in the lung along with the increased expression of activated caspases and DNA repair enzymes.

Conclusion: In the present article, respiratory symptoms, changes in PFTs, lung pathology and lung inflammation due to SM exposure and the similarities and differences between them and those observed in asthma and COPD were reviewed.     

Kinin receptors as targets for cancer therapy

Introduction: Biological fluids of cancer patients contain increased levels of kinins. Activation of kinin B₁ and B₂ receptors expressed on cancer cells produce an increase in cell proliferation, migration of tumor cells and release of MMPs, which are cellular and molecular events of primary importance for tumor growth. The effects of kinins on tumor cells may be amplified by stimulation of kinin receptors expressed on other cells, within the tumor microenvironment, which may in turn increase tumor growth.

Areas covered: This review provides a comprehensive discourse on kinins and their receptors in human neoplasia. Concepts that view kinin receptors as targets for human cancer are explored, whilst the molecular basis by which the new dimerized kinin receptor antagonists produce arrest of cell proliferation and apoptosis of cancer cells is also examined. Finally, the role of kinin receptor antagonists as therapeutic tools against human neoplasia is analyzed.

Expert opinion: At the present time the available potent, dimerized kinin peptide antagonists, are either specific for B₁ or B₂ receptors, or are effective on both receptor types. The novel approach of using kinin receptor antagonists either alone or in combination therapy will play a definitive role in the treatment of cancer.     

Novel IκB kinase inhibitors for treatment of nuclear factor-κB-related diseases

Introduction: NF-κB is a key regulator of inflammation and immunity in cancer development. The IκB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-κB activation.

Areas covered: NF-κB affects the progression of inflammation-related diseases, such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases.

Expert opinion: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.     

Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation

Introduction: AMP-activated protein kinase (AMPK) is the downstream component of a serine/threonine protein kinase cascade involved in the regulation of metabolism. Many studies have also revealed that AMPK activation can exert significant anti-inflammatory and immunosuppressive effects in a variety of cell types and models of inflammatory/autoimmune disease. Because metformin, an AMPK activator that is a favored first-line therapeutic option for type 2 diabetes, may confer benefits in chronic inflammatory diseases and cancers independent of its ability to normalize blood glucose, there is now considerable interest in identifying and exploiting AMPK's anti-inflammatory effects.

Areas covered: The authors provide a background to AMPK signaling and describe the pro-inflammatory signaling pathways and processes shown to be regulated by AMPK activation.

Expert opinion: Identification of AMPK subunits responsible for specific anti-inflammatory effects, and a molecular understanding of the mechanisms involved, will be necessary to exploit AMPK pathway activation in acute and chronic inflammatory disease settings while minimizing adverse reactions due to deregulation of AMPK's wide-ranging effects on metabolism.     

Adrenomedullin as a therapeutic target in angiogenesis

Importance of the field: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target.

Areas covered in this review: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models.

What the reader will gain: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target.

Take home message: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments.     

The emerging roles of liver X receptors and their ligands in cancer

Introduction: Liver X receptors (LXRs) are nuclear receptors with well-known functions in cholesterol transport, fatty acid and glucose metabolism, and modulation of immune responses. Natural and synthetic ligands have been identified and are under development for the treatment of metabolic and inflammatory conditions and diseases. There is mounting evidence pointing to functional roles for LXRs in a variety of malignancies and the potential therapeutic efficacy of their ligands.

Areas covered: This review summarizes the discovery and characterization of LXRs and their ligands, surveys their effects and mechanisms of action in cell-based and animal models of cancer, and proposes the future direction of basic and translational studies of LXRs and their ligands in cancer research and therapeutics.

Expert opinion: Targeting LXRs is a promising strategy for cancer treatment, particularly for those cancers which do not have effective treatment options. Key questions remain, however, regarding the specific mechanisms of action, effects on other target cells within the tumor microenvironment, and receptor status in patient populations. Moreover, LXR ligands optimized for disease-specific functions and cancer-related endpoints are currently not available. These issues represent both challenges and significant opportunities for future research and development efforts.     

Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders

Importance of the field: Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with inflammatory disorders such as pancreatitis, shock and disseminated intravascular coagulation (DIC). Previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties at sites of inflammation. However, the therapeutic effects of UTI in vivo remain unclarified, as commercial UTI has been developed to act against humans, with the activity and selectivity toward the relevant animal UTI being less characterized.

Areas covered in this review: In this review, we introduce the roles of UTI in experimental endotoxin (lipopolysaccharide; LPS)-related inflammatory disorders using UTI-deficient (-/-) and corresponding wild-type mice.

What the reader will gain: Our experiments using genetic approach suggest that endogenous UTI can protect against the systemic inflammatory response and subsequent organ injury induced by LPS, at least partly, through the inhibition of pro-inflammatory cytokine and chemokine expression, which provide important in vivo evidence and understanding about a protective role of UTI in inflammatory conditions.

Take home message: Using genetically targeted mice selectively lacking UTI, UTI has been evidenced to provide an attractive ‘rescue’ therapeutic option for endotoxin-related inflammatory disorders such as DIC, acute lung injury and acute liver injury.