Bone Marrow-Derived Stem Cells in Pathogenesis of Helicobacter pylori-Associated Gastrointestinal Cancer.

To the Editor: Yaghoobi[1] discussed selected findings on how bone marrow-derived stem cells (BMDSCs) compromise local immunity and skip local defense mechanisms to undergo malignant transformation, and the role of CXC chemokine receptor type 4 (CXCR-4) through binding to its ligand stromal-derived factor in migration of BMDSCs involved in Helicobacter pylori (Hp)-related gastric cancer pathogenesis.

In this regard, we previously summarized[2] the proposed mechanisms of Hp and stem cell interaction in gastric oncogenesis including the following: upregulation of Wnt signaling pathway; CagA-induced Src-homology 2 phosphatase dysfunction affecting the fibroblast growth factor signal; activation of bone morphogenetic protein/transforming growth factor-β signaling pathway; downregulation of sonic hedgehog signaling through CpG hypermethylation of hedgehog-interacting protein 1 promoter region; and recruitment of mesenchymal stem cells through the production of interleukin (IL)-6 and IL-8 and/or BMDSCs through chronic inflammation and cagA-related CXCR-4 expression, also mentioned by the author.[1]

Specifically, by using the cancer stem cell (CSC) and/or BMDSC indicator CD44, the CD44(+) gastric CSCs show the stem cell properties of self-renewal, the ability to form differentiated progeny and increased resistance for chemotherapy or radiation-induced cell death; Hp, either directly or through a local inflammatory response, is responsible for increased expression of CD44, thereby suggesting a possible Hp induction of CD44(+) gastric CSCs involved in gastric cancer production and progression.[2] Furthermore, glycoproteins CD44, normally expressed only in the crypts of the intestinal epithelium, are overexpressed in colorectal cancer (CRC) and their overexpression is an early event in the sequence colorectal adenoma (CRA)–CRC development.[3] In this respect, based on histology documenting active Hp-I, our studies showed that the presence of Hp-I with accompanying immunohistochemical expression of CD44 in biopsy specimens was found in 91% CRC patients, 81% CRA patients and 33% controls;[3] in particular, presence of Hp-I with CD44 expression was found in 88% of CRA patients accompanied with moderate/severe dysplasia and 91% CRC patients with moderate/severe degree of malignancy.[3] Importantly, CD44-mediated resistance to apoptosis in the colonic epithelium in vivo promotes cell transformation into a malignant phenotype in conjunction with other anti-apoptotic factors.[4] Moreover, CD44 stimulation might contribute to CRC cell invasion, leading to tumor cell extravasation and metastasis.[5]

Therefore, our results indicate that Hp-I might have an impact on colon oncogenesis by stimulating CSCs or recruiting BMDSCs, similar to upper gastrointestinal Hp-I-associated chronic inflammation–hyperplasia–metaplasia–dysplasia sequence and BMDSC recruitment that may facilitate tumor formation and progression in animal models and humans. However, further studies are needed to clarify the aforementioned consideration.