Articles on Inflammation & Cancer 

Khansari N. Shakiba Y. Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. [Review] [93 refs] Recent Patents on Inflammation & Allergy Drug Discovery. 3(1):73-80, 2009. Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes. Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders. This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging processes. 

Bromberg J. Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link.[comment]. Cancer Cell. 15(2):79-80, 2009 There is growing evidence that tumors are sustained and promoted by inflammatory signals from the surrounding microenvironment. Two papers by Grivennikov et al. and Bollrath et al. in this issue of Cancer Cell demonstrate the importance of the interleukin-6 family of proinflammatory cytokines and their downstream effector STAT3 in colitis-associated colon cancer. 

Walser T. Cui X. Yanagawa J. Lee JM. Heinrich E. Lee G. Sharma S. Dubinett SM. Smoking and lung cancer: the role of inflammation. Proceedings of the American Thoracic Society. 5(8):811-5, 2008 Worldwide over 1 million people die due to lung cancer each year. It is estimated that cigarette smoking explains almost 90% of lung cancer risk in men and 70 to 80% in women. Clinically evident lung cancers have multiple genetic and epigenetic abnormalities. These abnormalities may result in activation of oncogenes and inactivation of tumor-suppressor genes. Chronic inflammation, which is known to promote cancer, may result both from smoking and from genetic abnormalities. These mediators in turn may be responsible for increased macrophage recruitment, delayed neutrophil clearance, and increase in reactive oxygen species (ROS). Thus, the pulmonary environment presents a unique milieu in which lung carcinogenesis proceeds in complicity with the host cellular network. The pulmonary diseases that are associated with the greatest risk for lung cancer are characterized by abundant and deregulated inflammation. Pulmonary disorders such as chronic obstructive pulmonary disease (COPD)/emphysema are characterized by profound abnormalities in inflammatory and fibrotic pathways. The cytokines and growth factors aberrantly produced in COPD and the developing tumor microenvironment have been found to have deleterious properties that simultaneously pave the way for both epithelial-mesenchymal transition (EMT) and destruction of specific host cell-mediated immune responses. Full definition of these pathways will afford the opportunity to intervene in specific inflammatory events mediating lung tumorigenesis and resistance to therapy. 

Karan D. Holzbeierlein J. Thrasher JB. Macrophage inhibitory cytokine-1: possible bridge molecule of inflammation and prostate cancer. [Review] [35 refs] Cancer Research. 69(1):2-5, 2009 There is emerging evidence that inflammation may lead to prostate cancer development. Although inflammation is an essential response to injury or infection, chronic inflammation is harmful and causes tissue damage. Increasing evidence suggests that inflammation leads to the development of epithelial cancers; however, studies on inflammation-targeted genes that might contribute to the development of cancer are at the beginning stage. Here, we describe macrophage inhibitory cytokine-1, which provides a potential link between inflammation and prostate cancer. Understanding the regulation of macrophage inhibitory cytokine-1 in response to inflammation may have potential for novel therapeutic strategies. 

Fraser CC. G protein-coupled receptor connectivity to NF-kappaB in inflammation and cancer. [Review] [204 refs] International Reviews of Immunology. 27(5):320-50, 2008. Complex intracellular network interactions regulate gene expression and cellular behavior. Whether at the site of inflammation or within a tumor, individual cells are exposed to a plethora of signals. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes that control key cellular activities involved in inflammatory diseases and cancer. NF-kappaB is regulated by several distinct signaling pathways that may be activated individually or simultaneously. Multiple ligands and heterologous cell-cell interactions have an impact on NF-kappaB activity. The G protein-coupled receptor (GPCR) superfamily makes up the largest class of transmembrane receptors in the human genome and has multiple molecularly distinct natural ligands. GPCRs regulate proliferation, differentiation, and chemotaxis and play a major role in inflammatory diseases and cancer. Both GPCRs and NF-kappaB have been, and continue to be, major targets for drug discovery. A clear understanding of network interactions between GPCR signaling pathways and those that control NF-kB may be valuable for the development of better drugs and drug combinations. 

Hahn MA. Hahn T. Lee DH. Esworthy RS. Kim BW. Riggs AD. Chu FF. Pfeifer GP. Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. Cancer Research. 68(24):10280-9, 2008 Epigenetic changes are strongly associated with cancer development. DNA hypermethylation is associated with gene silencing and is often observed in CpG islands. Recently, it was suggested that aberrant CpG island methylation in tumors is directed by Polycomb (PcG) proteins. However, specific mechanisms responsible for methylation of PcG target genes in cancer are not known. Chronic infection and inflammation contribute to up to 25% of all cancers worldwide. Using glutathione peroxidase, Gpx1 and Gpx2, double knockout (Gpx1/2-KO) mice as a model of inflammatory bowel disease predisposing to intestinal cancer, we analyzed genome-wide DNA methylation in the mouse ileum during chronic inflammation, aging, and cancer. We found that inflammation leads to aberrant DNA methylation in PcG target genes, with 70% of the approximately 250 genes methylated in the inflamed tissue being PcG targets in embryonic stem cells and 59% of the methylated genes being marked by H3K27 trimethylation in the ileum of adult wild-type mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx1/2-KO mice frequently correlates with loss of H3K27 trimethylation at the same loci. Inflammation-associated DNA methylation occurs preferentially in tissue-specific silent genes and, importantly, is much more frequently represented in tumors than is age-dependent DNA methylation. Sixty percent of aberrant methylation found in tumors is also present in the inflamed tissue. In summary, inflammation creates a signature of aberrant DNA methylation, which is observed later in the malignant tissue and is directed by the PcG complex. 

Germano G. Allavena P. Mantovani A. Cytokines as a key component of cancer-related inflammation. [Review] [85 refs] Cytokine. 43(3):374-9, 2008 Inflammatory conditions in some tissues increase the risk of cancer. Cytokines and chemokines are components of an intensive dialog promoting angiogenesis, metastasis, subversion of adaptive immunity and changing response to hormones and to chemotherapeutic agents. Cytokines involved in cancer-related inflammation represent a target for innovative diagnostic and therapeutic strategies, and a future challenge for scientists and clinicians. 

Hofseth LJ. Nitric oxide as a target of complementary and alternative medicines to prevent and treat inflammation and cancer. [Review] [374 refs] Cancer Letters. 268(1):10-30, 2008 Nitric oxide (NO) and associated reactive nitrogen species (RNS) are involved in many physiological functions. There has been an ongoing debate to whether RNS can inhibit or perpetuate chronic inflammation and associated carcinogenesis. Although the final outcome depends on the genetic make-up of its target, the surrounding microenvironment, the activity and localization of nitric oxide synthase (NOS) isoforms, and overall levels of NO/RNS, evidence is accumulating that in general, RNS drive inflammation and cancers associated with inflammation. To this end, many complementary and alternative medicines (CAMs) that work in chemoprevention associated with chronic inflammation, are inhibitors of excessive NO observed in inflammatory conditions. Here, we review recent literature outlining a role of NO/RNS in chronic inflammation and cancer, and point toward NO as one of several targets for the success of CAMs in treating chronic inflammation and cancer associated with this inflammation. 

Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation. [Review] [98 refs] Nature. 454(7203):436-44, 2008 The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment. 

Allavena P. Garlanda C. Borrello MG. Sica A. Mantovani A. Pathways connecting inflammation and cancer. [Review] [73 refs] Current Opinion in Genetics & Development. 18(1):3-10, 2008. Chronic and persistent inflammation contributes to cancer development and can predispose to carcinogenesis. Infection-driven inflammations are involved in the pathogenesis of approximately 15-20% of human tumors. However, even tumors that are not epidemiologically linked to pathogens are characterized by the presence of an inflammatory component in their microenvironment. Hallmarks of cancer-associated inflammation include the presence of infiltrating leukocytes, cytokines, chemokines, growth factors, lipid messengers, and matrix-degrading enzymes. Schematically, two interrelated pathways link inflammation and cancer: (1) genetic events leading to neoplastic transformation promote the construction of an inflammatory milieu; (2) tumor-infiltrating leukocytes, in particular macrophages, are prime regulators of cancer inflammation. Thus, an intrinsic pathway of inflammation (driven in tumor cells), as well as an extrinsic pathway (in tumor-infiltrating leukocytes) have been described and both contribute to tumor progression.

Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation. [Review] [98 refs] Nature. 454(7203):436-44, 2008. The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

Farinati F. Cardin R. Cassaro M. Bortolami M. Nitti D. Tieppo C. Zaninotto G. Rugge M. Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway. [Review] [73 refs] European Journal of Cancer Prevention. 17(3):195-200, 2008. Gastric carcinogenesis is a complex, multistep and multifactorial event, characterized by progressive cyto-histological dedifferentiation, in which the role of Helicobacter pylori infection has been established. Among the pathways relevant to gastric carcinogenesis and correlated with H. pylori infection, it has been demonstrated that the production of reactive oxygen species, with damage to the DNA, may be quite important. Oxidative damage, alone and/or in combination with exogenous and endogenous factors, induces several molecular changes. The assumption is that, in precancerous lesions, these molecular changes belong to the same biological spectrum as their invasive counterpart. The molecular profile of these preneoplastic lesions is heterogeneous, however, and there are still no molecular markers enabling the distinction between atypical hyperplastic lesions and low-grade noninvasive neoplasia (NiN) or between high-grade NiN and early invasive neoplasia. Indeed, within the spectrum of morphological changes characterizing this multistep evolution, dysplasia (NiN) is the lesion coming closest to the development of invasive adenocarcinoma. Several of the genetic and epigenetic alterations reported in gastric precancerous lesions affect DNA repair system genes, tumor suppressor genes, oncogenes, cell cycle regulators, growth factors, and adhesion molecules. Although we await reliable molecular markers, it is best to monitor patients harboring NiN closely with endoscopy and extensive bioptic sampling, and to eradicate any H. pylori to prevent the accumulation of oxidative DNA damage and its consequent progression. The growing body of evidence of the regression of precancerous changes and the high prevalence of superficial gastric carcinoma demonstrated in long-term follow-up studies on NiN make this approach mandatory.

Hojilla CV. Wood GA. Khokha R. Inflammation and breast cancer: metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer. [Review] [86 refs] Breast Cancer Research. 10(2):205, 2008. Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease and uncover novel therapeutic strategies. The metalloproteinase class of enzymes is well studied in mammary gland development and physiology, but mostly in the context of extracellular matrix modification. Aberrant metalloproteinase expression has also been implicated in breast cancer progression, where these genes act as tumor modifiers. Here, we review how the metalloproteinase axis impacts mammary physiology and tumorigenesis and is associated with inflammatory cell influx in human breast cancer, and evaluate its potential as a regulator of inflammation in the mammary gland.

DeNardo DG. Johansson M. Coussens LM. Immune cells as mediators of solid tumor metastasis. [Review] [87 refs] Cancer & Metastasis Reviews. 27(1):11-8, 2008. Outgrowths of disseminated metastases remain the primary cause of mortality in cancer patients; however, molecular and cellular mechanisms regulating metastatic spread remain largely elusive. Recent insights into these mechanisms have refined the seed and soil hypothesis and it is now recognized that metastasis of solid tumors requires collaborative interactions between malignant cells and a diverse assortment of "activated" stromal cells at both primary and secondary tumor locations. Specifically, persistent pro-tumor immune responses (inflammation), now generally accepted as potentiating primary tumor development, are also being recognized as mediators of cancer metastasis. Thus, novel anti-cancer therapeutic strategies targeting molecular and/or cellular mechanisms regulating these collaborative interactions may provide efficacious relief for metastatic disease. This review focuses on recent literature revealing new mechanisms whereby immune cells regulate metastatic progression, with a primary focus on breast cancer. 

Levine PH. Veneroso C. The epidemiology of inflammatory breast cancer. [Review] [33 refs] Seminars in Oncology. 35(1):11-6, 2008. The epidemiology of inflammatory breast cancer (IBC) has been of great interest to a number of investigators, but epidemiological research has been hampered by the lack of an agreed upon case definition and the relatively small number of patients available to any single investigator or institution. Several features of IBC have become apparent through population-based studies, which, although varying somewhat in case definition, generally agree on some key features of the disease. These include the incidence of the disease, apparently less than 3% of breast cancer cases in the United States, the younger age of onset compared to non-inflammatory breast cancer, the much higher incidence in Black women compared to White, the generally poor outcome of this disease compared to non-inflammatory breast cancer, and the continued increase in reported incidence, particularly as compared with non-inflammatory breast cancer in general and locally advanced breast cancer (LABC) in particular. There is an apparent striking geographic pattern, with a higher percentage of cases reported from North Africa, best documented in Tunisia. The risk factors for developing IBC are suggested by smaller studies with concordant conclusions, and some appear to be different than the risk factors for developing breast cancer in general. For example, obesity appears to be a risk factor for premenopausal IBC but is not for premenopausal non-inflammatory breast cancer. In addition, there is evidence that a young age at first birth predisposes to IBC but is protective against developing non-inflammatory breast cancer. In some malignancies, the use of molecular markers is helpful in defining subgroups that could assist in improving case definition as well as predicting prognosis. The increasing combination of improved epidemiologic and laboratory methods will hopefully accelerate our understanding of this challenging disease. 

Stock D. Groome PA. Siemens DR. Inflammation and prostate cancer: a future target for prevention and therapy?. [Review] [117 refs] Urologic Clinics of North America. 35(1):117-30; vii, 2008. Given its long natural history, prostate cancer has become an ideal model for the clinical and basic science study of neoplastic disease in distinct pathologic phases: tumor initiation, progression, invasion, and metastasis. Chronic or recurrent acute inflammation, a product of infectious agents or other sources, has potential promotional roles in each of these phases. Nonsteroidal anti-inflammatory drugs (NSAIDs), because of their ability to attenuate inflammation, as well as possibly direct anti-cancer properties associated with the inhibition of stromal cyclooxygenase-2, are potential candidates for clinical use in prostate cancer. Though epidemiologic evidence indicating a reduced risk of prostate cancer for NSAID users supports a chemoprotective benefit, observational assessment and clinical trials of these agents among large cohorts of prostate cancer patients are needed to determine their value in prostate cancer management. 

Hold GL. El-Omar ME. Genetic aspects of inflammation and cancer. [Review] [155 refs] Biochemical Journal. 410(2):225-35, 2008. Chronic inflammation is involved in the pathogenesis of most common cancers. The aetiology of the inflammation is varied and includes microbial, chemical and physical agents. The chronically inflamed milieu is awash with pro-inflammatory cytokines and is characterized by the activation of signalling pathways that cross-talk between inflammation and carcinogenesis. Many of the factors involved in chronic inflammation play a dual role in the process, promoting neoplastic progression but also facilitating cancer prevention. A comprehensive understanding of the molecular and cellular inflammatory mechanisms involved is vital for developing preventive and therapeutic strategies against cancer. The purpose of the present review is to evaluate the mechanistic pathways that underlie chronic inflammation and cancer with particular emphasis on the role of host genetic factors that increase the risk of carcinogenesis. 

Hsing AW. Sakoda LC. Chua S Jr. Obesity, metabolic syndrome, and prostate cancer. [Review] [84 refs] American Journal of Clinical Nutrition. 86(3):s843-57, 2007. Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification. 

Calogero RA. Cordero F. Forni G. Cavallo F. Inflammation and breast cancer. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. [Review] [44 refs] Breast Cancer Research. 9(4):211, 2007. ABSTRACT : This review addresses genes differentially expressed in the mammary gland transcriptome during the progression of mammary carcinogenesis in BALB/c mice that are transgenic for the rat neu (ERBB2, or HER-2/neu) oncogene (BALB-neuT664V-E mice). The Ingenuity knowledge database was used to characterize four functional association networks whose hub genes are directly linked to inflammation (specifically, the genes encoding IL-1beta, tumour necrosis factor, interferon-gamma, and monocyte chemoattractant protein-1/CC chemokine ligand-2) and are increasingly expressed during such progression. In silico meta-analysis in a human breast cancer dataset suggests that proinflammatory activation in the mammary glands of these mice reflects a general pattern of human breast cancer. 

DeNardo DG. Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. [Review] [113 refs] Breast Cancer Research. 9(4):212, 2007. Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response elicited. Acute tumor-directed immune responses involving cytolytic T lymphocytes appear to protect against tumor development, whereas immune responses involving chronic activation of humoral immunity, infiltration by Th2 cells, and protumor-polarized innate inflammatory cells result in the promotion of tumor development and disease progression. Herein we review this body of literature and summarize important new findings revealing the paradoxical role of innate and adaptive leukocytes as regulators of breast carcinogenesis. 

Howe LR. Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. [Review] [82 refs] Breast Cancer Research. 9(4):210, 2007. Many human cancers exhibit elevated prostaglandin (PG) levels due to upregulation of cyclooxygenase-2 (COX-2), a key enzyme in eicosanoid biosynthesis. COX-2 over-expression has been observed in about 40% of cases of invasive breast carcinoma and at a higher frequency in preinvasive ductal carcinoma in situ tumors, Extensive pharmacologic and genetic evidence implicates COX enzymes in neoplasia. Epidemiologic analyses demonstrate a protective effect of COX-inhibiting nonsteroidal anti-inflammatory drugs with respect to human cancer. Complementary experimental studies have established that both conventional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors suppress mammary tumor formation in rodent breast cancer models. Furthermore, knocking out Cox-2 reduces mammary tumorigenesis and angiogenesis, and, conversely, transgenic COX-2 over-expression induces tumor formation. The utility of COX/PG signaling as a target for chemoprevention has been established by randomized controlled clinical trials. However, these studies also identified increased cardiovascular risk associated with use of selective COX-2 inhibitors. Thus, current efforts are directed toward identifying safer approaches to antagonizing COX/PG signaling for cancer prevention and treatment, with a particular focus on PGE2 regulation and signaling, because PGE2 is a key pro-tumorigenic prostanoid. 

Mantovani A. Marchesi F. Porta C. Sica A. Allavena P. Inflammation and cancer: breast cancer as a prototype. [Review] [79 refs] Breast. 16 Suppl 2:S27-33, 2007. Tumor-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, including promotion of angiogenesis, matrix remodeling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy. 

Rakoff-Nahoum S. Why cancer and inflammation?. [Review] [60 refs] Yale Journal of Biology & Medicine. 79(3-4):123-30, 2006. Central to the development of cancer are genetic changes that endow these "cancer cells" with many of the hallmarks of cancer, such as self-sufficient growth and resistance to anti-growth and pro-death signals. However, while the genetic changes that occur within cancer cells themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and progression are dependent on ancillary processes provided by cells of the tumor environment but that are not necessarily cancerous themselves. Inflammation has long been associated with the development of cancer. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer. 

Talmadge JE. Donkor M. Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. [Review] [337 refs] Cancer & Metastasis Reviews. 26(3-4):373-400, 2007. Inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, creating a Dr. Jekyll or Mr. Hyde conundrum when examining mechanisms of action. This is due to tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. Tumor infiltration by macrophages is generally associated with neoangiogenesis and negative outcomes, whereas dendritic cell (DC) infiltration is typically associated with a positive clinical outcome in association with their ability to present tumor antigens (Ags) and induce Ag-specific T cell responses. Myeloid-derived suppressor cells (MDSCs) also infiltrate tumors, inhibiting immune responses and facilitating tumor growth and metastasis. In contrast, T cell infiltration of tumors provides a positive prognostic surrogate, although subset analyses suggest that not all infiltrating T cells predict a positive outcome. In general, infiltration by CD8(+) T cells predicts a positive outcome, while CD4(+) cells predict a negative outcome. Therefore, the analysis of cellular phenotypes and potentially spatial distribution of infiltrating cells are critical for an accurate assessment of outcome. Similarly, cellular infiltration of metastatic foci is also a critical parameter for inducing therapeutic responses, as well as establishing tumor dormancy. Current strategies for cellular, gene, and molecular therapies are focused on the manipulation of infiltrating cellular populations. Within this review, we discuss the role of tumor infiltrating, myeloid-monocytic cells, and T lymphocytes, as well as their potential for tumor control, immunosuppression, and facilitation of metastasis. 

Douglas JL. Gustin JK. Dezube B. Pantanowitz JL. Moses AV. Kaposi's sarcoma: a model of both malignancy and chronic inflammation. [Review] [186 refs] Panminerva Medica. 49(3):119-38, 2007. Kaposi's sarcoma (KS) is a complex cancer characterized by angioproliferative multifocal tumors of the skin, mucosa and viscera. KS lesions are comprised of both distinctive spindle cells of endothelial origin and a variable inflammatory infiltrate. There are four different epidemiological forms of KS: classic (sporadic), African (endemic), AIDS-associated (epidemic), and immunosupression-associated (iatrogenic). Although these various forms of KS have different environmental and immunological components, the development of each depends upon infection with Kaposi's sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV8). KSHV encodes an arsenal of gene products that induce cellular proliferation, transformation, cell signaling, cytokine production, immune evasion, antiapoptosis and angiogenesis. Yet, KSHV alone is insufficient to give rise to KS. The exact origin of the tumor cell (spindle cell), which is generally agreed to be a type of endothelial cell, remains elusive. Current evidence supports their derivation from lymphatic endothelium. However, both lymphatic and vascular endothelial cell types can be infected by KSHV in vitro, and recent studies suggest that this virus may reprogram the target cell, thus masking the cell's true origin. It is also possible that the original target cell is an uncommitted progenitor. In addition to the potentially neoplastic spindle cells, the KS lesion also contains dendritic cells, macrophages, plasma cells and lymphocytes. The presence of this admixed immune infiltrate has led to the suggestion that KS may result from reactive hyperproliferation induced by chronic inflammation, and that it is therefore not a true neoplasm. This review details the data that support KS as a model of both oncogenesis and chronic inflammation. 

Federico A. Morgillo F. Tuccillo C. Ciardiello F. Loguercio C. Chronic inflammation and oxidative stress in human carcinogenesis. [Review] [103 refs] International Journal of Cancer. 121(11):2381-6, 2007. A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastic transformation. In general, the longer the inflammation persists, the higher the risk of cancer. A mutated cell is a sine qua non for carcinogenesis. Inflammatory processes may induce DNA mutations in cells via oxidative/nitrosative stress. This condition occurs when the generation of free radicals and active intermediates in a system exceeds the system's ability to neutralize and eliminate them. Inflammatory cells and cancer cells themselves produce free radicals and soluble mediators such as metabolites of arachidonic acid, cytokines and chemokines, which act by further producing reactive species. These, in turn, strongly recruit inflammatory cells in a vicious circle. Reactive intermediates of oxygen and nitrogen may directly oxidize DNA, or may interfere with mechanisms of DNA repair. These reactive substances may also rapidly react with proteins, carbohydrates and lipids, and the derivative products may induce a high perturbation in the intracellular and intercellular homeostasis, until DNA mutation. The main substances that link inflammation to cancer via oxidative/nitrosative stress are prostaglandins and cytokines. The effectors are represented by an imbalance between pro-oxidant and antioxidant enzyme activities (lipoxygenase, cyclooxygenase and phospholipid hydroperoxide glutathione-peroxidase), hydroperoxides and lipoperoxides, aldehydes and peroxinitrite. This review focalizes some of these intricate events by discussing the relationships occurring among oxidative/nitrosative/metabolic stress, inflammation and cancer. 

Perwez Hussain S. Harris CC. Inflammation and cancer: an ancient link with novel potentials. [Review] [128 refs] International Journal of Cancer. 121(11):2373-80, 2007. Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and post-translational modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer. Recent discovery of an interaction between microRNAs and innate immunity during inflammation has further strengthened the association between inflammation and cancer. 

Raman D. Baugher PJ. Thu YM. Richmond A. Role of chemokines in tumor growth. [Review] [280 refs] Cancer Letters. 256(2):137-65, 2007. Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma-associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed. 

Peebles KA. Lee JM. Mao JT. Hazra S. Reckamp KL. Krysan K. Dohadwala M. Heinrich EL. Walser TC. Cui X. Baratelli FE. Garon E. Sharma S. Dubinett SM. Inflammation and lung carcinogenesis: applying findings in prevention and treatment. [Review] [228 refs] Expert Review of Anticancer Therapy. 7(10):1405-21, 2007. Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer. 

Bower JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. [Review] [52 refs] Brain, Behavior, & Immunity. 21(7):863-71, 2007. Fatigue is one of the most common and distressing side effects of cancer and its treatment and may persist long after successful treatment completion. Emerging evidence suggests that inflammatory processes may be involved in cancer-related fatigue both during and after treatment. In this review, we consider the evidence for an association between inflammation and fatigue in cancer patients and survivors. Further, we identify potential mechanisms for persistent inflammation, focusing on the HPA axis. Risk factors and treatments for cancer-related fatigue are also discussed. 

de Moraes E. Dar NA. de Moura Gallo CV. Hainaut P. Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis. [Review] [92 refs] International Journal of Cancer. 121(5):929-37, 2007. Overexpression of Cyclooxygenase-2 (COX-2) is observed in most tumor types. Increased COX-2 activity and synthesis of prostaglandins stimulates proliferation, angiogenesis, invasiveness and inhibits apoptosis. Many stress and proinflammatory signals induce COX-2 expression, including oxyradicals or DNA-damaging agents. The latter also induces p53, a transcription factor often inactivated by mutation in cancer. Several studies have identified complex cross-talks between p53 and COX-2, whereby p53 can either up- or down-regulate COX-2, which in turn controls p53 transcriptional activity. However, the molecular basis of these effects are open to debate, in particular since no p53 binding sequences have been identified in COX-2 regulatory regions. In this review, we summarize the molecular mechanisms by which COX-2 contributes to carcinogenesis and discuss the experimental set-up, results and conclusions of studies analyzing cross-talks between p53 and COX-2. We propose 2 scenarios accounting for overexpression of COX-2 in precursor and cancer lesions. In the "inflammatory" scenario, p53, activated by DNA damage induced by oxygen and nitrogen species, recruits NF-kappaB to activate COX-2, resulting in antiapoptotic effects that contribute to cell expansion in inflammatory precursor lesions. In the "constitutive proliferation" scenario, oncogenic stress due to activation of growth signaling cascades may upregulate COX-2 promoter independently of NF-kappaB and p53, synergizing with TP53 mutation to promote cancer progression. These 2 scenarios, although not mutually exclusive, may account for the diversity of the correlations between COX-2 expression and TP53 mutation, which vary according to cancer types and biological contexts, and have implications for the use of COX-2 inhibitors in cancer prevention and therapy. 

Lin WW. Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. [Review] [125 refs] Journal of Clinical Investigation. 117(5):1175-83, 2007. It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression. 

Nelson WG. Prostate cancer prevention. [Review] [156 refs] Current Opinion in Urology. 17(3):157-67, 2007. PURPOSE OF REVIEW: Prostate cancer, a common cause of morbidity and mortality in the developed world, ought to be a preventable disease. This review focuses on prostate cancer prevention in the context of new mechanistic insights into human prostatic carcinogenesis. RECENT FINDINGS: Evidence is accumulating to implicate infection and inflammation as contributors to prostate cancer development. Inherited prostate cancer susceptibility genes discovered thus far encode participants in host responses to infection. Proliferative inflammatory atrophy, a prostate cancer precursor lesion, ties inflammatory responses to prostatic carcinogenesis. Somatic epigenetic alterations, present in all prostate cancers, appear to arise in the setting of inflammation. Finally, a newly identified somatic genome change, involving a fusion between an androgen-regulated gene, TMPRSS2, and genes encoding members of the ETS family of transcription factors, may provide a clue as to why prostate cancer cells exhibit androgen dependence for growth and survival. SUMMARY: The contributions of infection and inflammation to the early development of prostate cancer suggest prevention strategies featuring prevention or eradication of infection, amelioration of inflammation, or attenuation of genome-damaging reactive oxygen and nitrogen species. The acquisition of androgen dependence later during prostate cancer pathogenesis suggests the use of approaches targeting androgen signaling, including inhibitors of 5alpha-reductase. 

De Marzo AM. Platz EA. Sutcliffe S. Xu J. Gronberg H. Drake CG. Nakai Y. Isaacs WB. Nelson WG. Inflammation in prostate carcinogenesis. [Review] [158 refs] Nature Reviews. Cancer. 7(4):256-69, 2007. About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease. 

Tan TT. Coussens LM. Humoral immunity, inflammation and cancer. [Review] [54 refs] Current Opinion in Immunology. 19(2):209-16, 2007. Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironments where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Population-based studies examining individuals with chronic inflammatory disorders have revealed that states of suppressed cellular immunity, in combination with enhanced humoral immunity and humoral immunity-associated cytokines, cooperate and effectively suppress anti-tumor immune responses while simultaneously enhancing angiogenesis and presumably overall cancer risk in afflicted tissue. In addition, studies in transgenic mouse models of de novo organ-specific cancer development have revealed that inflammation mediated by immunoglobulins and immune complexes might be functionally significant parameters of tumor promotion and progression. These recent advances support the hypothesis that enhanced states of local humoral and innate immune activation, in combination with suppressed cellular immunity and failed cytotoxic T cell anti-tumor immunity, alter cancer risk and therefore represent powerful targets for anti-cancer immunotherapeutics. 

Wistuba II. Genetics of preneoplasia: lessons from lung cancer. [Review] [121 refs] Current Molecular Medicine. 7(1):3-14, 2007. From biological, histopathologic, and clinical perspectives, lung cancer is a highly complex neoplasm probably having multiple preneoplastic pathways. The sequence of histopathologic changes in the bronchial mucosa that precedes the development of squamous carcinomas of the lung has been identified. For the other major forms of lung cancer, however, such sequences have been poorly documented. This review summarizes the current knowledge regarding the molecular and histopathologic pathogenesis of lung cancer and discusses the complexity of identifying novel molecular mechanisms involved in the development of the lung premalignant disease, and their relevance to the development of new strategies for early detection and chemoprevention. Although our current knowledge of the molecular pathogenesis of lung cancer is still meager, work over the last decade has taught several important lessons about the molecular pathogenesis of this tumor, including the following: a) Better characterization of the high-risk population is needed. b) There are several histopathologic and molecular pathways associated with the development of the major types of non-small cell lung cancer. c) Although there is a field effect phenomenon for lung preneoplastic lesions, recent data suggest that there are at least two distinct lung airway compartments (central and peripheral) for lung cancer pathogenesis. d) Inflammation may play an important role in lung cancer development and could be an important component of the field effect phenomenon. e) For lung adenocarcinoma, at least two pathways (smoking-related and nonsmoking-related) have been identified. f) Finally, the identification of deregulated molecular signaling pathways in lung cancer preneoplasias may provide a rationale for designing novel strategies for early detection and targeted chemoprevention of lung cancer. 

Garodia P. Ichikawa H. Malani N. Sethi G. Aggarwal BB. From ancient medicine to modern medicine: ayurvedic concepts of health and their role in inflammation and cancer. [Review] [104 refs] Journal Of The Society For Integrative Oncology. 5(1):25-37, 2007. Recent statistics indicate that the overall cancer incidence in the United States, in spite of billions of dollars spent on research each year, has not changed significantly in the last half-century. Cancers of the prostate, breast, lung, and colon, although most common in the Western world, are least common in the Eastern world. Allopathic medicine commonly practiced currently is only 100 years old. Although traditional medicine has been around for thousands of years, no integration exists between it and allopathic medicine. Ayurveda, the science of long life and one of the most ancient medical systems still practiced on the Indian subcontinent, can be used in combination with modern medicine to provide better treatment of cancer. This review focuses on the ayurvedic concept of the causes of cancer and its linkage with inflammation, diagnosis, prevention, and treatment. How ayurvedic medicine can be integrated with allopathic medicine is also discussed in this review. 

Fox JG. Wang TC. Inflammation, atrophy, and gastric cancer. [Review] [126 refs] Journal of Clinical Investigation. 117(1):60-9, 2007. The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world's population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment. 

Hofseth LJ. Wargovich MJ. Inflammation, cancer, and targets of ginseng. [Review] [36 refs] Journal of Nutrition. 137(1 Suppl):183S-185S, 2007. Chronic inflammation is associated with a high cancer risk. At the molecular level, free radicals and aldehydes, produced during chronic inflammation, can induce deleterious gene mutation and posttranslational modifications of key cancer-related proteins. Other products of inflammation, including cytokines, growth factors, and transcription factors such as nuclear factor kappaB, control the expression of cancer genes (e.g., suppressor genes and oncogenes) and key inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen species and eicosanoid levels. The procancerous outcome of chronic inflammation is increased DNA damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways and cellular milieu, inhibition of apoptosis, and promotion of angiogenesis and invasion. Chronic inflammation is also associated with immunosuppression, which is a risk factor for cancer. Current treatment strategies for reactive species overload diseases are frequently aimed at treating or preventing the cause of inflammation. Although these strategies have led to some progress in combating reactive species overload diseases and associated cancers, exposure often occurs again after eradication, treatment to eradicate the cause fails, or the treatment has long-term side effects. Therefore, the identification of molecules and pathways involved in chronic inflammation and cancer is critical to the design of agents that may help in preventing the progression of reactive species overload disease and cancer associated with disease progression. Here, we use ginseng as an example of an antiinflammatory molecule that targets many of the key players in the inflammation-to-cancer sequence.