Summary Carcinoma associated fibroblasts (CAFs) that express α-smooth-muscle-actin (αSMA) contribute to cancer progression, but their precise origin and role is unclear. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow (BM) and derive from mesenchymal stem cells (MSCs). αSMA+ myofibroblasts (MF) are niche cells normally present in BM and increase markedly during cancer progression. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5α and BMP4, show DNA-hypomethylation, and promote tumor growth. Moreover, CAFs are generated from MSCs and are recruited to the tumor in TGF-β- and SDF-1α-dependent manner. Carcinogenesis therefore involves expansion and relocation of BM-niche cells to the tumor to create a niche to sustain cancer progression.

On the basis of a retrospective analysis of 124 patients, endoscopic therapy of WON by using LAMS is safe and effective. Creation of a large and sustained cystogastrostomy or cystoenterostomy tract is effective in the drainage and treatment of WON.

Chronic inflammation often precedes or accompanies a substantial number of cancers. Indeed, anti-inflammatory therapies have shown efficacy in cancer prevention and treatment. The exact mechanisms that turn a wound healing process into a cancer precursor are topics of intense research. A pathogenic link has been identified between inflammatory mediators, inflammation related gene polymorphisms and carcinogenesis. Animal models of cancer have been instrumental in demonstrating the diversity of mechanisms through which every tumor compartment and tumor stage may be affected by the underlying inflammatory process. In this review, we focus on the interaction between chronic inflammation, tumor stem cells and the tumor microenvironment. We summarize the proposed mechanisms that lead to the recruitment of bone marrow derived cells and explore the genetic and epigenetic alterations that may occur in inflammation associated cancers.

Global hypomethylation has long been recognized as a feature of the malignant epithelial component in human carcinomas. Here we show evidence for this same type of epigenetic alteration in cancer-associated stromal myofibroblasts. We used methylation-sensitive SNP array analysis (MSNP) to profile DNA methylation in early-passage cultures of stromal myofibroblasts isolated from human gastric cancers. The MSNP data indicated widespread hypomethylation in these cells, with rare focal gains of methylation, conclusions that were independently validated by bisulfite sequencing and by a methylation-sensitive cytosine incorporation assay. Immunohistochemistry with anti-5-methylcytosine (anti-5-methyl-C) in a series of gastrectomy specimens showed frequent loss of methylation in nuclei of both the malignant epithelial cells and A-smooth muscle actin (ASMA)-positive stromal myofibroblasts of both intestinal-type and diffuse carcinomas. We confirmed this phenomenon and established its onset at the stage of noninvasive dysplastic lesions by immunohistochemistry for anti-5-methyl-C in a transgenic mouse model of multistage gastric carcinogenesis. These findings indicate similar general classes of epigenetic alterations in carcinoma cells and their accompanying reactive stromal cells and add to accumulating evidence for biological differences between normal and cancer-associated myofibroblasts. [Cancer Res 2008;68(23):9900-8]

It is increasingly recognized that the non-neoplastic stromal compartment in most solid cancers plays an active role in tumor proliferation, invasion and metastasis. Cancer associated fibroblasts (CAFs) are one of the most abundant cell types in the tumor stroma, and these cells are pro-tumorigenic. Evidence that CAFs are epigenetically and possibly also genetically distinct from normal fibroblasts is beginning to define these cells as potential targets of anti-cancer therapy. Here, we review the cell of origin and molecular biology of CAFs, arguing that such knowledge provides a rational basis for designing therapeutic strategies to coordinately and synergistically target both the stromal and malignant epithelial component of human cancers.

Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field.

FISH significantly improves the diagnostic accuracy of brush cytology in indeterminate biliary strictures. In our series, the addition of 9p21 deletion to FISH polysomy and cytology further improved sensitivity. This suggests that 9p21 deletion may be added to the diagnostic criteria in indeterminate strictures.

Radiofrequency ablation is effective and safe in malignant biliary obstruction and seems to be associated with improved survival.