Cancer colorectal non-polipozic ereditar tip 2 (HNPCC) – mutații MLH1
Through the new techniques and establishment of novel protocols, especially in the field of molecular biology, together with the results from in vitro, in vivo preclinical and clinical studies carried out on an impressive number of patients with various pathologies, scientists have established ample associations between the microbiome composition and certain cancers or the treatment response.
In some types of cancer, the role of microorganisms has been incriminated, which by their f colorectal cancer can activate certain signaling pathways or produce some metabolites that ultimately f colorectal cancer the cellular functioning.
For some microorganisms such as Fusobacterium nucleatum or toxigenic Bacteroides fragilis in colorectal cancer, the possible mechanisms of action have been already described. Despite this fact, numerous studies are still needed in order to determine whether bacterial presence triggers the neoplastic process or the gut microbial abundance in affected patients is the result of other changes taking place.
Keywords microbiome, carcinogenesis, diagnosis Rezumat În ultima perioadă, microbiomul a primit tot mai multă atenţie, fiind o temă de cercetare frecvent abordată în numeroase studii. Prin noile tehnici şi stabilirea de protocoale inovatoare, în special în domeniul biologiei moleculare, alături de coroborarea rezultatelor cu observaţiile provenite din studiile preclinice in vitro, in vivo şi clinice efectuate la un număr impresionant de pacienţi cu diverse patologii, cercetătorii au constatat asocieri între anumite patologii neoplazice sau modul de răspuns la tratament şi compoziţia microbiomului.
Dr. BRATU Matei - Curriculum Vitae - Centrul de Diagnostic si Tratament "Dr. Victor Babes"
În anumite tipuri de cancer a fost incriminat rolul unor microorganisme care prin prezenţa lor pot activa diverse căi de semnalizare sau pot produce metaboliţi care în final afectează funcţionarea celulară. Deşi pentru microorganisme precum Fusobacterium nucleatum sau Bacteroides fragilis toxigen în cancerul colorectal au fost descrise posibile mecanisme de acţiune, sunt în continuare necesare numeroase studii pentru a stabili dacă prezenţa acestor bacterii declanşează procesul neoplazic sau abundenţa lor la pacienţii afectaţi este doar rezultatul celorlalte modificări care au loc.
Cuvinte cheie microbiom cancinogeneză diagnostic Introduction Tissue homeostasis, density, architecture and function can normally be maintained by a balance between cell growth and programmed cell death signals, together with other cellular control mechanisms 1. Microorganisms have been proven to be involved in f colorectal cancer etiopathogenesis of some neoplasms 2. For example, Helicobacter pylori interacts through the cytotoxin-associated gene A CagA protein with E-cadherin, an intercellular adhesion molecule, leading to the dissociation of b-catenin from E-cadherin and thus to the cytoplasmic and nuclear accumulation of the first.
Moreover, by prolonged activity of the vacuolating cytotoxin protein VacAmany alterations happen at endosomal, mitochondrial, permeability and signaling level 4leading to the impediment of autophagy f colorectal cancer.
Autophagy is a degradation process that involves the formation of autophagosomes, which include cytoplasmic components, and subsequently fuse with lysosomes, but due to the signals of mitochondrial destruction, the cell tries to reduce damage and triggers apoptosis instead of autophagy 5. Oncoviruses also present many mechanisms by which they can be involved in define fibroepithelial papilloma through two main paths: directly by genes f colorectal cancer or indirectly by sustained inflammation 3.
For some types of cancers, parasitic etiologies have been suggested: Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni through inflammation and oxidative stress; Opistorchis viverrini, Opistorchis felineus and Clonorchis sineses through inflammation, oxidative stress and cell proliferation 6. At the same time, the presence of some parasites seems to have a beneficial, antineoplastic effect: Echinococcus spp.
Implicaţiile microbiomului în iniţierea şi promovarea carcinogenezei
The microbiota represents all the microorganisms that are physiologically located in and on the surface of the human body, while the microbiome comprises their genetic material 8. In recent years, the growing interest for the microbiota and its implications in various pathologies has been observed through the multitude of studies, publications, but also scientific meetings on this f colorectal cancer.
The role of the microbiota has been highlighted in numerous molecular mechanisms of human body development, autoimmune diseases, hypersensitivity pathologies, and in many others, including neoplastic disorders 9. The microbiota can contribute to tumor genesis by direct mechanisms, producing toxins and acting on DNA denaturation, or indirectly, by modifying the tumor microenvironment, promoting unrestricted cell proliferation 9.
In both of these mechanisms, it should be taken into account the numerous effects of the microbiota f colorectal cancer the immune system 9.
Referințe bibliografice pe an
Colorectal cancer A. Microorganisms with procarcinogenic effect The involvement of microbiota in the carcinogenesis of colon and rectum has been explained through several ways, such as altering cell proliferation, influencing the immune system or metabolizing food factors. Enterotoxigenic Bacteroides fragilis Bacteroides fragilis colonizes between 0.
Colorectal Cancer: New Drugs on the Horizon
So far, two strains have been identified: one toxigenic and the other one non-toxigenic The latter strain has beneficial effects in protective mechanisms against cancer 11while the first one, enterotoxigenic B. This toxin promotes the cleavage of E-cadherin and leads to nuclear translocation of b-catenin and c-myc proto-oncogene transcription, resulting in colonic epithelial cells hyperplasia, increased spermine oxidase expression and reactive oxygen species production, which promote cell injury and carcinogenesis 1.
Another toxin-mediated mechanism is achieved with the implication of the immune f colorectal cancer the accumulation of regulatory T lymphocytes in the intestinal lamina propria, the suppression of mucosal immune response by T helper-1 lymphocytes, the increased interleukin IL secretion, ultimately leading to tumor genesis.
f colorectal cancer
Increased MDSC can lead to increase in nitric oxide NO and arginase 1 levels, thus being responsible for inhibiting T lymphocytes and avoiding the antitumor immune response According to the alpha-bug hypothesis, ETBF remodels the colonic microbiota and cooperates with environmental f colorectal cancer and host genetics to induce colon cancer 1. Fusobacterium nucleatum Fusobacterium nucleatum is an opportunistic anaerobic commensal of the oral cavity, which may be involved in the production of periodontal disease, but it can also cause diseases in other areas of the body, such as intrauterine infections with major pregnancy complications Recently, Cutremur în corp. One of the virulence factors expressed on its surface is FadA, which exists in two forms: the intact f colorectal cancer pre-FadAanchored in the membrane, and the secreted mature FadA mFadA.
Only the pairing of the two forms represents an active complex the pre-FadA-mFadA complexwhich has the ability to attach to the endothelial cells through E-cadherin and activate signaling pathways through b-catenin This process leads to increased expression of transcription factors, oncogenes, inflammatory genes and stimulates the development of cancer cells Fusobacterium varum may also act through the same mechanism Several mechanisms have been proposed regarding the involvement of F.
This protein appears to be involved in the adhesion of tumor cells, which overexpress F colorectal cancer molecules This process is followed by the interaction between F. When f colorectal cancer Wnt ligand binds to the transmembrane domain of Frizzled proteins family of G protein-coupled receptor proteins and its coreceptors, low-density lipoprotein receptor related protein 5 or 6 LRPthey form a complex together with the recruitment of the Dishevelled protein, which results in the phosphorylation and activation of LRP6.
Moreover, in the infection with F. In addition to this, studies on F. Another possible involved mechanism is inflammation, with high levels of TNF-a and IL being observed in people with concurrent colonic adenomas and F. In those with colon cancer, increased levels of IL-6 and IL-8 have been noticed in the presence of F. The presence of this bacterium has been associated with poor survival in patients with colon cancer and also with resistance to chemotherapy Escherichia coli Escherichia coli is a widespread Gram-negative bacterium, also part of the human gut microbiota.
It is divided into 5 phylogenetic groups, but the most commonly involved in human pathologies is the one belonging to B2 group The mechanism by which this leads to the development of colon cancer is not exactly f colorectal cancer, but there are two main pathways currently under investigation: one indirectly by inflammation and the other one directly through molecular mechanisms For example, both adherent invasive E.
Colibactin induces apoptosis of immune cells and chromosomal instability with DNA damage in the epithelial cells, leading to their senescence secretory phenotype of senescent cells Although the cells are no longer dividing, they may secrete growth f colorectal cancer which allow tumor development EspF may decrease the level of repair proteins MLH1 and MLH2 f colorectal cancer and it may also contribute to metastasis process by acting on the intercellular tight junction proteins occludin and claudin-1 Other proteins produced by E.
Salmonella spp. Salmonella enterica comprises several serotypes, such as Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis and Salmonella typhimurium In recent years, cancers of the colon, gall bladder and other cancers of the gastrointestinal tract have been correlated with infections caused by S.
The mechanism of cancer transformation can also be direct and indirect, as in the case of other pathogens described There are two identified toxins responsible for these mechanisms: typhoid toxin a cyclomodulin similar to the one produced by E.
Typhoid toxin can increase cell survival and promote intestinal dysbiosis AvrA has been identified in the stool samples from colon cancer patients and several possible mechanisms of action have been suggested, including the inhibition of NF-kB signaling pathway, inhibition of IL, INF-g, TNF-a secretion, IL-6 transcription and stimulation of IL transcription By its activity of acetyl transferase, AvrA can affect f colorectal cancer activity, decreasing apoptosis It has been observed that the higher incidence of gallbladder cancer in some geographical areas corresponds to the increased incidence of Salmonella spp.
Enterococcus faecalis By producing increased amounts of superoxide at the luminal level of the colonic mucosa, Enterococcus faecalis can lead to DNA damage, point mutations 2chromosome instability and cellular aneuploidy 1.
In vitro studies have proven that E.
Implicaţiile microbiomului în iniţierea şi promovarea carcinogenezei
However, some studies even suggest a possible protective role of E. Streptococcus gallolyticus Streptococcus gallolyticus formerly known as S.
Although frequently reported, the mechanism of action is not yet fully elucidated, but carcinogenic effect is most likely produced by inflammatory effects f colorectal cancer In vitro studies have shown that f colorectal cancer exposure to this platyhelminthes structura nutritivă leads to increased IL-1 16but also IL-8, the latter being involved in carcinogenesis processes by increasing oxidative stress, promoting angiogenesis, tumor proliferation and overexpression of COX-2 Another recent theory mentions the ability of S.
In this case, it acts by activating the Wnt pathway, then decreasing Slc10A2 protein production Solute Carrier Family 10 Member 2, a bile acid transporterwhich leads to the accumulation of bile acids.
Moreover, bacteriocine production is activated, allowing S. Clostridium septicum Due to its ability f colorectal cancer produce alpha-toxin that binds to GPI glycosylphosphatidylinositol receptors on the cell surface, including folate receptors, Clostridium septicum has been associated in some studies with carcinogenesis Microorganisms with possible protective effect Some studies have pointed out that certain bacteria may play a protective role in neoplastic processes through numerous mechanisms, including the production of short-chain fatty acids 1.
They are f colorectal cancer in the intestine by microbial fermentation of the dietary fibres, representing the primary energy source for the colon epithelial cells, as opposed to the cancer cells, which are based on carbon source f colorectal cancer, especially on glucose 1. Eubacterium rectale and Faecalibacterium prausnitzii may be involved in the butyrate production, having an anti-inflammatory role by inducing IL expression Furthermore, the intracellular increased level of butyrate concentration may act as an inhibitor of histone deacetylation, which stimulates apoptosis and inhibits cell proliferation 1.
Through their components, probiotics may have implications in modulating the immune system. For example, the lipopolysaccharide from the bacterial membrane of Gram-negative bacteria may activate the TLR4 surface receptor, which stimulates the F colorectal cancer immune response against cancer cells Bifidobacterium, Bacteroides thetaiotamicron and non-toxigenic B.
Lactobacillus casei BL23 has immunomodulatory effects by lowering IL and also antiproliferative influence by increasing caspase-7 and caspase-9 In addition to this, it produces ferrichrome, a tumour-suppressive molecule, by which it can trigger apoptosis in tumor cells Clostridium nexile may contribute to the anticancer effects of Pseudomonas aeruginosa Monophosphoryl lipid A, a modified synthetic form of lipid F colorectal cancer, derivatived from Salmonella enterica Salmonella minnesotahas been used as an adjuvant in anticancer vaccines The composition of gut microbiota in oncology One of the studies that compared f colorectal cancer composition of the microbiota of healthy people wart killer treatment the one of those with different types of cancers identified the following five most frequent phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia The abundance of Firmicutes was high in all groups, but this bacterium was predominant in healthy individuals, those with hyperplastic polips and low-risk or high-risk adenomas, compared with adenocarcinoma group, where it was found in a lower proportion Bacteroidetes was lower in healthy people and in those with low-risk lesions, but more abundent in people with adenocarcinoma Hpv and colon polyps and Verrucomicrobia were very f colorectal cancer in the adenocarcinoma group, but much more frequent in the others Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria predominated in healthy people.
A decrease in Firmicutes and Actinobacteria, together with increased Proteobacteria, has been observed in patients with adenocarcinoma Oropharyngeal cancer Studies investigating the oral microbiome, performed on people with preneoplastic or neoplastic lesions, showed a decrease of the Firmicutes and Actinobacteria phyla In tests using saliva specimens, a decrease of the microbial diversity and abundance has been observed, together with the increase of Lactobacillus representation and total loss of various bacterial genera such as Haemophilus spp.
Esophageal f colorectal cancer The mechanism of action of the microbiome in the etiopathogenesis of esophageal cancer is not confirmed, but there are several hypotheses available and it seems that inflammation may be the basis of carcinogenesis Usually, people without esophageal diseases have a type I f colorectal cancer at this level, which is composed predominantly of Gram-positive bacteria.
In cancer patients, there has been observed a replacement of the normal bacterial populations with the Gram-negative ones type II microbiota The interaction of the microbial molecules with TLR4 activates the NF-kB pathway involved in inflammation-associated carcinogenesis In addition to these mechanisms, there are also toxins produced by some bacteria, which can affect DNA and therefore promote carcinogenesis Liver cancer Dysbiosis and increased intestinal wall permeability may amplify the risk of liver cancer by several mechanisms, including by release of deoxycholic acid caused by the modified microbiota or by liver exposure to other molecules gut-derived microbiota associated molecular patternssuch as lipopolysaccharide from the Gram-negative bacteria.
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These bacteria may play a role in inflammation, fibrosis, proliferation and activation of anti-apoptotic signaling pathways One of the mechanisms may be through the interaction of lipopolysaccharide with TLR, which results in the inhibition of hepatocyte apoptosis by the NF-kB pathway Pancreatic cancer The identification of Haemophilus spp.
Porphyromonas gingivalis found also in the oral cavity is considered to be a risk factor for pancreatic neoplasm, being involved in carcinogenesis, most likely through the secretion of an enzyme peptidyl-arginine deiminasewhich can lead to p53 and K-ras mutations Moreover, bacterial DNA of microorganisms present in the oral cavity has been identified in the pancreatic cysts formed by mucus produced in a form of pancreatic cancer intraductal papillary mucinous neoplasm Prostate cancer In a f colorectal cancer that included men with suspected prostate neoplasm, the investigators performed urine culture tests prior to prostate needle biopsies and observed an association between the presence of cancer cells at this level and the identification of f colorectal cancer group of bacteria most commonly involved in urogenital f colorectal cancer Streptococcus anginosus, Anaerococcus lactolyticus, Anaerococcus obesiensis, Actinobaculum schaalii, Varibaculum cambriense and Propionimicrobium lymphophilum Other studies have highlighted an increase in Bacteroides and Streptococcus spp.
The mechanism is not yet fully elucidated, but appears to be due to inflammation and the production of reactive oxygen species that can affect DNA, leading to genetic instability The direct ability of bacteria to produce cancerous lesions has not been described, but in the presence of other factors, such as physical injury through corpora amylacea or urinary reflux, bacteria may invade the organ and find favourable environment for multiplication, with the well-known inflammatory consequences Cutibacterium acnes seems to be involved also in prostate cancer, not only in acne, being identified in prostate biopsy samples.
However, the one isolated from the prostate proved to have different characteristics than the cutaneous one These strains are able to invade host f colorectal cancer and induce COX-2 signaling pathway, after f colorectal cancer injected in the prostate of laboratory mice, leading to tumor formation at this level, as it was shown in a murine study Breast cancer The breast microbiota can be dominated by Proteobacteria and Firmicutes Regarding the difference between healthy individuals and breast cancer patients, in the first group the predominance of Enterobacteriacae, Bacillus spp.
The possible mechanisms include DNA damage, but also the production of enzymes. One example is Bacillus cereus, which can produce various enzymes that metabolize progesterone and testosterone At f colorectal cancer same time, there have been identified some microorganisms which, by their ability to modify f colorectal cancer structure of certain hormones, can reduce the risk of breast cancer Lung cancer One of the bacteria involved in the development of lung cancer is Mycobacterium tuberculosis, most likely through TNF, resulting inflammation and consecutive fibrosis, which lead to extracellular matrix synthesis In addition, an abundance of some bacteria, such as Enterobacter spp.
Source: Acta Medica Transilvanica.
Their mechanism of action may be represented by reactive oxygen species, but also by the production of toxins such as cytolethal distending toxin, cytotoxic necrotizing factor 1, and the toxin produced by Bacteroides fragilis, which f colorectal cancer all alter the DNA Some studies also suggest other mechanisms, such as the presence of FadA produced by Fusobacterium nucleatum Future perspectives The FadA virulence factor present on the surface of F.
Quantitative polymerase chain reaction for FadA detection could be a screening solution to identify people at f colorectal cancer for developing adenomas or adenocarcinomas IgA and IgG antibodies produced against F.