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The role of Helicobacter pylori infection in colorectal carcinogenesis

Explore the potential link between Helicobacter pylori infection and colorectal neoplasia, with an overview of global CRC statistics, H. pylori pathogenesis, and findings from meta-analyses and histological series.

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The role of Helicobacter pylori infection in colorectal carcinogenesis

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  1. The role of Helicobacter pylori infection in colorectal carcinogenesis Vasilios Papastergiou Gastroenterology Dept. Konstantopouleio-Patission General Hospital of Nea Ionia, Athens, Greece

  2. Disclosures nothing to disclose

  3. Colorectal Cancer • 3rd most common cancer worldwide • 4th leading cause of cancer-related death • 1.4 million new cases/700.000 deaths (2012) • More that 2/3 in countries with high HDI • The global burden of CRC is expected to increase by 60% (>2.2 million new cases/1.1 million deaths) by year 2030 Global patterns and trends in colorectal cancer incidence and mortality. Arnold M. et al. Gut 2016; 0:1-9.

  4. Sporadic CRC pathogenesis: multifactorial • Fatty diet • Red meat • Low Physical activity • Obesity • Smoking • Alcohol

  5. Adenoma to Carcinoma sequence Amersi et al. Clin Colon Rectal Surg, 2005 Zauber et al. NEJM, 2012

  6. CRC pathogenesis: role of infectious agents (?) • Bacteria -Streptococcus bovis -Bacteroidesfragilis -Enterococcus faecalis -Escherichia Coli • Helminths -Schistosoma japonicum -Schistosoma mansoni • Virus -JC virus -HPV -EBV -CMV • Universal human pathogen (50% of the world population and up to 80% in developing countries) • Recognized class I carcinogen (IARC) • Established role in gastric cancer (ADC, MALT) • Studies on its oncogenicity have been extended to examine its role in the development of other gastrointestinal malignancies -H. Pylori

  7. 1. H. Pylori infection status and colorectal neoplasia

  8. Case-control studies: n=18 (1991-2017) • Cross-sectional studies, n=6 (2010-2016) • Meta-analyses, n=8 (2006-2016) Published Studies evaluating a relationship between H. Pylori infection status and colorectal neoplasia

  9. HP infection and colorectal neoplasia: case-control studies (1)

  10. HP infection and colorectal neoplasia: case-control studies (2)

  11. HP infection and colorectal neoplasia: cross-sectional studies

  12. Case-control/Cross-sectional studies:pitfalls • Small sample size/hospital-based design (patient selection bias) • Retrospective design (retrospective recall bias) • Serological testing does not discriminate between current and past infections and may yield positive results for other Helicobacter species (eg; H. Heilmannii) • History of prior H. pylori eradication and/or prior polyp removal were not considered • Disparities in factors affecting the cancerogenic risk, as most studies controlled solely for age and gender or relied on a convenience sample. • CASE-CONTROL AND CROSS-SECTIONAL STUDIES MAY PROVE A STATISTICAL ASSOCIATION BUT THEY DO NOT PROVE CAUSATION

  13. HP infection and colorectal neoplasia: meta-analyses *Only case-control studies were included; **included only data on East-Asian population

  14. 2. H. Pylori-related chronic gastritis and colorectal neoplasia

  15. Nation-scale (USA) histological series of patients who underwent bidirectional endoscopy on the same day (biopsies from both procedures) • N=156.000 (mean age: 58.7 years, 41% males) • Patients with H. pylori gastritis (chronic active inflammation in the gastric mucosa with presence of H. pylori demonstrated by IHC) were more likely (than patients without H. Pylori) to have: • -Hyperplastic polyps (OR=1.24, 95%CI: 1.18-1.30) • -Adenomas (OR = 1.52, 95%CI: 1.46-1.57) • -Advanced adenomas (OR = 1.80, 95%CI: 1.69-1.92) • -Adenocarcinoma (OR = 2.35, 95%CI: 1.98-2.80) Sonnenberg and Genta, Am J Gastr, 2013

  16. 3. H. Pylori-related gastric premalignant lesions and colorectal neoplasia

  17. 20.928 males smokers aged 50-69 yrs who were participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) had serum PG-I levels measured. • 1665 with low (<25μg/l) PG-I levels were invited for gastroscopy • 1059 (63.6%) underwent gastroscopy and atrophic gastritis was histologically confirmed • During a mean follow-up of 11.3 years, 425 incident CRCs were diagnosed • Compared to subjects with normal PG-I, there was no increased risk of CRC among subjects with low PG-I (aHR: 0.71) and among those with histologically confirmed atrophic gastritis (aHR: 0.86). Laiyemo AO et al, Cancer Causes Control, 2010

  18. Atrophic gastritis (AG) and colorectal neoplasia • Two Japanese case-control studies with 339[1] and 478[2] subjects found no association between AG diagnosed on the basis PG-I and PG-I/II ratio and colorectal neoplasia • A smaller Japanese study (n=99) identified AG as an independent predictor of recurrence after endoscopic resection of colorectal neoplasia[3] • In a recent cross-sectional study (n=6.351) from Korea, H. pylori-related AG was significantly associated with the risk of advanced colorectal neoplasm (OR=1.40)[4] [1]Machida-Montani A et al, Helicobacter, 2007 [2] Inoue I et al, Int J Cancer, 2011 [3] Inoue I et al, MolClinOncol, 2013 [4] Lee JY et al, Gut and Liver, 2016

  19. Gastric intestinal metaplasia and colorectal neoplasia • Sonnenberg et al, Am J Gastr, 2013 The following conditions were found more frequently in patients with intestinal metaplasia (n=5651) than without intestinal metaplasia: -colon adenoma (OR: 1.83, 95%CI: 1.71-1.94) -advanced adenoma (OR: 2.02, 95%CI: 1.93-3.37) -CRC (OR: 2.55, 95%CI: 1.93-3.37) *Data concerning AG was not analyzed due to the absence of multiple mapped gastric biopsy specimens required to diagnose this condition

  20. Potential Oncogenic actions of H. Pylori to colorectal mucosa • Hypothesis #1: Trophic/mitogenic action of Gastrin on colonic mucosa • Hypothesis #2: Microbial dysbiosis secondary to reduced acid exposure • Hypothesis #3: Direct activation of colonic carcinogenesis by H. pylori Helicobacter pylori and colorectal neoplasia: is there a causal link? Papastergiou V, Karatapanis S, Georgopoulos SD; WJG, 2016.

  21. Hypothesis # 1: Gastrin • Persistent H. pylori exposure elicits hypergastrinemia • Gastrin is a putative trophic factor for the colorectal mucosa • Mitogenic on colonic cells in vitro • Hyperpropliferation of colonic mucosa in animal models (transgenic mice)

  22. Correlation between high gastrin levels and colorectal neoplasia • 2 prospective case-control studies Thorburn et al, Gastroenterology, 1998 Georgopoulos et al, Digestion, 2006

  23. Evidence against a role of Gastrin in Colorectal neoplasia • Several other studies could not detect any association (Fireman, Isr Med Assoc J, 2000; Machida-Montani, Helicobacter 2007; Penman, Gastroenterology, 1994; Kikendal Am J Gastr, 1992; Selgrad, Int J Cancer, 2014) • Human models of long-term hypergastrinemia (PPIs, ZES) showed no effect on the development of CRC (Singh, APT, 2007; Orbuch, DDS, 1996) • CRC tumors cells have been shown to produce gastrin themselves (likely act in an autocrine manner ) • Hypergastrinemia may be simply an epiphenomenon of CRC, as supported by the fact that the gastrin levels fall after surgical resection of the tumor (Bombski, Int J Colorctal Dis, 2003; Charnley, Ann R CollSurgEngl, 1992)

  24. Hypothesis #2: changes in intestinal microbiota induced by reduced acid secretion • H. pylori-related atrophic gastritis (AG) might contribute to colorectal carcinogenesis by promoting changes in the colorectal microflora. • Microbial dysbiosis with selective growth of certain microbial species (eg; Bacteroides, Prevotella, E. Faecalis), may promote the development of CRC 1) Sobhani et al, PLOS ONE, 2011; 2)Compare et al, TranslGastrointest Cancer, 2014

  25. Hypothesis #3: H. Pylori is a direct activator of colorectal carcinogenesis (?) • H. pylori is not an invader of the colonic epithelium • However, it moves through the colonic lumen, as indicated by reports of fecal shedding of viable H. pylori • Several reports of detection (IHC, PCR) of H. pylori in colonic neoplasms (Soylu, BMC Gastroenterol 2008; Jones, WJSO 2007; Kapetanakis, J GastrointesOncol 2012; Grahn, J Med Microbiol 2005) • Potential Mechanisms • Induction of inflammatory responses, with overproduction of cytokines (eg; IL-8, a known growth factor for CRC) • Promotion of neoangiogenesis • CagAseropositivity→ positive association with colorectal neoplasia according to some reports , disputed by others • Stimulation of stem cells and recruitment of bone marrow-derived cells (BMDC), similar to animal models of gastric carcinogenesis

  26. Conclusions (1) • Since more than 2 decades, several studies investigated the potential relationship between H. pylori and colorectal neoplasia • However, most investigation relied on relatively small hospital-based samples providing conflicting results • More recently, better designed population-based studies as well as the large-scale histological series by Sonnenberg and several meta-analyses have become available • Nevertheless, results should be interpreted cautiously, as the possibility of bias cannot be excluded.

  27. Conclusions (2) • Based on a critical analysis of available data, it appears that H. pylori infection/gastritis is associated with an increased, although modest, risk of colorectal neoplasia. • However, current evidence supports nothing more than a statistical relationship and a definitive proof of causality remains to be established. • In the future, large-scale prospective studies are awaited to confirm H. pylori as an infectious contributor in the complex multifactorial process of colorectal carcinogenesis.

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