Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer

Abstract

Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate‐generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and β‐catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and β‐catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and β‐catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid‐mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and β‐catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.

Phosphoglycerate Kinase 1 Promoting Tumor Progression and Metastasis in Gastric Cancer - Detected in a Tumor Mouse Model Using Positron Emission Tomography/Magnetic Resonance Imaging

“…In patients suffering from gastric cancer with peritoneal carcinomatosis we recently detected an overexpression of PGK1 [9]. We were able to show a direct connection between PGK1 signaling and the chemokine receptor CXCR4 [15]. Nevertheless, the lately most striking finding was that PGK1 seems to be the central molecule concerning tumor invasion and tumor growth in gastric cancer cells in vitro.…”

“…Although gastric cancer is a leading cause of global disease and mortality and frequently associated with metastasis and peritoneal dissemination [1,2], the complex underlying mechanisms for malignant spreading are not clearly investigated yet. Recently, the glycolytic enzyme PGK1 has been determined as a crucial factor for dissemination of gastric cancer, constituting a novel link to dissemination in gastric cancer and other malignancies [9,15]. Therefore a metastatic mouse model simulating human gastric cancer behavior by orthotopic implantation of human histologically proven tumor tissue onto the gastric serosa of nude mice was established.…”

“…Detection was carried out using Envision TM goatanti-mouse secondary antibody (Dako, DakoCytomation GmbH, Hamburg, Germany) for 60 minutes followed by incubation with diaminobenzidine (DAB). Nuclear as well as cytoplasmic staining was considered specific, and a moderate to strong expression was considered positive [15]. …”

“…The empty vector pEF-IRES was transfected, serving as a negative control. Transfected cells were selected by 5 µg/ml Puromycin (AppliChem, Darmstadt, Germany) 24 h after transfection [15,16].…”

Characterization of a Reduced Form of Plasma Plasminogen as the Precursor for Angiostatin Formation

“…PGK secretion by cultured tumor cells positively correlates with oxygen tension (12), which is in accordance with hypoxia being a driver of tumor angiogenesis. In addition, plasma levels of PGK negatively correlate with tumor angiogenesis and tumor growth in mice (13)(14)(15).…”