Abstract
Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblast-associated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects.
Highlights
Gastric cancers are histologically classified as intestinal or diffuse type of adenocarcinomas [1]
Anterior gradient 2 (Agr2) is highly expressed in gastric signet-ring cell carcinoma To study the role of Agr2 in SRCC, we initially examined the expression of Agr2 in archives of human gastric carcinoma diagnosed as SRCC, using immunohistochemistry
Because either coculture of normal fibroblasts with Tu-katoIII cells or addition of recombinant Agr2 protein activated the invasion of normal fibroblasts, we investigated whether expression of a-smooth muscle actin (a-SMA), a marker of activated fibroblasts or Cancer-associated fibroblasts (CAF), is induced in normal fibroblasts by Agr2
Summary
Gastric cancers are histologically classified as intestinal or diffuse type of adenocarcinomas [1]. The latter type comprises poorly differentiated cancers, including variant subtypes such as signet-ring cell carcinoma SRCCs are mucus-producing adenocarcinomas that represent approximately 15% of all primary carcinomas of the stomach [4, 5]. In SRCC cells, the mucus is retained in the cytoplasm, resulting in a characteristic cell morphology in which a large vacuole full of mucin displaces the nucleus to the periphery. When gastric SRCC metastasizes, it tends to disseminate to the peritoneum and develop lymphatic invasion. SRCC has a variable prognosis, it is frequently accompanied with scirrhous gastric cancer upon progression, which is associated
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