Potential oncogenic properties of mobilized stem cells in a subpopulation of inflammatory bowel disease patients infected with Helicobacter pylori.

To the Editor: Marlicz et al concluded that Crohn’s disease (CD) triggers the mobilization of various types of stem cells, such as hematopoietic stem progenitor cells, into peripheral blood in patients suffering from this disease, while the significance and precise role of these mobilized cells in repair of damaged intestine requires further study. However, the authors did not discuss the possibility of potential oncogenic properties of the mobilized stem cells, at least in the subgroup of patients possibly infected with Helicobacter pylori (H. pylori). In this regard, although relative data indicate an absence or inverse association between H. pylori and inflammatory bowel disease (IBD), the prevalence of H. pylori infection in the IBD patients appears to be 38.2%– 47% in Europe. Moreover, enterohepatic and gastric Helicobacter species have been documented in fecal specimens from children with CD using polymerase chain reaction (PCR), and H. pylori, for example, was recently found in the intestinal mucosa of a patient affected by CD. Experimental data indicate that H. pylori infection leads to development of chronic inflammation, hyperplasia, metaplasia, dysplasia, and recruitment and accumulation of bone marrow-derived cells (BMDCs) in the mouse gastric epithelial mucosa. Nearly 25% of dysplastic lesions include cells originating from BMDCs, thereby indicating that BMDCs can participate in preneoplastic lesions preceding gastric carcinoma development; there is a role for engraftment of circulating BMDCs, which may contribute to tumor formation in animal models with H. pylori-induced chronic gastric inflammatory processes, thus further suggesting the possibility of the potential contribution of BMDCs in human gastrointestinal carcinoma. In this regard, we recently conducted a pilot study using tissue sections of biopsies of human gastric cancer in which H. pylori was detected by Cresyl violet staining. Moreover, stem cells and neovessels were detected by immunohistochemical method using a monoclonal antibody, anti-CD34; CD34, also mentioned by the authors, is a surface glycoprotein expressed on hematopoietic stem cells and is used as an important marker of these cells and neovessels. In addition, cyclin D1, involved in the regulation of cell proliferation, was also detected by immunohistochemical method. Other relative data indicate that H. pyloriinduced cytotoxin VacA exhibits chemotactic activities to the BMDCs and induces BMDCs to produce proinflammatory cytokines, leading to chronic inflammation with potential oncogenic consequences. Therefore, it would be reasonable to speculate that chronic H. pylori infection in both mice and humans induces repopulation of the stomach with BMDCs that may facilitate gastric cancer progression. These findings present a new way of thinking about the pathogenesis of upper gastrointestinal malignancy. The observation that BMDCs are the origin of H. pylori-induced gastric cancer can also be combined with supporting observations of BMDCs in other tumors such as Barrett’s esophageal adenocarcinoma, Kaposi sarcoma, cancer-associated fibroblasts, or benign and malignant tumors of the skin. Other relative data, using the stem cell marker CD44 (the integral membrane molecule CD44 is a marker of human hematopoietic stem and progenitor cells), indicate that the CD44þ gastric cancer stem cells show the stem cell properties of selfrenewal, the ability to form differentiated progeny, and, moreover, increased resistance for chemotherapy or radiation-induced cell death; H. pylori either directly or through a local inflammatory response is responsible for increased expression of CD44 and its variant CD44 v9, thereby suggesting a possible H. pylori induction of CD44þ BMDCs/gastric cancer stem cells involved in gastric cancer development and progression. Because H. pylori also induces inflammatory changes in colonic mucosa, it would be reasonable to further speculate that chronic H. pylori infection in humans induces repopulation of the colon with BMDCs that might facilitate colon cancer development and progression. In this respect, our own preliminary studies indicated the presence of H. pylori in malignant colonic tissue in 34 of 41 (82.9%) patients with colorectal cancer (23 men, mean age 73.6 6 7.9 years). Moreover, increased expression of CD44 in malignant tissue but not in the adjacent normal colonic mucosa was noticed in 31 of 41 (75.6%) patients with colorectal cancer. Extending these preliminary data we currently included 50 patients (28 men, mean age 71.3 6 9.7 years) with colorectal cancer and 25 patients (13 men, mean age 72.8 6 10.1 years) with colonic polyps with the following results: H. pylori presence and increased expression of CD44 in malignant tissue of patients were observed in 84% and 78%, respectively, confirming our preliminary data. Comparable data in adenomatous tissue of patients with colonic polyps were also observed in 64% and 16% of patients, respectively Copyright VC 2012 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.22911 Published online inWiley Online Library (wileyonlinelibrary.com).