Erlotinib inhibits colon cancer metastasis through inactivation of TrkB-dependent ERK signaling pathway

The distal metastasis is the main cause of death in patients with colon cancer. Tyrosine receptor kinase B (TrkB) and ERK signals may be the potential targets for the treatment of colon cancer metastasis. This study aims to investigate whether erlotinib inhibits distant metastasis of colon cancer by regulating TrkB and ERK signaling pathway. Human colon adenocarcinoma cell lines (SW480 and Caco-2) pretreated with exogenous C-X-C motif chemokine ligand 8 (CXCL8) were used to assess the suppressive effect of erlotinib on tumor metastasis, including anoikis, epithelial-mesenchymal transformation (EMT), migration, and invasion. Through TrkB overexpression, Akt suppression, and ERK suppression, the roles of TrkB, Akt, and ERK in erlotinib-induced metastasis inhibition of colon cancer cells were explored. The results showed that erlotinib alleviated CXCL8-induced metastasis of the colon cancer cells. Overexpression of TrkB in colon cancer cells eliminated the effect of erlotinib on anoikis, inhibition of EMT, migration, and invasion, and downregulation of p-ERK and p-Akt. Furthermore, the inhibition of ERK activation instead of Akt activation was found to participate in erlotinib-mediated metastasis resistance, including anoikis, inhibition of EMT, migration, and invasion. In conclusion, erlotinib inhibits colon cancer cell anoikis resistance, EMT, migration, and invasion by inactivating TrkB-dependent ERK signaling pathway.     

Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

Colon and rectal cancer (colorectal cancer, CRC) is the third most common cancer worldwide. Deaths from CRC account for around 8% of all cancer deaths, making it the fourth most common cause of death from cancer. The high mortality rate of colon cancer is mainly attributable to its metastasis. Efforts have been made to identify metastasis suppressor genes, which encode proteins responsible for inhibiting the metastasis but not suppressing the growth of primary tumors. Studies on metastasis suppressor genes demonstrated that epigenetic modifications, such as DNA promoter methylation and histone modification, play crucial roles in regulating the expression of many metastasis suppressor genes, which indicates the association between aberrant epigenetic alterations and cancer metastasis. This review will focus on the recent findings regarding metastasis suppressors regulated by epigenetic modifications, particularly DNA methylation and histone modification, in CRC metastasis. Also discussed will be recent progress on the suppression of CRC metastasis by genistein, a soy isoflavone, with a focus on epigenetic mechanisms.     

iTRAQ analysis of colorectal cancer cell lines suggests Drebrin (DBN1) is overexpressed during liver metastasis

Colorectal cancer is currently the third in cancer incidence worldwide and the fourth most common cause of cancer deaths. Mortality in colorectal cancer is often ascribed to liver metastasis. In an effort to elucidate the proteins involved in colorectal cancer liver metastasis, we compared the proteome profiles of the human colon adenocarcinoma cell line HCT‐116 with its metastatic derivative E1, using the iTRAQ labelling technology, coupled to 2D‐LC and MALDI‐TOF/TOF MS. A total of 547 proteins were identified, of which 31 of them were differentially expressed in the E1 cell line. Among these proteins, the differential expressions of translationally controlled tumour protein 1, A‐kinase anchor protein 12 and Drebrin (DBN1) were validated using Western blot. In particular, DBN1, a protein not previously known to be involved in colorectal cancer metastasis, was found to be overexpressed in E1 as compared to HCT‐116 cells. The overexpression of DBN1 was further validated using immunohistochemistry on colorectal cancer tissue sections with matched lymph node and liver metastasis tissues. DBN1 is currently believed to be involved in actin cytoskeleton reorganisation and suppresses actin filament cross‐linking and bundling. Since actin reorganisation is an important process for tumour cell migration and invasion, DBN1 may have an important role during colorectal cancer metastasis.     

Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer

The objective of this study is to investigate the liver's metastasis-related genes and the relationship between Girdin protein expression and clinical and pathological characteristics and prognosis in colorectal cancer. The differential expression of genes between tumor cells from cases with liver metastasis and those from cases without liver metastasis were detected using an RT(2) Profiler? PCR Array. The expression of the stem cell gene Girdin was analyzed using immunohistochemistry staining. Subsequently, the relationship between Girdin and clinicopathological parameters of colorectal cancer was determined. The Girdin protein was verified as a gene related to liver metastasis and was expressed positively in 161 (37.01 %) of the 435 cases examined. The expression of Girdin protein was related to histological grade and distant metastasis (P = 0.007 and 0.007, respectively). After analyzing survival rates, cases with highly expressed Girdin protein were shown to attain a significantly higher rate of liver metastasis and poorer postoperative, disease-specific survival than those with no or low expressed Girdin protein (P = 0.001). In the Cox regression test, the depth of tumor invasion, histological grade, duke's stage, distant metastasis, and the Girdin protein were detected as an independent prognostic factor (0.020, 0.032, 0.001, 0.001, and 0.010, respectively). The Girdin protein may be a potential new early liver metastasis biomarker of colorectal cancer.     

The iron-regulated metastasis suppressor, Ndrg-1: identification of novel molecular targets

A recently identified metastasis suppressor, N-myc downstream regulated gene-1 (Ndrg-1), has been shown to reduce the invasion and metastasis of breast, colon, prostate and pancreatic cancer. Among its many functions, Ndrg-1 is involved in modulating differentiation, proliferation and angiogenesis. However, knowledge of the molecular targets of Ndrg-1 is limited. The current study has focused on examining the functions of Ndrg-1 in a number of different cancer cell models including prostate, colon, lung and pancreatic cancer to elucidate the known pleiotropic nature of this protein. Furthermore, the potential gene targets of Ndrg-1 were analyzed using whole genome gene array revealing a substantial number of genes whose expression was affected by this metastasis suppressor. Significantly, Ndrg-1 up-regulated thiamine triphosphatase (Thtpa) expression in three of the four cell models. Thtpa is known to decrease the levels of the energy currency molecule, thiamine triphosphate, suggesting a potential pathway for the anti-proliferative effects of Ndrg-1. Furthermore, Ndrg-1 reduced the protein levels of cathepsin C which plays a role in invasion, indicating a potential mechanism of its anti-metastatic role in pancreatic cancer cells. These findings provide a potential link between the observed functions of Ndrg-1 and its molecular targets, further demonstrating its anti-metastatic effect.     

Epigenetic inactivation of the metastasis suppressor RECK enhances invasion of human colon cancer cells

Down-regulation of RECK, an important metastasis suppressor gene, has been found in human colon cancer. However, the molecular mechanism for this down- regulation and its biological significance are still unclear. In the present study, we investigated whether down-regulation of RECK is caused by epigenetic inactivation via promoter methylation and tested the effect of DNA methyltransferase (DNMT) inhibitor on RECK expression and cell invasion. The mRNA and protein levels of RECK in colon tumor tissues and their normal counterparts were compared. We found that down-regulation of RECK was found in 48% of the twenty five tumors analyzed. MSP analysis demonstrated that methylation of RECK promoter was detected in 44% (11/25) of the tumor tissues and a strong correlation between down-regulation and promoter methylation was found (P = 0.028). Promoter methylation was also found in SW480 and SW620 human colon cancer cell lines. DNA methyltransferase (DNMT) inhibitor 5'-azacytidine reversed promoter methylation, restored RECK expression and suppressed invasion by these two cell lines. Restoration of RECK is critical for 5'-azacytidine-mediated suppression of cell invasion because inhibition of RECK by a specific antibody significantly attenuated the anti-invasive ability of 5'-azacytidine. Taken together, our results suggest that down-regulation of the metastasis suppressor RECK in colon cancer is associated with promoter methylation and that a DNMT inhibitor may restore RECK expression to inhibit cell invasion.     

Targeting S100P inhibits colon cancer growth and metastasis by Lentivirus-mediated RNA interference and proteomic analysis

S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and β-tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis.     

Expression Profiles in Stage II Colon Cancer According to APC Gene Status

Colorectal cancer is one of the most common cancers in the world. Histoclinical staging is efficient, but combination with molecular markers may improve the classification of stage II cancers. Several tumor-suppressor genes have been associated with colorectal cancer, and the most frequent allelic losses have been extensively studied for their prognosis effect, but the results remain controversial. In a previous study, we found a possible influence of the chromosome 5 status in the development of liver metastases in stage II colon cancers. We have here investigated the role of the APC gene, located in chromosome arm 5q, in a series of 183 colon adenocarcinomas through a combined analysis of gene expression, mutation, allelic loss and promoter methylation, and metastasis occurrence. Point mutations were found in 73% of cases and allelic losses were found in 39%; 59% of tumors presented with a biallelic inactivation, with a very strong interdependence of the two APC hits (P = 2.1 x 10(-9)). No association was found between expression, number and type of APC alterations, and metastatic evolution. Our results show that the determination of APC status cannot help in the prediction of metastasis and cannot be used to subclassify stage II colon cancers.     

Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice

NK4, originally prepared as a competitive antagonist for hepatocyte growth factor (HGF), is a bifunctional molecule that acts as an HGF-antagonist and angiogenesis inhibitor. When the expression plasmid for NK4 gene was administered into mice by hydrodynamics-based delivery, the repetitive increase in the plasma NK4 protein level was achieved by repetitive administration of NK4 gene. Mice were subcutaneously implanted with colon cancer cells and weekly given with the NK4 plasmid. The repetitive delivery and expression of NK4 gene inhibited angiogenesis and invasiveness of colon cancer cells in subcutaneous tumor tissue and this was associated with suppression of primary tumor growth. By fifty days after tumor implantation, cancer cells naturally metastasized to the liver, whereas NK4 gene expression potently inhibited liver metastasis. Inhibition of the HGF-Met receptor pathway and tumor angiogenesis by NK4 gene expression has potential therapeutic value toward inhibition of invasion, growth, and metastasis of colon cancer.     

Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation

Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model.     

Restoration of transforming growth factor-beta receptor II expression in colon cancer cells with microsatellite instability increases metastatic potential in vivo

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFβ signaling by re-expression of TGFβ receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFβ, indicating that TGFβ-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFβ signaling indicated that Bim is an effector of TGFβ-mediated survival. In addition, TGFβ-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFβ, and restoration of TGFβ signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFβ signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFβ receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.     

Triptolide inhibits CD133+/CD44+ colon cancer stem cell growth and migration through triggering apoptosis and represses epithelial-mesenchymal transition via downregulating expressions of snail,slug, and twist

High recurrence and metastatic behavior patterns are the most important reasons for the failure of treatment strategies in patients with colon cancer. Cancer stem cells (CSCs), which are considered root of cancer, are thought to be associated with therapy resistance, relapse, and metastasis, and, therefore, targeting CSCs rather than the bulk population may be an effective approach. In cancer studies, there is an increasing interest in close friendship between epithelial-mesenchymal transition (EMT) and CSCs. Triptolide (TPL) isolated from Chinese herb Tripterygium wilfordii has important effects on the prevention of migration and metastasis as well as cytotoxic effect against cancer cells. The potential lethal efficacy of TPL on CSCs that is highly resistant to the drug is an unsolved mystery. Fundamentally, the present study basically aims to find answers to two questions: (a) is it possible to target colon CSCs with TPL? and (b) what are the mechanisms underlying TPL's potential to eliminate CSCs? Cytotoxic effects of TPL on CSCs were evaluated by WST-1 and Muse count and viability assays. Apoptosis assay and cell-cycle analysis were performed to investigate the inhibitory effect of TPL. Moreover, the effects of TPL on spheroid formation capacity, migration, and EMT processes, which are associated with CSC phenotype, were also investigated. The results revealed that TPL triggered cell death and apoptosis and altered cell cycle distribution. Moreover, TPL significantly reduced the snail slug and twist expressions associated with EMT. TPL has been shown to be effective in colon CSCs by in vitro experiments, and it might be a highly effective agent against colon cancer has been implicated in need of supporting in vivo and clinical studies.     

Effect of AOB, a fermented-grain food supplement, on oxidative stress in type 2 diabetic rats

Reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic complications. Antioxidant Biofactor (AOB) is a mixture of commercially available fermented grain foods and has strong antioxidant activity. This study investigated the effect of AOB supplementation of standard rat food on markers of oxidative stress and inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes. Blood glucose, hemoglobin A1c, plasma free fatty acid, triacylglycerol and plasminogen activator inhibitor-1 (PAI-1) were significantly higher in OLETF rats than in non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats at 29 weeks. AOB (6.5% of diet) was given to rats during 29-33 weeks of diabetic phase in OLETF rats. OLETF rats with AOB supplementation showed decreased blood glucose, hemoglobin A1c, triacyglycerol, low density lipoprotein, cholesterol and PAI-1. Mitochondrial ROS production was significantly increased in heart, aorta, liver and renal artery of OLETF rats. Uncoupling protein 2 (UCP2) is known to regulate ROS production. We found aortic UCP2 protein expression increased in OLETF rats, and AOB returned UCP2 expression to normal. Aortic endothelial NO synthase (eNOS) was also increased in OLETF rats more than in LETO rats at 33 weeks. In contrast, phosphorylated vasodilator-stimulated phosphoprotein, an index of the NO-cGMP pathway, was significantly diminished. AOB increased eNOS proteins in LETO and OLETF rats. In conclusion, AOB significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. The data suggest that dietary supplementation with AOB contributes to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.     

Matrix metalloproteinase-2 and -9 in bile as a marker of liver metastasis in colorectal cancer

Matrix metallproteinases (MMP)-2 and -9 are associated with cancer invasion and metastasis. MMP-2 and MMP-9 activities have never been assayed in bile. In the present study we investigated whether MMP-2 and -9 activities in the bile could be a marker for evaluation of liver metastasis in colorectal cancer. Fifty-three patients underwent colorectal resection for histologically verified adenocarcinoma. Twenty-six patients had colorectal cancer without liver metastasis and 27 patients had metastatic liver tumor. Six patients were studied as carcinoma-free control. MMP-2 and MMP-9 activities were assayed in bile using gelatin zymography and quantitated. Active MMP-2 activity of colorectal cancer with liver metastasis group (24.1 +/- 2.5 pixel count) was significantly higher than that of colorectal cancer without liver metastasis group (11.4 +/- 1.3 pixel count) (P < 0.001) or of control group (6.4 +/- 1.0 pixel count) (P < 0.001). Active MMP-9 was not detected in bile. ProMMP-9 activity of colorectal cancer with liver metastasis group (530.3 +/- 127.5 pixel count) was significantly higher than that of colorectal cancer without liver metastasis group (213.9 +/- 33.2 pixel count) (P = 0.008). This is the first report showing that the levels of active MMP-2 and proMMP-9 in bile were significantly higher in liver metastasis of colorectal cancer than in metastasis-free colorectal cancer. The results suggest that activities of active MMP-2 and proMMP-9 in the bile may be useful markers for predicting liver metastasis in colorectal cancer.     

Co‐expression of CD133+/CD44+ in human colon cancer and liver metastasis

Although relatively good therapeutic results are achieved in non‐advanced cancer, the prognosis of the advanced colon cancer still remains poor, dependent on local or distant recurrence of the disease. One of the factors responsible for recurrence is supposed to be cancer stem cells (CSCs) or tumor‐initiating cells, which are a population of cancer cells with ability to perpetuate themselves through self‐renewal and to generate differentiated cells, thought to be responsible for tumor recurrence. This study globally approach the possible role of tissue‐derived stem cells in the initiation of colon cancer and its metastatic process in the liver. Fresh surgical specimens from colon cancer, non‐tumor tissue and liver metastasis were obtained directly from the operating room, examined, and immediately processed. CSCs were selected under serum‐free conditions and characterized by CD44 and CD133 expression levels. CD133⁺/CD44⁺ cell populations were then investigated in paraffin‐embedded tissues and circulating tumor cells isolated from peripheral blood of the same group of colon cancer patients. Our data demonstrate that metastatic properties of cell populations from blood and liver metastasis, differently from primitive tumors, seem to be strictly related to the phenotype CD133 positive and CD44 positive. J. Cell. Physiol. 228: 408–415, 2013. © 2012 Wiley Periodicals, Inc.     

Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans

ATB(0,+) (SLC6A14) is a Na(+)/Cl(-)-coupled arginine transporter expressed at low levels in normal colon. Arginine is an essential amino acid for tumor cells. Arginine is also the substrate for nitric oxide synthases (NOSs). Since arginine and arginine-derived nitric oxide (NO) play a critical role in cancer, we examined the expression of ATB(0,+) in colorectal cancer. Paired normal and cancer tissues from colectomy specimens of 10 patients with colorectal cancer and from the liver tissue of one patient with hepatic metastasis from a colonic primary were used for the analysis of the levels of ATB(0,+) mRNA, inducible NOS (iNOS) mRNA and the corresponding proteins. Tissues samples from the colon, liver, and lymph nodes of an additional patient with metastatic colon cancer were analyzed for ATB(0,+) protein alone. We also examined the levels of nitrotyrosylated proteins. The ATB(0,+) mRNA increased 22.9+/-3.0-fold in colorectal cancer compared to normal tissue and the increase was evident in each of the 10 cases examined. iNOS mRNA increased 5.2+/-1.1-fold in cancer specimens. The changes in mRNA levels were associated with an increase in ATB(0,+), iNOS, and nitrotyrosylated proteins. The increased expression of ATB(0,+) and iNOS was also demonstrated in liver and lymph node specimens with metastases from colonic primaries. This study strongly suggests that the upregulation of ATB(0,+) may have a pathogenic role in colorectal cancer. Since ATB(0,+) is a versatile transporter not only for arginine but also for several drugs including NOS inhibitors, these findings have significant clinical and therapeutic relevance.     

Fluorescent-Antibody Targeting of Insulin-Like Growth Factor-1 Receptor Visualizes Metastatic Human Colon Cancer in Orthotopic Mouse Models

Fluorescent-antibody targeting of metastatic cancer has been demonstrated by our laboratory to enable tumor visualization and effective fluorescence-guided surgery. The goal of the present study was to determine whether insulin-like growth factor-1 receptor (IGF-1R) antibodies, conjugated with bright fluorophores, could enable visualization of metastatic colon cancer in orthotopic nude mouse models. IGF-1R antibody (clone 24–31) was conjugated with 550 nm, 650 nm or PEGylated 650 nm fluorophores. Subcutaneous, orthotopic, and liver metastasis models of colon cancer in nude mice were targeted with the fluorescent IGF-1R antibodies. Western blotting confirmed the expression of IGF-1R in HT-29 and HCT 116 human colon cancer cell lines, both expressing green fluorescent protein (GFP). Labeling with fluorophore-conjugated IGF-1R antibody demonstrated fluorescent foci on the membrane of colon cancer cells. Subcutaneously- and orthotopically-transplanted HT-29-GFP and HCT 116-GFP tumors brightly fluoresced at the longer wavelengths after intravenous administration of fluorescent IGF-1R antibodies. Orthotopically-transplanted HCT 116-GFP tumors were brightly labeled by fluorescent IGF-1R antibodies such that they could be imaged non-invasively at the longer wavelengths. In an experimental liver metastasis model, IGF-1R antibodies conjugated with PEGylated 650 nm fluorophores selectively highlighted the liver metastases, which could then be non-invasively imaged. The IGF-1R fluorescent-antibody labeled liver metastases were very bright compared to the normal liver and the fluorescent-antibody label co-located with green fluorescent protein (GFP) expression of the colon cancer cells. The present study thus demonstrates that fluorophore-conjugated IGF-1R antibodies selectively visualize metastatic colon cancer and have clinical potential for improved diagnosis and fluorescence-guided surgery.     

The role of gelatinases in colorectal cancer progression and metastasis

Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the multifunctionality of gelatinases, it is unpredictable at what stage of cancer development and in which processes gelatinase activity is involved. Therefore, it is concluded that the use of MMP inhibitors to treat cancer should be considered carefully.     

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)