The role of clusterin in trans-/dedifferentiation of chief cells in the stomach followingTamoxifen-induced acute gastric oxyntic atrophy
Gastric adenocarcinomas are one of the leading causes of cancer-related deaths worldwide. The sequence of events leading to development of pre-cancerous gastric dysplasia often begins with the loss of acid-secreting parietal cells, a process called gastric oxyntic atrophy. Spasmolytic polypeptide-expressing metaplasia (SPEM) is such a pre-cancerous alteration in the oxyntic epithelium of the stomach, thought to derive from trans-/dedifferentiation of chief cells following gastric oxyntic atrophy.
Intraperitoneal injection of the selective estrogen receptor modulator, tamoxifen (normally used in conditional gene targeting in Cre-ER recombinase transgenic mice), has recently been shown to induce a rapid onset and reversible SPEM in mice. Clusterin is a stress-induced multifunctional protein associated with tumor progression and treatment resistance in several tissues. Expression of clusterin in the gastric mucosa rises early during both induction of SPEM and following potent acid inhibition and hypergastrinemia. Whether clusterin promotes or counteracts metaplasia is not known, but clusterin has been associated with tissue remodeling, anti-apoptosis and cell migration/invasion; processes that all can be part of metaplastic transformation. Findings in samples of metaplasia from humans and rodents suggest that clusterin may be involved in the putative transition of SPEM into pre-cancerous intestinal metaplasia. On the other hand, increased expression of clusterin in chief cells following parietal cell ablation, anacidity and hypergastrinemia may be part of a protective mechanism; exploiting clusterin’s function as a stress-induced chaperone counteracting alteration of mucosal homeostasis.
This study is part of the larger project “Molecular mechanisms of cellular stress responses in gastric cancer and their therapeutic implications”. In the present study we aim to study the role of clusterin in the pre-malignant process of trans-/dedifferentiation of chief cells following acute oxyntic atrophy. Increased knowledge of the early events of gastric carcinogenesis is important to aid a earlier detection and diagnosis of this disease. we will use intraperitoneal injections of tamoxifen to induce oxyntic atrophy and compare ordinary mice with mice that lack clusterin (transgenic clusterin-/- knockout mice). We will use different molecular and histomorphological analysis to examine the oxyntic mucosa at different intervals (day 3, 7 and 21) from receiving tamoxifen. The injections are considered a minimal burden for the mice and no reduction of the animals well-being is expected. At the end of the study the mice will be anesthetized and organs and blood harvested before sacrifice. Only the minimal number of animals necessary for the analysis will be used and a pilot study will be performed for refinement.
Intraperitoneal injection of the selective estrogen receptor modulator, tamoxifen (normally used in conditional gene targeting in Cre-ER recombinase transgenic mice), has recently been shown to induce a rapid onset and reversible SPEM in mice. Clusterin is a stress-induced multifunctional protein associated with tumor progression and treatment resistance in several tissues. Expression of clusterin in the gastric mucosa rises early during both induction of SPEM and following potent acid inhibition and hypergastrinemia. Whether clusterin promotes or counteracts metaplasia is not known, but clusterin has been associated with tissue remodeling, anti-apoptosis and cell migration/invasion; processes that all can be part of metaplastic transformation. Findings in samples of metaplasia from humans and rodents suggest that clusterin may be involved in the putative transition of SPEM into pre-cancerous intestinal metaplasia. On the other hand, increased expression of clusterin in chief cells following parietal cell ablation, anacidity and hypergastrinemia may be part of a protective mechanism; exploiting clusterin’s function as a stress-induced chaperone counteracting alteration of mucosal homeostasis.
This study is part of the larger project “Molecular mechanisms of cellular stress responses in gastric cancer and their therapeutic implications”. In the present study we aim to study the role of clusterin in the pre-malignant process of trans-/dedifferentiation of chief cells following acute oxyntic atrophy. Increased knowledge of the early events of gastric carcinogenesis is important to aid a earlier detection and diagnosis of this disease. we will use intraperitoneal injections of tamoxifen to induce oxyntic atrophy and compare ordinary mice with mice that lack clusterin (transgenic clusterin-/- knockout mice). We will use different molecular and histomorphological analysis to examine the oxyntic mucosa at different intervals (day 3, 7 and 21) from receiving tamoxifen. The injections are considered a minimal burden for the mice and no reduction of the animals well-being is expected. At the end of the study the mice will be anesthetized and organs and blood harvested before sacrifice. Only the minimal number of animals necessary for the analysis will be used and a pilot study will be performed for refinement.