This is a repository copy of AQP5 enriches for stem cells and cancer origins in the distal stomach.

Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(−) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here we show that the epidermal growth factor receptor (EGFR) interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake as well as increased glutamate which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface.

Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia-carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(-), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v + metaplastic cells manifested upregulation of xCT expression compared with CD44v À cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v-xCT could thus prove effective for prevention or attenuation of the CD44v-dependent development of preneoplastic lesions and cancer. (Cancer Sci 2013; 104: 1323-1329 G astric cancer is strongly linked to inflammation and histopathologic progression of the stomach epithelium initiated by chronic infection with Helicobacter pylori. Gastric carcinogenesis triggered by infection with this bacterium is thus characterized by a transition from normal mucosa to gastritis, which then leads to metaplasia and eventually to adenocarcinoma.(1) Spasmolytic polypeptide-expressing metaplasia (SPEM) results from a metaplastic change in H. pylori-infected gastric mucosa and is observed in the mucosa adjacent to gastric adenocarcinoma. (2)(3)(4) We previously showed that prostaglandin E 2 (PGE 2 ) and the inflammatory cytokine tumor necrosis factor-a play key roles in the development of SPEM in mice.(5) More recently, interleukin-1b has been shown to initiate the development of gastric metaplasia and dysplasia in transgenic mice.(6) Although the emergence of metaplasia or dysplasia is a key event in inflammation-related gastric carcinogenesis, the molecular mechanism underlying the development of such preneoplastic lesions is largely unknown.A major adhesion molecule for the ECM, CD44, has been implicated in a wide variety of physiological processes, including leukocyte homing and activation, wound healing, and cell migration, as well as in tumor cell invasion and metastasis. (7)(8)(9)(10) CD44 is expressed at a higher level in gastric epithelial cells isolated from the non-cancerous stomach of H. pylori-positive individuals than in those from H. pylori-negative individuals.(11) Furthermore, the abundance of CD44 mRNA has been found to be increased in gastric tissue...

Table. Pathological Features and Molecular Profile of Early-Onset Colorectal Cancer Pathological features Molecular profile Poor differentiation Microsatellite stability Mucinous tumors More likely to exhibit LINE-1 hypomethylation and TP53 sequence variations Signet-ring morphology Less frequently harbor KRAS, BRAF V600E, and APC sequence variations Perineural/venous invasion Promoter methylation of CpG islands Abbreviations: APC, adenomatous polyposis coli; BRAF, B-Raf; KRAS, K-Ras; LINE-1, long interspersed nuclear elements; TP53, tumor protein 53.