Helicobacter Pylori Infection Induces Gastric Cancer and the Cancer/Testis Antigens Expression
Received Date: Dec 08, 2017 / Accepted Date: Dec 12, 2017 / Published Date: Dec 15, 2017
Helicobacter pylori (HP) are known to induce gastritis, atrophy, intestinal metaplasia, dysplasia, and stomach malignancy. HP infection also induces cancer/testis antigens (CTAs) during or after gastric malignancy. This study aims to elucidate the relationship between HP and CTAs, especially melanoma antigen-A3 and Kitakyushu lung cancer antigen-1.
Keywords: Helicobacter pylori; Gastric cancer; Tumor antigen; Cancer/testis antigen; KK-LC-1; MAGE
HP: Helicobacter pylori; KK-LC-1: Kitakyushu Lung Cancer Antigen-1; MAGE: Melanoma Antigen Gene; NY-ESO-1: New York Esophageal Squamous Cell Carcinoma-1; CTL: Cytotoxic T Lymphocyte; TIL: Tumor-Infiltrating Lymphocyte.
Helicobacter pylori (HP) are a rare Gram-negative bacterium, which is pathogenic and exists in the stomach. It colonizes the gastric mucosa of more than half of the world’s population. Owing to its colonization, a majority of infected individuals exhibit histological signs of chronic gastritis. Furthermore, 20% of individuals develop HP-associated diseases such as peptic ulcers, intestinal metaplasia, dysplasia, and gastric cancer .
After lung and liver cancers, gastric cancer is the third leading cause of cancer-related death worldwide . In Japan, however, gastric cancer has the second highest incidence rate among all cancers, and almost all cases are caused by HP infection . Perhaps, detection and eradication of HP infection might reduce the risk of gastric cancer. Furthermore, ABC diagnosis using an anti-HP antibody and measurement of pepsinogen I/II serum level could be an approach for identification of the risk of gastric cancer . However, these approaches lack precision and can indicate only 1%–5% occurrence of gastric cancer in high-risk groups, thereby necessitating the development of more precise methods for risk diagnosis .
Several tumor-associated antigens are identified as tumor-specific phenomena in various human cancers . These antigens are classified into four categories, excluding extrinsic viral antigens, as follows: cancer/testis antigens (CTAs), differentiation antigens, amplification or overexpression antigens, and tumor-specific mutated antigens recently defined as neo-antigens. Of these, CTAs are especially attractive targets for immunotherapy because they are not or minimally expressed in normal tissues except for the testis and are aberrantly expressed in various human cancers . Hence, immune targeting of these antigens is considered to have negligible adverse effects. Furthermore, they might be advantageous molecules for systemic diagnosis of cancer because of their specific expression patterns.
A recent study suggested that γ-radiation, which is used for standard cancer therapy and is a tumorigenic factor, induces the expression of specific CTA . Here we suggest that HP, a tumorigenic factor, also induces specific CTAs.
CTA induction by HP
We co-cultured HP strain NCTC11637 with Meth-A, a cell line of mouse fibrosarcoma, in vitro to prove the HP’s potential for CTAs induction. Meth-A induced the expression of the melanoma antigen (Mage)-A3-encoding gene and retained its expression without HP . Notably, the ability of CTAs to express permanently is crucial for the diagnosis and therapy of cancer. Reportedly, epigenetic alteration promotes the expression of CTAs in gastric cancer . HP alters epigenetic alterations of host cells, which might be both temporary and permanent . Mage-A3 expression might be induced by permanent epigenetic alterations.
Expression of CTAs in clinical cancer tumor
To date, several laboratories have researched the expression of CTAs in clinical cancer tissues. The expression rate of the CTAs-encoding gene is commonly less than 40% (Table 1) [12-16], except for the specific CTA in the specific tissue cancer such as 80% expression of MAGE-A1 in hepatic cell carcinoma . Although the expression rate of Kitakyushu lung cancer antigen-1 (KK-LC-1) was typical in other tissue cancers (Table 2), it was highest among the CTAs in gastric cancer , implying that KK-LC-1 would be induced by specific tumorigenic factors, such as HP, in the stomach.
|Cancer/Testis antigen||Gene expression (%)||Reference|
Table 1: The expression frequency of each cancer/testis antigen in cancer from each organ.
|CTA||IgG titer (Average)||p-Value|
|Negative expression||Positive expression|
|MAGE-A1||59.6 ± 10.0||43.3 ± 11.2||0.2503|
|MAGE-A3||60.9 ± 10.3||43.3 ± 10.7||0.2109|
|MAGE-A4||48.3 ± 8.3||69.1 ± 16.7||0.3415|
|NY-ESO-1||56.8 ± 8.6||38.8 ± 15.3||0.2794|
|KK-LC-1||15.7 ± 14.8||61.6 ± 7.4||0.0098|
|P value was determined by Wilcoxon rank-sum test.|
Table 2: Anti-Helicobacter pylori IgG titer in each cancer/testis antigen-expression group.
Expression of CTAs in clinical gastric cancer tumor with HP infection
With or without the expression of each CTA-encoding gene, the IgG titer against HP in the serum was assessed in patients with gastric cancer as an indicator of HP infection. The titer was significantly higher in the group with expression of KK-LC-1 than in those without the expression. There was no difference observed between the groups with and without CTA (Table 1) , which implied that HP infection induces the expression of the specific CTA, KK-LC-1, with tumorigenesis. In addition, the discrepancy in the effect of HP between mouse Mage-A3 induction in vitro and human MAGE-A3 of clinical gastric cancer was attributed to the fact that homology between human and mouse MAGE-A3/Mage-A3 is 42%  and that HP directly induces mouse Mage-A3 expression. However, the direct induction of the MAGE-A3 expression by HP remains unclear. HP infection induces an immune response in vitro, which in turn induces tumorigenesis . In fact, HP did not induce the expression of KK-LC-1 in human gastric cancer cell lines.
KK-LC-1 is frequently expressed in gastric cancer with 79% expression reported during the early stage of gastric cancer (Table 3), indicating that the expression of KK-LC-1 occurs at the beginning of malignancy and is maintained after that . Hence, KK-LC-1 seems a potential candidate for the diagnosis of early gastric cancer. In addition, KK-LC-1 is frequently expressed in 75% of patients with triple-negative breast cancer . KK-LC-1 therapy would be an attractive option for patients with TNBC because no existing hormone or antibody therapy is employed. KK-LC-1 has multiple epitope peptides recognized by cytotoxic T lymphocytes (CTLs) [22,23]. When CTLs against KK-LC-1 predominantly accumulate among tumor-infiltrating lymphocytes (TILs), adaptive immunotherapy using TILs leads to a good response . In future, immunotherapy against KK-LC-1 could be considered as the first option for cancer treatment for pre-cancer patients or patients with cancer of the stomach caused by HP and TNBC.
|Stage||The expression rate of each CTA (%)|
|P value was calculated by chi-square test|
Table 3: The expression rate of cancer/testis antigens in early gastric cancer.
- Cover TL, Blaser MJ (2009) Helicobacter pylori in health and disease. Gastroenterology 136: 1863-1873.
- Stewart BW (2014) World Cancer Report. Lyon, France: International Agency for Research on Cancer.
- Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, et al. (2001) Helicobacter pylori Infection and the Development of Gastric Cancer. N Engl J Med 345: 784-789.
- Miki K (2011) Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels-“ABC method”. Proc Jpn Acad Ser B Phys Biol Sci 87: 405-414.
- Mizuno S, Miki I, Ishida T, Yoshida M, Onoyama M, et al. (2010) Prescreening of a high-risk group for gastric cancer by serologically determined Helicobacter pylori infection and atrophic gastritis. Dig Dis Sci 55: 3132-3137.
- van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, et al. (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254: 1643-1647.
- Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4: 1.
- Sharma A, Bode B, Wenger RH, Lehmann K, Sartori AA, et al. (2011) γ-Radiation Promotes Immunological Recognition of Cancer Cells through Increased Expression of Cancer-Testis Antigens In Vitro and In Vivo. PLoS One 6: e28217.
- Fukuyama T, Yamazaki T, Fujita T, Uematsu T, Ichiki Y, et al. (2012) Helicobacter pylori, a carcinogen, induces the expression of melanoma antigen-encoding gene (Mage)-A3, a cancer/testis antigen. Tumour Biol 33: 1881-1887.
- Honda T, Tamura G, Waki T, Kawata S, Terashima M, et al. (2004) Demethylation of MAGE promoters during gastric cancer progression. Br J Cancer 90: 838-843.
- Nakajima T, Enomoto S, Ushijima T (2008) DNA methylation: a marker for carcinogen exposure and cancer risk. Environ Health Prev Med 13: 8-15.
- Shigematsu Y, Hanagiri T, Shiota H, Kuroda K, Baba T, et al. (2010) Clinical significance of cancer/testis antigens expression in patients with non-small cell lung cancer. Lung Cancer 68: 105-110.
- Yoshimatsu T, Yoshino I, Ohgami A, Takenoyama M, Hanagiri T, et al. (1998) Expression of the melanoma antigen-encoding gene in human lung cancer. J Surg Oncol 67: 126-129.
- Futawatari N, Fukuyama T, Yamamura R, Shida A, Takahashi Y, Nishi Y, et al. (2017) Early Gastric Cancer Frequently Has High Expression of KK-LC-1, a Cancer-Testis Antigen. World J Gastroenterol 23: 8200-8206.
- Yao J, Caballero OL, Yung WK, Weinstein JN, Riggins GJ, et al. (2014) Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. Cancer Immunol Res 2: 371-379.
- Fukuyama T, Futawatari N, Ichiki Y, Shida A3, Yamazaki T, et al. (2017) Correlation Between Expression of the Cancer/Testis Antigen KK-LC-1 and Helicobacter pylori Infection in Gastric Cancer. In Vivo 31: 403-407.
- Van den Eynde BJ, van der Bruggen P (1997) T cell defined tumor antigens. Curr Opin Immunol 9: 684-93.
- Shida A, Futawatari N, Fukuyama T, Ichiki Y, Takahashi Y, et al. (2015) Frequent High Expression of Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) in Gastric Cancer. Anticancer Res 35: 3575-3579.
- De Plaen E, De Backer O, Arnaud D, Bonjean B, Chomez P, et al. (1999) A new family of mouse genes homologous to the human MAGE genes. Genomics 55: 176-184.
- Oshima H, Ishikawa T, Yoshida GJ, Naoi K, Maeda Y, et al. (2014) TNF-alpha/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. Oncogene 33: 3820-3829.
- Paret C, Simon P, Vormbrock K, Bender C, Kölsch A, et al. (2015) CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer. Oncotarget 6: 25356-25367.
- Fukuyama T, Hanagiri T, Takenoyama M, Ichiki Y, Mizukami M, et al. (2006) Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma. Cancer Res 66: 4922-4928.
- Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, et al. (2017) Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356: 200-205.
Citation: Futawatari N, Fukuyama T, Yamamura R, Kobayashi N (2017) Helicobacter Pylori Infection Induces Gastric Cancer and the Cancer/Testis Antigens Expression. J Infect Dis Ther 5: 345. DOI: 10.4172/2332-0877.1000345
Copyright: © 2017 Futuwatari N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
Open Access Journals
- Total views: 2235
- [From(publication date): 0-2017 - Jan 22, 2021]
- Breakdown by view type
- HTML page views: 2099
- PDF downloads: 136