Chronic Intestinal Parasitosis: A Clinical Model of a Role of Inflammation in Colorectal Carcinogenesis ?

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

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Medycyna w ujęciu Jędrzeja Śniadeckiego

Opuscula Musealia ◽

10.4467/20843852.om.18.001.10994 ◽

2019 ◽

Vol 26 ◽

pp. 7-19

Author(s):

Ryszard W. Gryglewski

Keyword(s):

Clinical Medicine ◽

Clinical Work ◽

Convincing Evidence ◽

Clinical Model ◽

Highly Educated ◽

Pathological Model ◽

The Subject ◽

The 19Th Century ◽

Derived Data

Medicine in terms of Jędrzej Śniadecki Jędrzej Śniadecki (1768–1838) remains one of most eminent scholars of his times. Remembered as a founder of modern chemistry in Poland, one of early pioneers in anthropology and social sciences, and author of the two volume book Theory of organic being (Teoria jestestw organicznych), in which the modern metabolic concept of life processes can be considered as grounded; he was also a highly educated and gifted physician. This paper aims to show the importance of medicine in Śniadecki’s theory of life, in its physiological and pathological manifestations in regard to the clinical model and the medical practice which he followed. It deals with the concept of illness as described in Śniadecki’s writings, focusing on the role of irritation and organic reaction as the major components of his proposed pathological model. The dynamic and variable conditions of diseases are explained by means of metabolic changes, which was a truly pioneering concept, already described in Śniadecki’s earlier theoretical works on the subject of life and nature. The paper discusses the problem of influence in terms of the leading medical doctrines at the end of the 18th and the beginning of the 19th century, namely those of John Brown (1735–1788) and François Broussais (1772–1838), on Śniadecki as a researcher and practitioner. For practical (clinical) medicine his reserve towards auscultation and percussion, then a slowly gaining field in clinical subjects, is clearly present in Śniadecki’s writings and teaching. His passive and, as far as we can tell, sceptical attitude is explained by the lack of convincing evidence, based on empirical and experimental data, which would enable to connect the physical signs of a diagnosis fulfilled by means of stethoscope to that of the percussion process. It must be remembered that the books by Adam Raciborski (1809–1871) and Joseph Škoda (1805–1881) were both published in the 1830s, where modern diagnosing methods were established using a suitable scientific background to explain their importance. This was too late to influence the clinical work of Śniadecki. The same scepticism, with an obvious demand for strict and experimentally derived data, is probably responsible for the conservative therapy present in Śniadecki’s teaching.

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PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712345115 ◽

2018 ◽

Vol 115 (17) ◽

pp. E4061-E4070 ◽

Cited By ~ 22

Author(s):

Bastian Dörsam ◽

Nina Seiwert ◽

Sebastian Foersch ◽

Svenja Stroh ◽

Georg Nagel ◽

...

Keyword(s):

Cell Death ◽

Dna Repair ◽

Tumor Progression ◽

Dna Methyltransferase ◽

Intestinal Inflammation ◽

Colorectal Tumor ◽

Colorectal Carcinogenesis ◽

Dependent Manner ◽

Parp 1

Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1−/−) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1−/− mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1−/− animals were then crossed with O6-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1−/−/MGMT−/− double knockout (DKO) mice developed more, but much smaller tumors than MGMT−/− animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O6-methylguanine levels. Studies with PARP-1−/− cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O6-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression.

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The role of intestinal microbiota in the colorectal carcinogenesis

10.1016/b978-0-323-90055-3.00036-3 ◽

2022 ◽

pp. 495-512

Author(s):

Alejandra Cardelle-Cobas ◽

Beatriz I. Vázquez ◽

José Luis Ulla Rocha ◽

Carlos N. Franco ◽

Margarita Poza ◽

...

Keyword(s):

Intestinal Microbiota ◽

Colorectal Carcinogenesis

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The Role of Vitamin D Receptor Gene Polymorphisms in Colorectal Cancer Risk

Cancers ◽

10.3390/cancers12061379 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1379

Author(s):

Ippokratis Messaritakis ◽

Asimina Koulouridi ◽

Maria Sfakianaki ◽

Konstantinos Vogiatzoglou ◽

Nikolaos Gouvas ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin D ◽

Vitamin D Receptor ◽

Bacillus Stearothermophilus ◽

Receptor Gene ◽

Stage Iv ◽

Colorectal Carcinogenesis ◽

Thermus Aquaticus ◽

Vdr Gene

Vitamin D deficiency has been associated with increased colorectal cancer (CRC) incidence risk and mortality. Vitamin D mediates its action through the binding of the vitamin D receptor (VDR), and polymorphisms of the VDR might explain these inverse associations. The aim of the study was the investigation of the relevance of rs731236; Thermus aquaticus I (TaqI), rs7975232; Acetobacter pasteurianus sub. pasteurianus I (ApaI), rs2228570; Flavobacterium okeanokoites I (FokI) and rs1544410, Bacillus stearothermophilus I (BsmI) polymorphisms of the VDR gene to colorectal carcinogenesis (CRC) and progression. Peripheral blood was obtained from 397 patients with early operable stage II/III (n = 202) and stage IV (n = 195) CRC. Moreover, samples from 100 healthy donors and 40 patients with adenomatous polyps were also included as control groups. Genotyping in the samples from patients and controls was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). A significant association was revealed between all four polymorphisms and cancer. Individuals with homozygous mutant (tt, aa, ff or bb) genotypes were more susceptible to the disease (p < 0.001). All of the mutant genotypes detected were also significantly associated with stage IV (p < 0.001), leading to significantly decreased survival (p < 0.001). Moreover, all four polymorphisms were significantly associated with KRAS (Kirsten ras oncogene) mutations and Toll-like receptor (TLR2, TLR4 and TLR9) genetic variants. In multivariate analysis, tt, aa and ff genotypes emerged as independent factors associated with decreased overall survival (OS) (p = 0.001, p < 0.001 and p = 0.001, respectively). The detection of higher frequencies of the VDR polymorphisms in CRC patients highlights the role of these polymorphisms in cancer development and progression.

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The Role of Fusobacterium nucleatum in Colorectal Carcinogenesis

Pathobiology ◽

10.1159/000512175 ◽

2020 ◽

pp. 1-14

Author(s):

José Guilherme Datorre ◽

Ana Carolina de Carvalho ◽

Denise Peixoto Guimarães ◽

Rui Manuel Reis

Keyword(s):

Clinical Utility ◽

Therapy Response ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Intestinal Microbiome ◽

Bacterial Strains ◽

Molecular Features ◽

Important Target ◽

Intestinal Dysbiosis

Colorectal cancer (CRC) is one of the most frequent and deadly neoplasms worldwide. Genetic factors, lifestyle habits, and inflammation are important risk factors associated with CRC development. In recent years, growing evidence has supporting the significant role of the intestinal microbiome in CRC carcinogenesis. Disturbances in the healthy microbial balance, known as dysbiosis, are frequently observed in these patients. Pathogenic microorganisms that induce intestinal dysbiosis have become an important target to determine the role of bacterial infection in tumorigenesis. Interestingly, the presence of different bacterial strains, such as Fusobacterium nucleatum, has been detected in tissue and stool from patients with CRC and associated with substantial clinical and molecular features, as well as with patient therapy response. Therefore, understanding how the presence and levels of F. nucleatumstrains in the gut affect the risk of CRC onset and progression may inform suitable candidates for interventions focused on modulation of this bacteria. Here we review new insights into the role of gut microbiota in CRC carcinogenesis and the clinical utility of using the detection of F. nucleatum in different settings such as screening, prognosis, and microbiota modulation as a means to prevent cancer, augment therapies, and reduce adverse effects of treatment.

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Smad7 and Colorectal Carcinogenesis: A Double-Edged Sword

Cancers ◽

10.3390/cancers11050612 ◽

2019 ◽

Vol 11 (5) ◽

pp. 612 ◽

Cited By ~ 5

Author(s):

Edoardo Troncone ◽

Giovanni Monteleone

Keyword(s):

Immune Cells ◽

Transforming Growth Factor ◽

Intestinal Inflammation ◽

Association Studies ◽

Cell Subset ◽

Colorectal Carcinogenesis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Chronic Intestinal Inflammation

Colorectal carcinogenesis is a complex process in which many immune and non-immune cells and a huge number of mediators are involved. Among these latter factors, Smad7, an inhibitor of the transforming growth factor (TGF)-β1 signaling that has been involved in the amplification of the inflammatory process sustaining chronic intestinal inflammation, is supposed to make a valid contribution to the growth and survival of colorectal cancer (CRC) cells. Smad7 is over-expressed by tumoral cells in both sporadic CRC and colitis-associated CRC, where it sustains neoplastic processes through activation of either TGFβ-dependent or non-dependent pathways. Consistently, genome-wide association studies have identified single nucleotide polymorphisms of the Smad7 gene associated with CRC and shown that either amplification or deletion of the Smad7 gene associates with a poor prognosis or better outcome, respectively. On the other hand, there is evidence that over-expression of Smad7 in immune cells infiltrating the inflamed gut of patients with inflammatory bowel disease can elicit anti-tumor responses, with the down-stream effect of attenuating CRC cell growth. Taken together, these observations suggest a double role of Smad7 in colorectal carcinogenesis, which probably depends on the cell subset and the biological context analyzed. In this review, we summarize the available evidences about the role of Smad7 in both sporadic and colitis-associated CRC.

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Antioxidant Agents and Colorectal Carcinogenesis: Role of β-Carotene, Vitamin E and Vitamin C

Tumori Journal ◽

10.1177/030089169608200102 ◽

1996 ◽

Vol 82 (1) ◽

pp. 6-11 ◽

Cited By ~ 7

Author(s):

Giuseppe Pappalardo ◽

Antonio Guadalaxara ◽

Giuseppe Maiani ◽

Giovanni Illomei ◽

Mauro Trifero ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Vitamin C ◽

Colonic Mucosa ◽

Genetic Alterations ◽

Colorectal Carcinogenesis ◽

Normal Colonic Mucosa ◽

Antioxidant Agents ◽

Β Carotene

In consideration of findings reported in the literature and of our study, we examined the correlation between antioxidants (β-carotene, vitamin C, vitamin E) and colorectal carcinogenesis. Although diagnostic progress has been made in the last decades, no significant improvements in death rates have been achieved in the western world. Exogenous factors might be responsible for a complex alteration process of normal colonic mucosa into adenoma and carcinoma. Free radicals and reactive oxygen metabolites, due to increased production or to reduced inactivation, following a decrease in the antioxidant burden in the mucosa, might cause damage to DNA, thereby resulting in genetic alterations. This might represent the cause of the transformation process: normal mucosa→ adenoma→ carcinoma. In a prospective study, we observed a reduction of β-carotene levels in normal colonic mucosa in patients with polyps and colorectal cancer. We also showed that β-carotene supplementation raises levels of this micronutrient in the colonic mucosa of these patients. Findings from the literature and our trials show a significant decrease in the antioxidant capacity of colorectal mucosa in patients affected by colorectal cancer, although there is a significant interindividual variability. Such results suggest a possible chemopreventive role of antioxidant agents in colorectal cancer.

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