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World J Gastroenterol. Aug 7, 2014; 20(29): 9716-9731
Published online Aug 7, 2014. doi: 10.3748/wjg.v20.i29.9716
Inflammatory pathways in the early steps of colorectal cancer development
Francesco Mariani, Paola Sena, Luca Roncucci
Francesco Mariani, Luca Roncucci, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
Paola Sena, Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, 41124 Modena, Italy
Author contributions: Mariani F, Sena P, Roncucci L solely contributed to this paper.
Supported by The Fondazione Umberto Veronesi (FUV) and the Associazione Ricerca Tumori Intestinali (ARTI) of Modena
Correspondence to: Luca Roncucci, MD, PhD, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via Università, 4, 41124 Modena, Italy.
Telephone: +39-59-4224052 Fax: +39-59-4222958
Received: September 27, 2013
Revised: December 5, 2013
Accepted: April 21, 2014
Published online: August 7, 2014


Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal.

Key Words: Myeloperoxidase, Colorectal carcinogenesis, Inflammation, Aberrant crypt foci, Autophagy, Hypoxia, Apoptosis

Core tip: This paper examines the most important inflammatory pathways involved in the very early steps of colorectal carcinogenesis. In particular, it emphasizes the role played by cells of the immune system and key proteins, like cyclooxygenases, resistins, hypoxia-inducible factor 1, nuclear factor E2-related factor 2, and sirtuins, in fostering changes in mechanisms, like cell proliferation, DNA damage, apoptosis and autophagy, anaerobial metabolism and tissue remodeling, considered central for colorectal cancer development.


Colorectal cancer is still a major health concern. In recent years new hypotheses have been considered on the mechanisms involved in the early stages of colorectal carcinogenesis. Among them, it has been postulated that inflammation, and in general colorectal mucosa injury caused by several environmental agents, can play an important role. Indeed, tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. If the immune response fails to resolve injury, a microenvironment rich in cytokines, growth factors, and products of cellular respiration substaines a prolonged proliferation in attempt to repair, resulting in the accumulation of genetic errors and continued inappropriate proliferation. Evidence supports a role for inflammatory responses in the development of colorectal cancer. Chronic inflammation of the large bowel [as in inflammatory bowel diseases (IBD)], has been associated with the subsequent development of colorectal cancer.

Here we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. A second chapter is targeted to the description of the tumor microenvironment and its oxidative and anaerobic metabolism. Finally, the role of inflammation in colorectal tissue remodelling is discussed.


Macrophages (Mfs) represent 10%-20% of all mononuclear cells found in the intestinal lamina propria making the intestine the largest reservoir of Mfs in humans.

Type I macrophages (M1) (classical activated) as cells able to produce large amounts of proinflammatory cytokines, are implicated in the mechanism of killing pathogens and tumor cells by secreting agents such as tumor necrosis factor α (TNF-α), interleukin (IL)-12, reactive nitrogen (iNOS), and oxygen intermediates (ROS). In contrast, Type II macrophages (M2) (alternative activated), generated by various signals which include IL-4, IL-13, IL-10, and glucocorticoid hormones, moderate the inflammatory response, eliminate cell wastes, promote angiogenesis and tissue remodeling, and release cytokines, including IL-10[1-4].

Macrophages in tumors, usually termed tumor-associated macrophages (TAMs), play important roles in determining the clinical outcome, and often express the M2 phenotype. M1 macrophages are often abundant in chronic inflammatory sites, and where tumors are initiated and start to develop. Moreover, it is possible that the macrophages switch to an M2-like phenotype as the tumor begins to invade, vascularize, and develop [5,6].

IL-23 is produced by macrophages within a few hours after the activation. This, in turn, triggers rapid IL-17 responses from tissue-resident macrophages. IL-17 promotes the production of IL-1, IL-6, IL-8, CXC ligand 1 and TNF-α in stromal, epithelial and endothelial cells, and also in a subset of monocytes. Together, these proinflammatory cytokines rapidly recruit neutrophils to the site of infection. Neutrophils normally traffic to peripheral tissues, where they are phagocytosed by Mfs after transmigration and apoptosis. Apoptotic cell phagocytosis might downregulate IL-23 secretion and then curb IL-17 and granulocyte colony stimulating factor (G-CSF) production and eventually granulopoiesis. If this processes were interrupted, tissue Mfs would continue to express IL-23. This could drive IL-17 expression and increase neutrophils retrieval in peripheral tissues[7-9].

The production of arginase has been associated with M2 type macrophages. The switch from (nitric oxide) NO production to induction of arginase in these “alternatively activated” cells up-regulates polyamine and proline biosynthesis, that can stimulate cell replication, collagen deposition, and tissue repair[10,11]. Some in vivo evidences indicate that an exacerbated local M1 macrophage-like inflammation favors oxidative microenvironment, while M2 macrophage-like inflammation substains progressive tumor growth[12-14] (Figure 1).

Figure 1
Figure 1 Inflammatory cells and proteins in the early phases of colorectal carcinogenesis. A: Inflammation and necrosis lead to monocytes recruitment and macrophages M1 polarization, with establishment of an inflammatory microenvironment and cytokines release [tumor necrosis factor α (TNFα), interleukin (IL)-12, IL-23]. Stromal, epithelial, and endothelial cells express lipooxygenases (5-LOX, 12-LOX), and cyclooxygenases 2 (COX2) proteins, with formation of inflammatory mediators leukotrienes and prostaglandins (i.e., LTB4, PGE2) that drive neutrophils recruitment. Neutrophils, at the site of injury, amplify inflammation through myeloperoxydase (MPO), reactive oxygen species (ROS) and matrix metalloproteinases (MMP); B: If the inflammatory stimulus is switched-off the stromal and epithelial cells expressing 15-LOX drive the formation of pro-resolving mediators lipoxins (LXA4 and LXB4). These lipids block the neutrophils migration and stimulate the phagocytosis of apoptotic neutrophils by macrophages M1. The clearance of neutrophils sustain the switch to M2-phenotype, with secretion of anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGFβ); C: If the stimulus is not resolved, the stromal and epithelial cells amplify the inflammatory signals (through IL-1, IL-8, 5-LOX and 12-LOX). In this way neutrophils apoptosis is inhibited, with continuous tissue and DNA damage by MPO, ROS and MMPs. The macrophages M1 support the inflammatory environment and the phagocyte afflux (IL-23 and IL-17), while M2 macrophages cause tissue remodeling.

Immune cells are known to express specific recognition molecules for cell surface glycans, such as galectins, sialic acid binding Ig-like lectins (siglecs), and selectins. Some carbohydrate determinants are preferentially expressed in nonmalignant epithelial cells, whereas other determinants are expressed in association with cancers. The carbohydrate determinants associated with cancers, such as sialyl Lewis-A or sialyl Lewis-X, are clinically used as tumor markers. Most siglecs are known to inhibit excess activation of immune cells. It is noteworthy that only the glycans that are expressed in normal epithelial cells serve as ligands for siglec-7 and -9, whereas cancer-associated glycans do not. Their expression is lost at the early stage of colon carcinogenesis as a result of epigenetic silencing of glycol-genes involved in their synthesis. The majority of immune cells expressing siglec-7 and -9 in normal colonic mucosa are macrophages/monocytes. The ligation of siglec-7 and -9 suppresses lipopolysaccharide (LPS) induced cyclooxygenases (COX)-2 and PGE2 production. These results suggest that normal glycans of colonic epithelial cells exert a suppressive effect on tissue macrophage COX2 expression in colonic mucosa, thus maintaining immunological homeostasis in normal mucosal membranes. These results also imply that the cancer-associated impaired glycosylation of siglec-7 and -9 ligands serves to enhance COX2 production by mucosal macrophages[15-18].


Neutrophils (polymorphonuclear cells, PMN) have a well-established role in the first line of defence against microbial pathogens but, because of their short life and fully differentiated phenotype, their role in cancer-related inflammation has long been considered negligible.

Upon encountering inflammatory signals, neutrophils change their responsiveness to allow directed migration and enhancement of microbicidal capacity. Neutrophil life-span is influenced during inflammation to enhance their anti-microbial action. Activated PMN are able to produce and release pro-inflammatory mediators, such as IL-1, IL-8, and macrophage inflammatory protein (MIP)-1s. PMN synthesize and store within cytoplasmic granules large quantities of serine proteinases (e.g., neutrophil elastase), enzymes, including myeloperoxidase (MPO) and lysozyme, and ROS. The most abundant granule enzyme is MPO, which forms cytotoxic hypochlorous acid (HOCl) from the reaction of chloride anion with hydrogen peroxide produced after the respiratory burst[19,20].

In addition, cytokines IL-23 and IL-17 activate the inflammatory program of PMN by inducing the synthesis and the release of MPO and metalloproteinases {neutrophil collagenase [matrix metalloproteinases (MMP)-8], gelatinase B (MMP-9)} contributing, like serine proteinases, to tissue destruction through their proteolytic activity.

Once their physiological function has been performed in the tissues, neutrophils change their phenotype from a pro-inflammatory state, where they produce and release pro-inflammatory mediators such as LTB4 and PAF, to a more anti-inflammatory pro-resolution state whereby they release products (e.g., lipoxins) that can influence the resolution phase of inflammation[8,9,21,22].

The resolution of inflammation therefore relies on the effective “switching off’ of the neutrophil, the promotion of apoptosis and the successful recognition and uptake of cells by phagocytes such as macrophages. The apoptotic neutrophils stimulate macrophages into a proresolution phenotype, reducing the inappropriate inflammatory response further. In the intestine, the process of PMN apoptosis can be delayed or accelerated by a number of factors. Several host-derived cytokines, including IL-1, IL-8, and granulocyte-macrophage colony stimulating factor (GM-CSF), inhibit PMN apoptosis. There is now evidence that suggests MPO can act as a paracrine signalling molecule, promoting neutrophil survival. By contrast, the cytokines IL-10 and TNF-α and the products of respiratory burst, can induce apoptosis[23-26].

Under a persistent inflammation, this regulatory mechanism can be compromised. Indeed, it has been demonstrated that a low level of persistent inflammation in normal colorectal mucosa does exist in patients with colorectal cancer or adenomas[27]. Neutrophils continually accumulate within the intestinal mucosa and apoptotic neutrophils that are not eliminated by macrophages undergo secondary necrosis and release the contents of intracellular granules, which can induce pathological tissue damage[28,29] (Figure 1).

COX and resolvins

Lipid mediators such as eicosanoids, which are derived from the arachidonic acid, are among the earliest signals released in response to injury or an inflammatory stimulus. Two families of enzymes, namely, the cyclooxygenases (COX-1 and COX-2) and the lipoxygenases [5-lipoxygenase (5-LOX), 12-LOX, and 15-LOX], metabolize arachidonic acid to form lipid autacoids[30].

The 5-LOX pathway is closely related to chronic inflammation and carcinogenesis. Evidence suggests a potential role of 5-LOX products in early stages of colorectal carcinogenesis. 5-LOX is highly expressed in neutrophils and monocytes and is upregulated upon stimulation with IL-4 and IL-13. During cell activation, arachidonic acid released from membrane phospholipids is converted by 5-LOX in leukotriene B4 (LTB4) or LTC4. Two types of receptors, LTB4 receptor 1 (BLT1) and receptor 2 (BLT2) are known, and BLT1 is mainly involved in inflammatory responses. Overproduction of LTB4 in human colon cancer tissue and LTB4-mediated proliferation of colon cancer cells were reported. It has also been demonstrated a strong expression of BLT1 in the carcinomatous regions of human colon tissues, but not in the normal regions. Leukotriene B4 has been implicated in the pathogenesis of IBD[31-33].

The COX pathway contributes to neutrophil accumulation, and PGE2, a prominent product of the COX-2 pathway, plays a central role in checking leukocyte function by activating a specific PGE2 receptor. During the tissue progression of inflammatory events, PGE2 inhibits the production of proinflammatory cytokines, acts upreguling M2-type responses in Mfs but may also perpetuate chronic inflammatory responses by causing more prooxidant conditions, leading to DNA damage or reduced DNA repair. Thus, chronic inflammation leads to a chronic infiltration of neutrophils and macrophages with consequent damage to tissue. The increase in PGE2 production mediated by overexpression of COX-2, promotes colorectal tumorigenesis and activates the Wnt signaling pathway in colorectal cancer[34-37].

12-LOX metabolites promote cancer cell proliferation, metastasis, and angiogenesis, whereas 15-LOX metabolites seem to be protective against inflammation and carcinogenesis. 15-LOX is important for the resolution of inflammation and for the terminal differentiation of normal cells. 15-LOX enzymes are usually preferentially expressed in normal tissues and benign lesions, but not in carcinoma of the colon. In contrast, 5-LOX and 12-LOX are generally absent in normal epithelia, but they can be induced by pro-inflammatory stimuli, and are often constitutively expressed in various epithelial cancers including colonic ones. A strong correlation between 5-LOX expression and increased polyp size, higher tumor grade and histological epithelial localisation has been reported, and a 5-LOX overexpression has been seen in adenomatous colonic polyps and cancer compared to normal mucosa. This data support a role for 5-LOX in the early stages of colon cancer[38-41]. Signaling pathways leading to PGE2 and PGD2 in turn actively induce the formation of lipoxin (LX) A4 and lipoxin B4, which stop further recruitment of neutrophils and stimulate non-phlogistic monocyte infiltration. Both PGE2 and/or PGD2 switch eicosanoid biosynthesis from predominantly “proinflammatory” LTB4 to “antiinflammatory” LXA4 production. Specific lipoxins and the related members of the resolvin and protectin families provide potent signals that selectively stop neutrophil and eosinophil infiltration; stimulate non-phlogistic recruitment of monocytes (that is, without elaborating pro-inflammatory mediators); promote the uptake and clearance of apoptotic cells and microorganisms by macrophages; increase the exit of phagocytes from the inflamed site through the lymphatics; and stimulate the expression of molecules involved in antimicrobial defence. LXA4 treatment exerts anti-inflammatory responses in immune cells, reducing bowel inflammation via NF-κB and decreasing the damage caused to the intestinal epithelium, and some studies have shown that LXA4 analogs attenuated chemically induced colitis in rodents. Resolvin E1 (RvE1) reduces PMN transendothelial migration, superoxide generation and release, and attenuate colonic mucosal inflammation in vivo, probably by inhibiting phosphorylation of NF-κB and decreasing the levels of pro-inflammatory mediators. The resolvins have also recently been found to influence neutrophil apoptosis by suppressing MPO-induced survival mechanisms with improved resolution of inflammation[42-44].

Therefore, it has been hypothesized that the balance struck by linoleic and arachidonic acid metabolisms in the LOX pathway activity shifts from the antitumorigenic 15-LOX-1 and 15-LOX-2 pathways to the protumorigenic 5-LOX and 12-LOX pathways during tumorigenesis[45] (Figure 1).

Recently a role for the acyl-CoA synthetase 4 (ACSL4) in this shift has been reported. ACSL4 is an enzyme that esterifies arachidonic acid (AA) into arachidonoyl-CoA. It is poorly expressed in the gastrointestinal tract, but its expression is increased in colon cancer. It has been reported that ACSL4 leads to increased COX-2 and LOX-5 levels and controls both lipooxygenase and cyclooxygenase metabolism of AA, resulting in inhibition of apoptosis and increase in cell proliferation. Thus, a new association therapy has been proposed, according to which a concomitant ACSL4, LOX and COX-2 inhibition may reduce side effects and improve cancer treatment[46,47].

DNA damage

The chronic inflammatory response represents a fine balance between active inflammation, repair, and destruction occurring in response to a persistent stimulus over a prolonged period of time. The activation of immune cells in response to a stimulus results in the elaboration of cytokines, chemokines, ROS, and reactive nitrogen species (RNS). Consequently, oxidative stress comes from the imbalance between endogenous generation of ROS and anti-oxidant defence systems that involve scavenging of low reactive ROS such as superoxide radical (HO2·) and hydrogen peroxide (H2O2), the precursors of highly damaging hydroxyl radical (OH·). The release of large amounts of ROS and RNS leads to oxidation of nucleic acids, proteins and lipids, and induction of several promutagenic DNA lesions. Indeed, DNA damage accumulation is associated with decrease of antioxidant defences[48-51].

It is estimated that ROS derived from chronic inflammatory cells may be a primary factor in the development of up to one-third of all cancers. Neutrophils and macrophages are a major source of oxidants that causes genetic alterations and may promote cancer development. Moreover, it has been reported a key role of MPO-mediated metabolic activation of inhaled chemical carcinogens in early stages of pulmonary carcinogenesis. Furthermore, it has been established that the type of DNA base modifications, as detected in target cells exposed to reagent H2O2, is highly comparable with the damage induced by activated neutrophils. In addition, HOCl also has been demonstrated to be an inhibitor of DNA strand break repair. Consequently the defects in DNA repair proteins genes may carry early to a mutated neoplastic clone, presumably as a result of markedly increased epithelial cell proliferation associated with inflammation, also in non-neoplastic colonic tissue. Unlike normal colonic mucosa, inflamed colonic mucosa shows abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer, and it has been reported by several works that the number of gene mutations in individually growing tumors was associated with the number of infiltrating neutrophils[52-54].

In addition, in colitis-associated colon carcinogenesis, ROS/RNS may contribute to the p53 mutations and can functionally impair the protein components of the DNA mismatch repair system[55]. iNOS expression is induced during inflammation and catalyzes the production of nitric oxide (NO). Moreover, depending on the concentration, genetic background, and NO enzyme involved, NO may induce protective effects. Clinical data show that iNOS levels are elevated in actively inflamed mucosa from inflammatory bowel diseases; however, there is controversy about its role in intestinal carcinogenesis[56,57].

Also carcinoma associated fibroblasts (CAFs), originated either by resident fibroblasts or by recruitment of circulating mesenchymal stem cells, are profoundly affected by oxidative stress. CAFs activation leads to lactate production and to lactate upload by neighbouring cancer cells, thus supporting their respiration and anabolic functions[58,59].

Thus, a persistent oxidative stress may, first, induce DNA damage such as modified base products and strand breaks that may lead to further mutation and chromosomal aberration of cancer (genomic instability) and, secondly, constantly activate transcription factors and induce expression of proto-oncogenes, such as NF-κB, c-fos, c-jun, and c-myc. In addition, ROS are involved in tumor angiogenesis, through the release of vascular endothelial growth factor, angiopoietin, and apoptosis evasion. The accumulation of tissue damage and the subsequent angiogenesis, remodeling, and connective tissue replacement, with a loss of cell cycle control, may contribute to tumor initiation.

Anaerobial metabolism

The inflammation sites are associated with changes in the tissue metabolism. More than 80 years ago, Otto Warburg suggested that cancer could be caused by a decrease in the energy metabolism of mitochondria in parallel with an increased glycolytic flux. In the following years it has been shown that cancer cells exhibit multiple alterations in structure, function and activity of mitochondria and glycolytic enzymes. The imbalance in glucose uptake and lactic acid production in the colonic neoplastic cells when compared with non-neoplastic cells has been well documented, and insulin signalling has been linked to an increased colon cancer risk. According to some studies, insulin pro-tumorigenic action may be due to an overproduction of ROS with subsequent DNA damage[60]. In this view, the mitochondria contribute to ROS generation, thus leading to DNA alteration. Both nuclear and mitochondrial DNA damage has been related to cancer development. Mitochondrial transcription factor A (TFAM) is a protein involved in transcription, replication and repair of mtDNA. It is essential also for mitochondrial biogenesis and function. Recent studies reported that its expression is related to clinical and pathological gradient of colorectal cancer, and that its loss can induce mtDNA instability with enhanced carcinogenic potential[61,62].

Hypoxia inducible factor 1

Inflammation can cause a significant hypoxia, resulting in the induction of hypoxia-response genes. Hypoxia leads to a coordinated transcriptional response mainly through the activation of the transcription factor hypoxia inducible factor 1 (HIF1), which is composed by two subunits: HIF-1α that is oxygen-sensitive and HIF-1β [known also as aryl hydrocarbon receptor nuclear translocator] that is constitutively expressed.

HIF undergoes a negative regulation in normoxia. The stabilization of HIF-1α protein, however, is not limited to hypoxic conditions, and the so-called “hypoxic response” can also start with a suitable support of oxygen. This oxygen-independent hypoxic response can result from a wide variety of genetic abnormalities and dysfunctions in signaling pathways, such as tumor suppressor genes deletion (VHL, p53, PTEN), or by the activation of oncogenic pathways related to PI3K/Akt, Src, or activation of growth factors (such as EGF or IGF). Further, ROS, NO, and the heat shock promote HIF-1α expression in normoxic conditions. Pyruvate and oxaloacetate, the major products of the tricarboxylic acid cycle, contribute to the stabilization of HIF. Promoter analysis revealed that HIF-1α directly regulates more than 60 target genes, and genes induced by HIF-1α in hypoxic conditions are similar to those induced in normoxic conditions[63-67].

HIF-1 mediates adaptation to hypoxia through the activation of genes that increase the glycolysis, as the glucose transporter Glut1. This mechanism increases glucose entry into the cell and accelerates glycolysis. Enzymes such as aldolase, phosphoglycerate kinase [whose levels are increased already at the stage of aberrant crypt foci (ACF), early lesions in colorectal cancer development], Enolase, Lactate Dehydrogenase, and the carrier of lactate MCT4 contain consensus sequences for HIF. The increased induction of HIF target enzymes increases the environment acidity[68-71] (Figure 2).

Figure 2
Figure 2 Oxidative microenvironment in the inflammatory milieu of colorectal mucosa. Inflammation leads to an oxidative microenvironment with consequent modification of cell metabolism. The major players of these changes is hypoxia inducible factor 1 (HIF1), nuclear factor erythroid 2-related factor 2 (Nrf2), and sirtuins (SIRT). HIF1 activation supports the metabolic switch to anaerobial metabolism [fructose-1,6 bisphosphate aldolase (ALD); phosphoglycerate kinase (PGK); enolase 1 (ENO1); lactate dehydrogenase (LDH)]. Nrf2 is involved in the antioxidant defences of epithelial cells [NAD(P)H dehydrogenase (NQO1); glutathione S-transferase (GST); heme oxygenase-1 (HO-1)], while sirtuins affect apoptosis and anti-inflammatory genes.

It has been shown that the generation of mitochondrial reactive oxygen species during hypoxia promotes HIF stabilization. In turn, HIF-1α is also implicated in the control of mitochondrial activity. HIF-1α controls the expression of cytochrome c oxidase subunit IV (COX IV, isoform2) through HRE elements present on the gene. A continuous ROS production contributes to create mutations in the mitochondrial DNA. The presence of these mutations has been indicated as a factor promoting colorectal carcinogenesis[72-74].

A hypoxic microenvironment is established very early during the development of the tumor when the tumor has a volume of about 2-3 mm in diameter (possibly at the stage of aberrant crypt foci, ACF)[75]. HIF directly activates the genes coding for transferrin, vascular endothelial growth factor (VEGF), endothelin1 and nitric oxide synthase, which are involved in vasodilation and neovascularization. So, the tumor responds by increasing the glycolytic metabolism and angiogenic potential; thus, HIF is an important player in all the phases of neoplastic growth by regulating survival, inhibition of apoptosis, neoangiogenesis and tumor metastasis[76,77].

Nuclear factor E2-related factor 2

Nrf2, or nuclear factor erythroid 2-related factor 2, is a positive regulator of the human antioxidant response element (ARE) that drives the expression of antioxidant enzymes such as NAD(P)H: quinone oxidoreductase 1 (NQO1), those involved in glutathione synthesis, and genes involved in limiting the inflammatory process[78,79].

Nrf2 signaling in physiological conditions acts as a switch that is turned on by the presence of stressors in the cellular microenvironment and that is rapidly deactivated when the insult is withdrawn and homeostasis is restored. However, under pathological conditions, the tight regulation of Nrf2 by rapid protein turnover is highly susceptible to being altered. This could result in the loss of responsiveness to cell stressors and subsequent vulnerability of the cell to various insults or in the acquisition of a constitutively active phenotype[80,81].

Constitutive signalling toward the expression of cytoprotective enzymes would confer cells a survival advantage under adverse conditions. Therefore, constitutive activation or augmented signalling of the Nrf2 pathway might be decisive for cell fate during tumorigenesis and affect the response to chemotherapy. Under these conditions, Nrf2 can be defined as a proto-oncogene[82] (Figure 2).

The involvement of Nrf2 in cancer pathogenesis is a controversial topic, provided a number of reports that still assign Nrf2 a role in cancer chemoprevention from genotoxic agents or inflammation[83].

Nrf2 knockout leads to an enhanced oxidative and inflammatory environment which would contribute to an increased level of free radicals, PGE2, LKTB4 and NO accumulation in the cells, leading to hyperproliferation of colonic crypts. However, some reports have shown that drugs that activate Nrf2 can promote cell growth, and an increasing number of works points to a potential role for Nrf2 and its transcriptional target genes in tumorigenesis. In conclusion Nrf2 can function as a proto-oncogene in plenty of solid tumors and leukemias. Nrf2 can be activated by numerous compounds and is also frequently deregulated in a wide variety of cancers by mutations, aberrant epigenetic or posttranslational regulation, or hyperactivation of oncogenic signalling pathways involving other transcription factors such as NF-κB, various protein kinases, structural proteins such as E-cadherin, or other regulators such as p62. Overexpressed or hyperactivated Nrf2 can participate in tumorigenesis by helping cells escape from diverse forms of stress through the induction of anti-oxidant target genes or by directly promoting cell survival, proliferation, and even metastasis[84,85].


Mammals express seven sirtuins (SIRT1-7) that have been demonstrated to play important roles in many physiological and pathophysiological conditions, including metabolism, cell survival, cancer, aging and caloric restriction-mediated longevity[86,87].

Sirtuins are a group of highly phylogenetically conserved proteins that catalyze the deacetylation of target proteins. The deacetylation reaction spends NAD+, a key molecule in energy metabolism, thus linking protein regulatory control to metabolic conditions[88].

Mitochondrial SIRT3 is involved in tumor metabolism. SIRT3 induces fatty acid oxidation and regulates ROS homeostasis by targeting the mitochondrial enzymes Mn-SOD and SOD2. SIRT3 seems to maintain genomic stability by controlling ROS levels, that have been associated with mutagenesis promotion and genomic instability. ROS can modulate both cell survival and apoptotic pathways; thus SIRT3 may also promote tumorigenesis and prevent apoptosis, maintaining ROS at the appropriate level for a proliferative and aggressive phenotype. In contrast, some reports support a role for SIRT3 in inducing growth arrest and apoptosis in colorectal carcinoma[89,90].

SIRT1 regulates both apoptosis and autophagy by deacetylating p53 and other proteins involved in these pathways[91]. As a consequence, SIRT1 might be considered a facilitator for cancer development. Nevertheless, although pro-oncogenic effects of SIRT1 have been reported in some studies, there are also reports showing a tumor-suppressor role for this protein as well. Although information about the role of sirtuins in IBD is limited, there are several reports that show an antiinflammatory effect for these molecules. In fact, the best-known SIRT1 activator is resveratrol, that reverses colitis-associated decrease in SIRT1 gene expression, provokes the down-regulation of NF-κB and the increase of COX-2 expression, and other changes, in a dextran sulfate sodium-induced colitis, and resveratrol suppresses colon cancer associated with colitis[92,93]. In addition, SIRT1 is a negative regulator of NF-κB activity. With respect to colorectal cancer, several studies support the notion that SIRT1 could be involved in carcinogenesis, and SIRT1 has been found to be upregulated in various human cancers, including colon cancer[94,95]. SIRT1 expression is associated with microsatellite instability and CpG island methylator phenotype in human colorectal cancer. Conversely, there are also studies that indicate that SIRT1 can act as tumor suppressor. SIRT1 suppresses intestinal tumorigenesis and colon cancer growth in a β-catenin-driven mouse model of colon cancer[96,97]. SIRT1 has been shown to regulate Wnt signalling, to promote constitutive Wnt signalling and Wnt-induced cell migration, showing more a protumor action than an antitumor effect. In another study, SIRT1 has properties of a growth suppressor. Knockdown of SIRT1 increases the rate of tumor growth, whereas overexpression of SIRT1 reduces tumor formation in nude mice. Furthermore, pharmacological inhibition of SIRT1 increases the rate of cell proliferation in culture. These results together suggest that SIRT1 has properties of a context-dependent tumor suppressor[98,99]. These results show that sirtuins have pleiotropic effects on cancer development (Figure 2).


Generally, the repair of the damaged epithelium can rapidly be completed following the decrease of intestinal inflammation. Very few tissues in adult mammals have the ability for true regeneration; among them are the bone marrow, liver, intestinal epithelium, and epidermis of the skin.

There is accumulating evidence that loss of control over normal tissue repair or renewal mechanisms may lead to malignant transformation. Cancer has been described as a “wound that does not heal” or “the wound is a tumor that heals itself”. But is there a link between tissue repair and cancer? The association between cancer and persistent inflammatory or regenerative states strongly suggests this connection[100,101] (Figure 3).

Figure 3
Figure 3 Inflammation and remodelling of colorectal mucosa. Macrophages and neutrophils cause tissue damage and DNA damage by reactive oxygen species (ROS) formation. Inflammatory cytokines stimulate crypt stem cells proliferation driven by Wingless and Hedgehog. Defects in apoptosis and autophagy systems cause accumulation and proliferation of transformed cells. Indeed, inflammatory cells cause extracellular matrix (ECM) modifications, substaining disassembly of normal tissue architecture, angiogenesis and tumor invasion. CAF: Carcinoma associated fibroblasts; TAMs: Tumor-associated macrophages; MMP: Matrix metalloproteinases.

Further, PMNs recruited to the inflammation site act also by producing and releasing IL-22. IL-22 has a beneficial action on intestinal epithelial barrier by promoting cell proliferation, migration, and mucus production. This action is mediated probably by the IL-22 receptor (IL-22R), that is expressed by the epithelial cells of the gastrointestinal tract. There is also a soluble receptor for IL-22, IL-22BP, that acts by preventing the binding to the membrane-bound IL-22R and thus terminating the IL-22-induced regenerative program. So, as decreased levels of IL-22 are detrimental to the regeneration of epithelial monolayer, a defective control by IL-22BP can speed colon cancer development by sustaining a prolonged epithelial proliferation[102,103].


Macrophages remove apoptotic neutrophils, the phagocytosis of which may lead to a change toward a more reparative (M2) macrophage phenotype and the resolution of the inflammatory phase of wound healing[104-106].

There is evidence for extracellular matrix (ECM) proteins and activated ECs increasing the lifespan of neutrophils. The protection against neutrophil apoptosis is a result of adhesion to matrix proteins fibronectin and laminin, and activated EC-coated substrates, leading to an appropriate function[107,108].

The proliferative phase of wound healing involves new ECM deposition, including the deposition of dense fibrous connective tissue, within the site of injury. The architecture of the collagen scaffolds in tumors is severely altered. Tumor-associated collagens are often linearized and crosslinked, reflecting elevated deposition and significant posttranslational modification[109,110].

The ECM provides a physical scaffold for cell adhesion and migration, it influences tissue tension, and it signals to cells through ECM receptors. Proteolysis of the ECM regulates cellular migration by modifying the structure of the ECM scaffold and by releasing ECM fragments with biological functions. ECM proteolysis is therefore tightly controlled in normal tissues but typically deregulated in tumors[111-113].

Following the deposition of significant amounts of ECM (predominantly collagens type I and III) during the proliferative phase, the remodeling phase of wound healing begins. This phase is characterized by MMP and tissue inhibitor of metalloproteinase (TIMP)-mediated degradation and remodeling of the newly deposited collagen. An altered expression of some MMPs has also been reported in colorectal carcinogenesis[114,115].

TIMPs, which are secreted proteins, bind and inhibit enzymatically active MMPs at a 1:1 molar stechiometric proportion, thus inhibiting the proteolytic activity of MMPs. The impact of TIMPs is essential for the homeostasis of the ECM. The sensitive balance between MMPs and TIMPs is essential for many physiological processes in the gut[116].

Moreover, it has been demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2, were significantly increased in patients with ulcerative colitis and crohn disease compared to controls. These results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD[117].

M2-like TAMs release a number of potent proangiogenic cytokines, such as VEGF-A, VEGF-C, TNF-α, IL-8, and bFGF. Additionally, these TAMs also express a broad array of proteases known to play roles in the angiogenic process. These proteases include urokinase-type plasminogen activator (uPA), the matrix metalloproteinases MMP-2, MMP-7, MMP-9, and MMP-12, and elastase uPA and MMP support angiogenesis by remodeling and breaking down the ECM. Degradation of ECM leads to the mobilization of growth factors and facilitates the migration of vascular cells into new environments[118,119].

Among the proteolytic enzymes expressed by TAMs there are several members of the cysteine cathepsin family, which have been implicated in cancer progression. Cysteine cathepsins are specifically involved in cancer, cysteine cathepsins B and L have been investigated most intensively, and invariably their increased expression and/or activity correlates with malignant progression[120]. Several investigations have confirmed significantly higher levels of cathepsins D, L, H, and, in particular, cathepsin B in colorectal carcinoma[121].

Fibroblasts are among the most active cell types of the stroma. They are present in the stroma of normal tissues, including colorectal, where they perform tissue repair functions under certain physiological conditions, and in the stroma of tumors, in which they might represent the main component. They have been given various names: tumor-associated fibroblasts, CAF or myofibroblasts.

The differentiation of fibroblasts into myofibroblasts is an important step in tissue repair. Migration of colonic fibroblasts into and through the extracellular matrix during the initial phase of mucosal healing appears to be a fundamental component of wound contraction[122,123].

After differentiation, subepithelial myofibroblasts form a pericryptal fibroblast sheet adjacent to the basal lamina of colonic crypts. Intestinal subepithelial myofibroblasts contribute to the coordination of tissue regeneration by producing TGF-β, epidermal growth factor, basic fibroblast growth factor, proinflammatory cytokines, and the formation of new basement membrane.

In a state of permanent activation, fibroblasts can promote tumor growth and tumor progression, favoring a variety of tumor-specific mechanisms. These activated fibroblasts can be characterized molecularly by several markers that should be expressed by the fibroblasts in their activated state. Some of the most common CAF markers are α-smooth muscle actin, fibroblast-specific protein 1 (FSP1 or S100A4) and fibroblast activation protein. Together with M2 macrophages, and as previously stated above, CAF are a large component of the stroma and generally tumor promoting[124-126].


Thus, rapid resealing of the epithelial surface barrier following injuries or physiological damage is essential to preserve the normal homeostasis. In a state of chronic injury or inflammation, stem cells are under a continuous stimulus of proliferation; pathway activation and presumed expansion of stem cell pools would persist so long as repeated injury prevents full regeneration[127].

Epithelial cell proliferation is stimulated in crypts near the damaged mucosal area to replenish the decreased cell pool. This appears as an elongation of the crypt, which may subsequently divide into two crypts. Maturation and differentiation of undifferentiated epithelial cells is needed to maintain the numerous functional activities of the mucosal epithelium[128,129].

Recent studies have revealed that the key signal regulating the proliferation of immature epithelial cells in the crypt may be Wnt signaling. Wnt signaling is an important part of normal epithelial renewal within the small and large intestine. Wnt signaling has long been studied in the development of colon cancer, a disease characterized by the unregulated proliferation of intestinal epithelial cells. A series of studies in mice has revealed that Wnt signaling also regulates the proliferation of immature epithelial cells within the normal crypt. Two morphogenic signaling pathways, specifically Hedgehog (Hh) and Wingless (Wnt), serve to illustrate how pathways involved in stem cell proliferation during development, and regeneration have also been implicated in several different epithelial cancers. These observations suggest that cancer growth may represent the continuous operation of an unregulated state of tissue repair and that continuous Hh/Wnt pathway activities in carcinogenesis may represent a deviation from the return to quiescence that normally follows regeneration[130-133].


Autophagy is usually considered as a tumor-suppressing mechanism, though it can also enable tumor cell survival upon stress, and may promote metastasis formation. Autophagy is a key response mechanism to numerous extracellular and intracellular stresses. These include, for example, nutrient and growth factor deprivation and hypoxia. Autophagy is the only cellular catabolic process that can eliminate damaged or ROS-overproducing mitochondria, and thereby limit general oxidative damage. Nutrient or growth factor limitation, hypoxia and other cellular stressors are known to deactivate the signaling system that leads to autophagy induction and suppression of cell growth and proliferation[134,135].

Several pathways (including RAS/PKA, RAS/ERK, IRE1/JNK, TGF-β, WNT/GSK3, HIF) and transcription factors (TFs), such as NRF2, FoxO and p53 have been described to affect autophagy. Interestingly, these signaling pathways are also important in cell growth, proliferation, angiogenesis, immunity, cell survival and cell death, functions whose alteration are listed among the hallmarks of cancer. Thus, these data show that the control of autophagy is affected during tumorigenesis[136-138]. Numerous studies examined the role of autophagy in cancer, but the results are rather ambiguous. On the one hand, autophagy has tumor suppressing functions by suppressing chromosomal instability, restricting oxidative stress, promoting oncogene-induced senescence, and reducing intratumoral necrosis and local inflammation. On the other hand, enhanced autophagy represents a prominent mechanism used by tumor cells to escape from hypoxic, metabolic, detachment-induced and therapeutic stress as well as to develop metastasis and dormant tumor cells. During tumorigenesis, autophagy is frequently switched on and off, resulting in highly regulated anti- and pro-tumorigenic effects. Therefore, autophagy can be considered as a double-edged sword during tumorigenesis.

During tumorigenesis, cells not only increase their proliferative potential but also need to develop mechanisms that allow them to escape their own tumor suppressor systems. Impairment or deregulation of the main apoptotic pathways is a major characteristic of cancer cells. In this regard, a cross link between Nrf2 and some effectors of the main apoptotic pathways has been proposed on several occasions. Tumor suppressor p53, which induces apoptosis upon DNA damage, partially in a ROS-dependent fashion, has been shown to inhibit the transcriptional activation of Nrf2 target genes in various cancer cell lines. This finding is supported by another report in which mice with decreased p53 levels showed enhanced expression of Nrf2 target genes after treatment with a genotoxic agent. These data suggest that Nrf2 inhibition is needed for p53-dependent apoptosis[139].

Many derangements in cell signaling occur within chronically inflamed tissues, which may lead to inappropriate suppression of apoptosis and subsequent tumorigenesis. Through careful microdissection of chronically inflamed and neoplastic tissues, several consistently upregulated survival signaling pathways have been identified, with subsequent attempts made to develop inhibitors to key pathway intermediates[140].


NF-κB is a ubiquitously expressed transcription factor that plays a pivotal role in regulating cellular responses to environmental challenges, such as stress, infection, and inflammation. NF-κB is activated in response to cytokines and inflammatory mediators such as TNF-α, IL-1, LPS and ROS, and its regulatory products include growth factors, cytokines, immunoreceptors, and cell survival proteins, making it a complex modulator of the immune response.

Moreover, there is growing evidence of a connection between inflammation, NF-κB and tumor development. Viral oncogenes and some chemical and physical carcinogens, especially nicotine and carcinogens in tobacco, promote cell proliferation, survival, and inflammation via NF-κB activation. The role of NF-κB in promoting carcinogenesis is evidenced by numerous studies which indicate that this factor blocks apoptosis by regulating anti-apoptotic proteins, or by inhibiting the accumulation of ROS[141,142]. In chronic inflammation, the cytokines and chemokines produced by inflammatory cells activate NF-κB, which translocates into the nucleus, inducing the expression of certain tumorigenic, adhesion proteins, chemokines, and inhibitors of apoptosis that promote cell survival. Therefore, NF-κB may contribute to the development of colitis-associated colorectal cancer by sustaining the ongoing inflammatory process in the gut mucosa. NF-κB is also connected to the regulation of many genes differently expressed in invasion and metastasis: cyclin D1 and cMyc oncogenes, and VEGF and IL-8 are directly or indirectly enhanced by NF-κB activation. Several products have been suggested to inhibit NF-κB activation, including curcumin, ginseng extract, resveratrol, green tea extract, among others, and are known for their antiproliferative properties[143,144].


Several cells and proteins are involved in the early steps of colorectal carcinogenesis, and the most important are summarized in Table 1. They are components of a complex environment with continuous cross-talking between the epithelium and the stroma of the mucosal layer. Recent evidence has suggested that the stroma plays an important role in influencing important mechanisms both promoting and inhibiting the multistep process of carcinogenesis. Early injury to the colorectal mucosa caused by carcinogens coming from the environment, or any other agent damaging the mucosa may elicit an inflammatory process. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Moreover, the activation of these pathways establishes an oxidative environment with further DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism, thus awaking other proteins and altering other mechanisms, such as autophagy, proliferation and apoptosis, with final failure to control normal mucosal repair and renewal. However, the picture of the early events in colorectal carcinogenesis is still incomplete: future studies are needed in order to draw a more definite one.

Table 1 Main players in inflammatory pathways related to early phases of colorectal cancer development.
PlayerRole in early steps of colorectal cancer
IL-23Induction of IL-17, activation of PMN respiratory burst
IL-17Production of inflammatory cytokines, neutrophils recruitment and activation
ArginaseStimulation of cell growth, collagen deposition, and tissue repair
sialyl Lewis-A and sialyl Lewis-XTheir accumulation on neoplastic cell escape the binding with siglec-7 and -9 in macrophages, thus enhancing COX-2 production
MPOHypochlorous acid (HOCl) formation, promotion of neutrophil survival
MMP-8, MMP-9Tissue destruction and remodeling
5-LOXInduced by IL-4 and IL-13, role in first step of leukotriene synthesis. Generally absent in normal epithelia
LTB4, LTC4, LTD4, LTE4Chemoattraction of PMN, eosinophils, and macrophages. Activation of PMN. Increased microvascular permeability. Proliferation of colon cancer cells
COX-2PGE production, neutrophil accumulation, perpetuate of inflammatory responses, Wnt signalling activation
12-LOXCancer cell proliferation, metastasis, and angiogenesis. Generally absent in normal epithelia
15-LOXResolution of inflammation. Generally absent in cancer cells
Lipoxins, resolvins and protectinsResolution of inflammation (stop of PMN recruitment and superoxide generation and release, stimulation of non-phlogistic monocyte infiltration, promotion of the uptake and clearance of apoptotic cells, increase the exit of phagocytes from the inflamed site)
ACSL4Increased COX-2 and LOX-5 levels, controls of COX-2 and LOX-5 metabolism of AA, inhibition of apoptosis and increased cell proliferation
TFAMRegulation of mtDNA transcription, replication and repair. Essential for mitochondrial biogenesis and function
HIF-1Activate also by ROS, mediates adaptation to hypoxia. Regulation of cell survival, inhibition of apoptosis, neoangiogenesis and tumor metastasis
Nrf2Antioxidant enzymes expression, , promotion of cells survival by escaping to stress, cells proliferation, and metastasis
SIRT1Regulation of both apoptosis and autophagy
SIRT3Regulation of ROS homeostasis
IL-22Promotion of epithelial repair
NF-κBActivated by TNF-α, IL-1 and ROS, regulation of infection and inflammation. Apoptosis inhibition. Regulation of cyclin D1, cMyc, VEGF and IL-8

P- Reviewer: Cerwenka HR, Herszenyi L, Sgourakis G S- Editor: Gou SX L- Editor: A E- Editor: Wang CH

1.  Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79:319-326.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958-969.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5085]  [Cited by in F6Publishing: 4991]  [Article Influence: 363.2]  [Reference Citation Analysis (0)]
3.  Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-555.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23-35.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Biswas SK, Sica A, Lewis CE. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol. 2008;180:2011-2017.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065-1073.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 844]  [Cited by in F6Publishing: 826]  [Article Influence: 64.9]  [Reference Citation Analysis (0)]
7.  McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 2006;27:17-23.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005;22:285-294.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Rubino SJ, Geddes K, Girardin SE. Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol. 2012;33:112-118.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 70]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
10.  Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677-686.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Curran JN, Winter DC, Bouchier-Hayes D. Biological fate and clinical implications of arginine metabolism in tissue healing. Wound Repair Regen. 2006;14:376-386.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Ganster RW, Taylor BS, Shao L, Geller DA. Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Proc Natl Acad Sci USA. 2001;98:8638-8643.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol. 1998;160:5347-5354.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Lamagna C, Aurrand-Lions M, Imhof BA. Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol. 2006;80:705-713.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol. 2007;7:255-266.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Miyazaki K, Ohmori K, Izawa M, Koike T, Kumamoto K, Furukawa K, Ando T, Kiso M, Yamaji T, Hashimoto Y. Loss of disialyl Lewis(a), the ligand for lymphocyte inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) associated with increased sialyl Lewis(a) expression on human colon cancers. Cancer Res. 2004;64:4498-4505.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Kawamura YI, Toyota M, Kawashima R, Hagiwara T, Suzuki H, Imai K, Shinomura Y, Tokino T, Kannagi R, Dohi T. DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Gastroenterology. 2008;135:142-151.e3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 73]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
18.  Miyazaki K, Sakuma K, Kawamura YI, Izawa M, Ohmori K, Mitsuki M, Yamaji T, Hashimoto Y, Suzuki A, Saito Y. Colonic epithelial cells express specific ligands for mucosal macrophage immunosuppressive receptors siglec-7 and -9. J Immunol. 2012;188:4690-4700.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 47]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
19.  Lau D, Mollnau H, Eiserich JP, Freeman BA, Daiber A, Gehling UM, Brümmer J, Rudolph V, Münzel T, Heitzer T. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci USA. 2005;102:431-436.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Winterbourn CC. Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology. 2002;181-182:223-227.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007;25:101-137.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol. 2010;10:427-439.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 612]  [Cited by in F6Publishing: 602]  [Article Influence: 51.0]  [Reference Citation Analysis (0)]
23.  Leitch AE, Duffin R, Haslett C, Rossi AG. Relevance of granulocyte apoptosis to resolution of inflammation at the respiratory mucosa. Mucosal Immunol. 2008;1:350-363.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 46]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
24.  Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C. Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest. 1989;83:865-875.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Simon HU. Neutrophil apoptosis pathways and their modifications in inflammation. Immunol Rev. 2003;193:101-110.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77:598-625.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Roncucci L, Mora E, Mariani F, Bursi S, Pezzi A, Rossi G, Pedroni M, Luppi D, Santoro L, Monni S. Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17:2291-2297.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 35]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
28.  Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011;35:445-455.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 332]  [Cited by in F6Publishing: 312]  [Article Influence: 30.2]  [Reference Citation Analysis (0)]
29.  Savill J, Dransfield I, Gregory C, Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002;2:965-975.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871-1875.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Ohd JF, Nielsen CK, Campbell J, Landberg G, Löfberg H, Sjölander A. Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas. Gastroenterology. 2003;124:57-70.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Bortuzzo C, Hanif R, Kashfi K, Staiano-Coico L, Shiff SJ, Rigas B. The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim Biophys Acta. 1996;1300:240-246.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001;108:15-23.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Stenson WF. Prostaglandins and epithelial response to injury. Curr Opin Gastroenterol. 2007;23:107-110.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Castellone MD, Teramoto H, Gutkind JS. Cyclooxygenase-2 and colorectal cancer chemoprevention: the beta-catenin connection. Cancer Res. 2006;66:11085-11088.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Mutoh M, Watanabe K, Kitamura T, Shoji Y, Takahashi M, Kawamori T, Tani K, Kobayashi M, Maruyama T, Kobayashi K. Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 2002;62:28-32.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Sinicrope FA, Gill S. Role of cyclooxygenase-2 in colorectal cancer. Cancer Metastasis Rev. 2004;23:63-75.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Moussalli MJ, Wu Y, Zuo X, Yang XL, Wistuba II, Raso MG, Morris JS, Bowser JL, Minna JD, Lotan R. Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion. Cancer Prev Res (Phila). 2011;4:1961-1972.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 14]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
39.  Nixon JB, Kim KS, Lamb PW, Bottone FG, Eling TE. 15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. Prostaglandins Leukot Essent Fatty Acids. 2004;70:7-15.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Melstrom LG, Bentrem DJ, Salabat MR, Kennedy TJ, Ding XZ, Strouch M, Rao SM, Witt RC, Ternent CA, Talamonti MS. Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin Cancer Res. 2008;14:6525-6530.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 51]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
41.  Wasilewicz MP, Kołodziej B, Bojułko T, Kaczmarczyk M, Sulzyc-Bielicka V, Bielicki D, Ciepiela K. Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis. Int J Colorectal Dis. 2010;25:1079-1085.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 28]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
42.  Lawrence T, Willoughby DA, Gilroy DW. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol. 2002;2:787-795.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  McMahon B, Mitchell S, Brady HR, Godson C. Lipoxins: revelations on resolution. Trends Pharmacol Sci. 2001;22:391-395.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  El Kebir D, József L, Pan W, Wang L, Petasis NA, Serhan CN, Filep JG. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med. 2009;180:311-319.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 136]  [Cited by in F6Publishing: 93]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
45.  Shureiqi I, Lippman SM. Lipoxygenase modulation to reverse carcinogenesis. Cancer Res. 2001;61:6307-6312.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Orlando UD, Garona J, Ripoll GV, Maloberti PM, Solano ÁR, Avagnina A, Gomez DE, Alonso DF, Podestá EJ. The functional interaction between Acyl-CoA synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth: a novel therapeutic target. PLoS One. 2012;7:e40794.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 28]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
47.  Maloberti PM, Duarte AB, Orlando UD, Pasqualini ME, Solano AR, López-Otín C, Podestá EJ. Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells. PLoS One. 2010;5:e15540.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 54]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
48.  Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res. 2004;567:1-61.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49:1603-1616.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2540]  [Cited by in F6Publishing: 2298]  [Article Influence: 211.7]  [Reference Citation Analysis (0)]
50.  Ferguson LR. Chronic inflammation and mutagenesis. Mutat Res. 2010;690:3-11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 82]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
51.  Lonkar P, Dedon PC. Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates. Int J Cancer. 2011;128:1999-2009.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 177]  [Cited by in F6Publishing: 176]  [Article Influence: 16.1]  [Reference Citation Analysis (0)]
52.  DalleDonne I, Milzani A, Colombo R. H2O2-treated actin: assembly and polymer interactions with cross-linking proteins. Biophys J. 1995;69:2710-2719.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Knaapen AM, Güngör N, Schins RP, Borm PJ, Van Schooten FJ. Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Mutagenesis. 2006;21:225-236.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Güngör N, Godschalk RW, Pachen DM, Van Schooten FJ, Knaapen AM. Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells: role of myeloperoxidase. FASEB J. 2007;21:2359-2367.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, Rickman BH, Rogers AB, Moroski-Erkul CA, McFaline JL. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest. 2008;118:2516-2525.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 220]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
56.  Martín MJ, Jiménez MD, Motilva V. New issues about nitric oxide and its effects on the gastrointestinal tract. Curr Pharm Des. 2001;7:881-908.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Seril DN, Liao J, Yang GY. Colorectal carcinoma development in inducible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis. Mol Carcinog. 2007;46:341-353.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med. 2010;2:211-230.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 163]  [Cited by in F6Publishing: 192]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
59.  Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392-401.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Othman EM, Leyh A, Stopper H. Insulin mediated DNA damage in mammalian colon cells and human lymphocytes in vitro. Mutat Res. 2013;745-746:34-39.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 25]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
61.  Woo DK, Green PD, Santos JH, D’Souza AD, Walther Z, Martin WD, Christian BE, Chandel NS, Shadel GS. Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APC(Min/+) mice. Am J Pathol. 2012;180:24-31.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 86]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]
62.  Nakayama Y, Yamauchi M, Minagawa N, Torigoe T, Izumi H, Kohno K, Yamaguchi K. Clinical significance of mitochondrial transcription factor A expression in patients with colorectal cancer. Oncol Rep. 2012;27:1325-1330.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 7]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
63.  Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678-685.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 517]  [Cited by in F6Publishing: 500]  [Article Influence: 36.9]  [Reference Citation Analysis (0)]
64.  Kaidi A, Qualtrough D, Williams AC, Paraskeva C. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 2006;66:6683-6691.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Dang DT, Chen F, Gardner LB, Cummins JM, Rago C, Bunz F, Kantsevoy SV, Dang LH. Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res. 2006;66:1684-1936.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL, Simon MC, Thompson CB. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007;21:1037-1049.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  López-Lázaro M. HIF-1: hypoxia-inducible factor or dysoxia-inducible factor? FASEB J. 2006;20:828-832.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Børresen-Dale AL. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 2006;3:e47.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269:23757-23763.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Glebov OK, Rodriguez LM, Soballe P, DeNobile J, Cliatt J, Nakahara K, Kirsch IR. Gene expression patterns distinguish colonoscopically isolated human aberrant crypt foci from normal colonic mucosa. Cancer Epidemiol Biomarkers Prev. 2006;15:2253-2262.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006;281:9030-9037.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129:111-122.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Nishikawa M, Oshitani N, Matsumoto T, Nishigami T, Arakawa T, Inoue M. Accumulation of mitochondrial DNA mutation with colorectal carcinogenesis in ulcerative colitis. Br J Cancer. 2005;93:331-337.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Sui G, Zhou S, Wang J, Canto M, Lee EE, Eshleman JR, Montgomery EA, Sidransky D, Califano JA, Maitra A. Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: a biomarker for the early detection of cancer. Mol Cancer. 2006;5:73.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Mariani F, Sena P, Marzona L, Riccio M, Fano R, Manni P, Gregorio CD, Pezzi A, Leon MP, Monni S. Cyclooxygenase-2 and Hypoxia-Inducible Factor-1alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis. Cancer Lett. 2009;279:221-229.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 49]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
76.  Yu JX, Cui L, Zhang QY, Chen H, Ji P, Wei HJ, Ma HY. Expression of NOS and HIF-1alpha in human colorectal carcinoma and implication in tumor angiogenesis. World J Gastroenterol. 2006;12:4660-4664.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Li C, Hashimi SM, Cao S, Mellick AS, Duan W, Good D, Wei MQ. The mechanisms of chansu in inducing efficient apoptosis in colon cancer cells. Evid Based Complement Alternat Med. 2013;2013:849054.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 16]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
78.  Giudice A, Montella M. Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays. 2006;28:169-181.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Kikuchi N, Ishii Y, Morishima Y, Yageta Y, Haraguchi N, Itoh K, Yamamoto M, Hizawa N. Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance. Respir Res. 2010;11:31.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 102]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
80.  Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA. 1999;96:12731-12736.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci. 2001;59:169-177.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Shelton P, Jaiswal AK. The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? FASEB J. 2013;27:414-423.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 122]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
83.  Shen H, Zhou S, Wang J. The paradoxical role of Nrf2 in tumor biology. Crit Rev Eukaryot Gene Expr. 2013;23:37-47.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Cheung KL, Lee JH, Khor TO, Wu TY, Li GX, Chan J, Yang CS, Kong AN. Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. Mol Carcinog. 2014;53:77-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 56]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
85.  Zhang L, Wang N, Zhou S, Ye W, Jing G, Zhang M. Propofol induces proliferation and invasion of gallbladder cancer cells through activation of Nrf2. J Exp Clin Cancer Res. 2012;31:66.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 52]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
86.  Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404:1-13.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene. 2007;26:5489-5504.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Zhang T, Kraus WL. SIRT1-dependent regulation of chromatin and transcription: linking NAD(+) metabolism and signaling to the control of cellular functions. Biochim Biophys Acta. 2010;1804:1666-1675.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 184]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
89.  Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12:662-667.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 804]  [Cited by in F6Publishing: 773]  [Article Influence: 73.1]  [Reference Citation Analysis (0)]
90.  Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17:41-52.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 531]  [Cited by in F6Publishing: 510]  [Article Influence: 44.3]  [Reference Citation Analysis (0)]
91.  Motilva V, García-Mauriño S, Talero E, Illanes M. New paradigms in chronic intestinal inflammation and colon cancer: role of melatonin. J Pineal Res. 2011;51:44-60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
92.  Singh UP, Singh NP, Singh B, Hofseth LJ, Price RL, Nagarkatti M, Nagarkatti PS. Resveratrol (trans-3,5,4’-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther. 2010;332:829-839.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 120]  [Cited by in F6Publishing: 125]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
93.  Cui X, Jin Y, Hofseth AB, Pena E, Habiger J, Chumanevich A, Poudyal D, Nagarkatti M, Nagarkatti PS, Singh UP. Resveratrol suppresses colitis and colon cancer associated with colitis. Cancer Prev Res (Phila). 2010;3:549-559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 71]  [Article Influence: 11.0]  [Reference Citation Analysis (0)]
94.  Jung-Hynes B, Reiter RJ, Ahmad N. Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res. 2010;48:9-19.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 150]  [Cited by in F6Publishing: 49]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
95.  Ford J, Jiang M, Milner J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 2005;65:10457-10463.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Nosho K, Shima K, Irahara N, Kure S, Firestein R, Baba Y, Toyoda S, Chen L, Hazra A, Giovannucci EL. SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Mod Pathol. 2009;22:922-932.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 74]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
97.  Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 2008;3:e2020.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 420]  [Cited by in F6Publishing: 403]  [Article Influence: 30.0]  [Reference Citation Analysis (0)]
98.  Holloway KR, Calhoun TN, Saxena M, Metoyer CF, Kandler EF, Rivera CA, Pruitt K. SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling. Proc Natl Acad Sci USA. 2010;107:9216-9221.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 75]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
99.  Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C, Yeatman T, Coppola D, Chen J. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem. 2009;284:18210-18217.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 63]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
100.  Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650-1659.  [PubMed]  [DOI]  [Cited in This Article: ]
101.  Haddow A. Molecular repair, wound healing, and carcinogenesis: tumor production a possible overhealing? Adv Cancer Res. 1972;16:181-234.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O’Connor W, Murphy AJ. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 2012;491:259-263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 466]  [Cited by in F6Publishing: 432]  [Article Influence: 46.6]  [Reference Citation Analysis (0)]
103.  Zindl CL, Lai JF, Lee YK, Maynard CL, Harbour SN, Ouyang W, Chaplin DD, Weaver CT. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci USA. 2013;110:12768-12773.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 215]  [Cited by in F6Publishing: 209]  [Article Influence: 23.9]  [Reference Citation Analysis (0)]
104.  Erwig LP, Henson PM. Immunological consequences of apoptotic cell phagocytosis. Am J Pathol. 2007;171:2-8.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Sylvia CJ. The role of neutrophil apoptosis in influencing tissue repair. J Wound Care. 2003;12:13-16.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 734]  [Cited by in F6Publishing: 357]  [Article Influence: 66.7]  [Reference Citation Analysis (0)]
107.  Kettritz R, Xu YX, Kerren T, Quass P, Klein JB, Luft FC, Haller H. Extracellular matrix regulates apoptosis in human neutrophils. Kidney Int. 1999;55:562-571.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Ginis I, Faller DV. Protection from apoptosis in human neutrophils is determined by the surface of adhesion. Am J Physiol. 1997;272:C295-C309.  [PubMed]  [DOI]  [Cited in This Article: ]
109.  López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1:303-314.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 403]  [Cited by in F6Publishing: 390]  [Article Influence: 33.6]  [Reference Citation Analysis (0)]
110.  Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22:697-706.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 520]  [Cited by in F6Publishing: 499]  [Article Influence: 43.3]  [Reference Citation Analysis (0)]
111.  Gill SE, Parks WC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol. 2008;40:1334-1347.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245-257.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 778]  [Cited by in F6Publishing: 760]  [Article Influence: 64.8]  [Reference Citation Analysis (0)]
113.  Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4:38.  [PubMed]  [DOI]  [Cited in This Article: ]
114.  Asano T, Tada M, Cheng S, Takemoto N, Kuramae T, Abe M, Takahashi O, Miyamoto M, Hamada J, Moriuchi T. Prognostic values of matrix metalloproteinase family expression in human colorectal carcinoma. J Surg Res. 2008;146:32-42.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Sena P, Roncucci L, Marzona L, Mariani F, Maffei S, Manenti A, De Pol A. Altered expression of apoptosis biomarkers in human colorectal microadenomas. Cancer Epidemiol Biomarkers Prev. 2010;19:351-357.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 4]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
116.  Kapsoritakis AN, Kapsoritaki AI, Davidi IP, Lotis VD, Manolakis AC, Mylonis PI, Theodoridou AT, Germenis AE, Potamianos SP. Imbalance of tissue inhibitors of metalloproteinases (TIMP) - 1 and - 4 serum levels, in patients with inflammatory bowel disease. BMC Gastroenterol. 2008;8:55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 10]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
117.  Lakatos G, Hritz I, Varga MZ, Juhász M, Miheller P, Cierny G, Tulassay Z, Herszényi L. The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases. Dig Dis. 2012;30:289-295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 56]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
118.  Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723-737.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2688]  [Cited by in F6Publishing: 2608]  [Article Influence: 244.4]  [Reference Citation Analysis (0)]
119.  Wynn TA, Barron L, Thompson RW, Madala SK, Wilson MS, Cheever AW, Ramalingam T. Quantitative assessment of macrophage functions in repair and fibrosis. Curr Protoc Immunol. 2011;Chapter 14:Unit14.22.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 42]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
120.  Berdowska I. Cysteine proteases as disease markers. Clin Chim Acta. 2004;342:41-69.  [PubMed]  [DOI]  [Cited in This Article: ]
121.  Talieri M, Papadopoulou S, Scorilas A, Xynopoulos D, Arnogianaki N, Plataniotis G, Yotis J, Agnanti N. Cathepsin B and cathepsin D expression in the progression of colorectal adenoma to carcinoma. Cancer Lett. 2004;205:97-106.  [PubMed]  [DOI]  [Cited in This Article: ]
122.  Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200:500-503.  [PubMed]  [DOI]  [Cited in This Article: ]
123.  Brenmoehl J, Miller SN, Hofmann C, Vogl D, Falk W, Schölmerich J, Rogler G. Transforming growth factor-beta 1 induces intestinal myofibroblast differentiation and modulates their migration. World J Gastroenterol. 2009;15:1431-1442.  [PubMed]  [DOI]  [Cited in This Article: ]
124.  Xouri G, Christian S. Origin and function of tumor stroma fibroblasts. Semin Cell Dev Biol. 2010;21:40-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 70]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
125.  Kwak JM, Lee HJ, Kim SH, Kim HK, Mok YJ, Park YT, Choi JS, Moon HY. Expression of protein S100A4 is a predictor of recurrence in colorectal cancer. World J Gastroenterol. 2010;16:3897-3904.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res. 2007;13:2082-2090.  [PubMed]  [DOI]  [Cited in This Article: ]
127.  Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324-331.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Okamoto R, Watanabe M. Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J Gastroenterol. 2004;39:1-6.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Brown SL, Riehl TE, Walker MR, Geske MJ, Doherty JM, Stenson WF, Stappenbeck TS. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest. 2007;117:258-269.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103:311-320.  [PubMed]  [DOI]  [Cited in This Article: ]
131.  Pinto D, Gregorieff A, Begthel H, Clevers H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17:1709-1713.  [PubMed]  [DOI]  [Cited in This Article: ]
132.  Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846-851.  [PubMed]  [DOI]  [Cited in This Article: ]
133.  Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127:2763-2772.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Morselli E, Galluzzi L, Kepp O, Vicencio JM, Criollo A, Maiuri MC, Kroemer G. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta. 2009;1793:1524-1532.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 253]  [Cited by in F6Publishing: 247]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
135.  White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 2009;15:5308-5316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 702]  [Cited by in F6Publishing: 449]  [Article Influence: 54.0]  [Reference Citation Analysis (0)]
136.  He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67-93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2316]  [Cited by in F6Publishing: 2243]  [Article Influence: 178.2]  [Reference Citation Analysis (0)]
137.  Vellai T, Takács-Vellai K, Sass M, Klionsky DJ. The regulation of aging: does autophagy underlie longevity? Trends Cell Biol. 2009;19:487-494.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 98]  [Cited by in F6Publishing: 93]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
138.  Botti J, Djavaheri-Mergny M, Pilatte Y, Codogno P. Autophagy signaling and the cogwheels of cancer. Autophagy. 2006;2:67-73.  [PubMed]  [DOI]  [Cited in This Article: ]
139.  Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213-223.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1317]  [Cited by in F6Publishing: 1279]  [Article Influence: 109.8]  [Reference Citation Analysis (0)]
140.  Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F. p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem. 2006;281:39776-39784.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461-466.  [PubMed]  [DOI]  [Cited in This Article: ]
142.  Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. J Clin Invest. 2005;115:2625-2632.  [PubMed]  [DOI]  [Cited in This Article: ]
143.  Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2002;2:664-674.  [PubMed]  [DOI]  [Cited in This Article: ]
144.  Bharti AC, Aggarwal BB. Chemopreventive agents induce suppression of nuclear factor-kappaB leading to chemosensitization. Ann N Y Acad Sci. 2002;973:392-395.  [PubMed]  [DOI]  [Cited in This Article: ]