Gastric cancer stem cells

Abstract

Cancer stem cells are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. Accumulating evidence in recent years strongly indicate the existence of cancer stem cells in solid tumors of a wide variety of organs. In this review, we will discuss the possible existence of a gastric cancer stem cell. Our recent data suggest that a subpopulation with a defined marker shows spheroid colony formation in serum-free media in vitro, as well as tumorigenic ability in immunodeficient mice in vivo. We will also discuss the possible origins of the gastric cancer stem cell from an organ-specific stem cell versus a recently recognized new candidate bone marrow-derived cell (BMDC). We have previously shown that BMDC contributed to malignant epithelial cells in the mouse model of Helicobacter-associated gastric cancer. On the basis of these findings from animal model, we propose that a similar phenomenon may also occur in human cancer biology, particularly in the cancer origin of other inflammation-associated cancers. The expanding research field of cancer stem-cell biology may offer a novel clinical apparatus to the diagnosis and treatment of cancer.

Fig 1

(A) Skin tumor created by human gastric cancer cell line 1 in severe combined immunodeficiency (SCID) mouse. Human gastric cancer cell line 1 (500,000 cells/site) was subcutaneously injected into SCID mice. A few months later, injected cells produced skin tumor. (B) Hematoxylin and eosin staining (magnification, 40×).

Fig 2

(A-F) β-galactosidase immunohistochemistry of stomachs from Helicobacter felis (H felis )–infected C57BL/6 mice transplanted with ROSA26 marrow. (A and C) Mock-infected mice do not demonstrate any bone marrow–derived cell (BMDC) engraftment, as evidenced by lack of β-galactosidase staining. (B and D) H felis–infected mice have substantial architectural distortion and β-galactosidaseβpositive (brown) GI intraepithelial neoplasia (GIN). Fluorescence immunohistochemistry for cytokeratin (green) and β-galactosidase (red). (E) Glands within GIN from an infected mouse transplanted with wild-type marrow do not express β-galactosidase. (F) Glands within GIN from an infected mouse transplanted with ROSA26 marrow demonstrate β-galactosidase expression (red), colocalized with cytokeratin (green) to form yellow, confirming epithelial differentiation of integrated BMDC. Occasional mononuclear leukocytes are β-galactosidase positive (red) and cytokeratin negative. Scale bars, 400 μm (A and B), 160 μm (C and D), 40 μm (E and F). Adapted from Houghton et al with permission of the publisher.

Fig 3

Bone marrow (BM)–derived cells (BMDCs) in gastric tumor initiation and progression. Helicobacter pylori–associated chronic inflammation, driven by macrophages and Th1-polarized lymphocytes, results in increased cytokine and chemokine production that mobilizes and recruits BMDCs from the circulation. The proinflammatory milieu leads to an altered stem-cell niche, characterized by increased numbers of activated myofibroblasts, which can originate from both BMDCs and local stromal populations. Some of the BMDCs may also be recruited into the progenitor zone, giving rising to epithelial metaplasia and dysplasia (ie, cancer stem cells). Adapted from Fox and Wang with permission of the publisher. IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; SDF, stromal cell–derived factor.