ABSTRACT
BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.
Subject(s)
Energy Metabolism , Fatty Acids , Metaplasia , Organoids , Proto-Oncogene Proteins p21(ras) , Stomach Neoplasms , Animals , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Stomach Neoplasms/genetics , Humans , Fatty Acids/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Organoids/metabolism , Mice , Disease Models, Animal , Carcinogenesis/metabolism , Carcinogenesis/genetics , Carcinogenesis/pathology , Chief Cells, Gastric/metabolism , Chief Cells, Gastric/pathology , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Cell Transformation, Neoplastic/genetics , Mice, Transgenic , Glycolysis , Adenocarcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/genetics , Disease Progression , Precancerous Conditions/pathology , Precancerous Conditions/metabolism , Precancerous Conditions/geneticsABSTRACT
SUMMARY: Diabetes mellitus (DM) is a metabolic disorder with rising incidences worldwide. Gastric symptoms of DM have been reported, including nausea, vomiting, bloating, and epigastric pain. Moreover, acute to chronic gastritis and atrophic gastritis occur in DM can affect the chief cells of the gastric gland. Chief cells are vital because of their ability to digest and separate vitamin B12 from protein. Lack of vitamin B12 leads to impaired DNA synthesis and abnormal metabolism in red blood cells, and eventually leading to pernicious anemia. Furthermore, decreased vibratory and positional senses, numbness, ataxia with subacute combined degeneration, and dementia are present in pernicious anemic patients. Twenty-four male adult Sprague-Dawley rats were used in this study. The rats were divided into control (n = 12) and diabetic (n = 12) groups. The rats were further separated into two categories: short-term (4 weeks) and long-term (24 weeks) groups. DM model was induced by manually injecting intraperitoneally with streptozotocin in citrate buffer at a dose of 60 mg/kg body weight. The same amount of buffer was injected into the control group. After sacrifice, three regions of the stomach (the cardia, body, and pylorus) were dissected. Histopathology was performed by staining with toluidine blue. Image analysis was used to quantify the zymogen granule accumulation in chief cells. The data were compared between the control and DM rats in each period using Student's t-test. In addition, transmission electron microscopy (TEM) was also used to examine the ultrastructures. There was a significant decrease in the percentage of zymogen granules in DM rats. Under TEM, the destructions of mitochondria, rough endoplasmic reticulum, and Golgi apparatus in the DM rat were observed in the chief cells. In rats with uncontrolled diabetes, there is damage to the chief cells all over the area of the stomach, affecting digestion and malabsorption of vitamin B12. Therefore, this result helps clinicians recognize that diabetic patients with gastric symptoms may have hidden pernicious anemia.
La diabetes mellitus (DM) es un trastorno metabólico con incidencia creciente a nivel mundial. Se han informado síntomas gástricos de DM, que incluyen náuseas, vómitos, distensión abdominal y dolor epigástrico. Además, la gastritis aguda a crónica y la gastritis atrófica que ocurren en la DM pueden afectar las células principales de la glándula gástrica. Las células principales son vitales debido a su capacidad para digerir y separar la vitamina B12 de las proteínas. La falta de vitamina B12 conduce a una síntesis de ADN deteriorada y un metabolismo anormal en los glóbulos rojos, lo que eventualmente conduce a una anemia perniciosa. Además, los pacientes con anemia perniciosa presentan disminución de los sentidos vibratorio y posicional, entumecimiento, ataxia con degeneración combinada subaguda y demencia. En este estudio se usaron 24 ratas Sprague-Dawley macho adultas. Las ratas se dividieron en grupos control (n = 12) y diabéticas (n = 12). Las ratas se separaron además en dos categorías: grupos a corto plazo (4 semanas) y a largo plazo (24 semanas). El modelo de DM se indujo inyectando manualmente por vía intraperitoneal estreptozotocina en tampón de citrato a una dosis de 60 mg/kg de peso corporal. Se inyectó la misma cantidad de tampón en el grupo control. Después del sacrificio, se disecaron tres regiones del estómago (cardias, cuerpo y píloro). La histopatología se realizó mediante tinción con azul de toluidina. El análisis de imágenes se utilizó para cuantificar la acumulación de gránulos de zimógeno en las células principales. Los datos se compararon entre las ratas control y DM en cada período utilizando la prueba t de Student. Además, se utilizó microscopía electrónica de transmisión (TEM) para examinar la ultraestructura celular. Hubo una disminución significativa en el porcentaje de gránulos de zimógeno en ratas DM. Bajo TEM, se observaron en las células principales las destrucción de las mitocondrias, del retículo endoplásmico rugoso y del complejo golgiense en la rata DM. En ratas con diabetes no controlada, hay daño en las células principales de toda el área del estómago, lo que afecta la digestión y la malabsorción de vitamina B12. Por lo tanto, este resultado ayuda a los médicos a reconocer que los pacientes diabéticos con síntomas gástricos pueden tener una anemia perniciosa oculta.
Subject(s)
Animals , Male , Rats , Diabetes Mellitus, Experimental , Gastric Mucosa/pathology , Rats, Sprague-Dawley , Chief Cells, Gastric/pathology , Microscopy, Electron, TransmissionABSTRACT
La heterotopia gástrica es más frecuente en intestino delgado,vesícula y tracto biliar, divertículo de Meckel, colon y recto, peropuede encontrarse en otras localizaciones. Es especialmente rara encavidad oral. Sólo encontramos un caso que coincide con fisura palatina(1). Nosotros presentamos el caso de un niño con heterotopia gástricay fisura palatina, además de otras malformaciones congénitas enprincipio no relacionadas. Hacemos una breve revisión de la literatura, mostrando la patogénesis de la heterotopia y su posible asociación con la fisura palatina (AU)
Gastric heterotopia is more frequently in small intestine, gall bladder, biliary tract, Meckels diverticulum, colon and rectum, but it can be found in other locations. It is especially rare in oral cavity. We only find one case that concurs with cleft palate. We present the case of a neonate with gastric heterotopia and cleft palate in addition to other congenital malformations not related at first. We make a brief revision of literature, showing the pathogenesis of heterotopia and its possible association with the cleft palate Gastric heterotopia is more frequently in small intestine, gall bladder, biliary tract, Meckels diverticulum, colon and rectum, but it can be found in other locations. It is especially rare in oral cavity. We only find one case that concurs with cleft palate. We present the case of a neonate with gastric heterotopia and cleft palate in addition to other congenital malformations not related at first. We make a brief revision of literature, showing the pathogenesis of heterotopia and its possible association with the cleft palate (AU)