动物造模,药效评价,基因修饰胰腺癌 z-bio 2024-08-02 396

　　[Modeling mechanism] During the early diagnosis and treatment of pancreatic cancer, it was found that the abnormal molecular genetics of pancreatic intraductal epithelioma, the precancerous lesion of pancreatic cancer, was directly related to pancreatic cancer. Intraductal epithelioma of the pancreas is considered to be the precancerous lesion of pancreatic cancer, which is derived from tubular epithelium. Recent studies have shown that pancreatic intraductal epithelial tumors originate from acinar cells. Under the action of various tumor causing factors, acinar cells transform into tubular cells and form tubular complexes, gradually evolving into pancreatic intraductal epithelial tumors. The heterogeneity of acinar cells and pancreatic intraductal epithelial tumors is closely related; In addition, studies have shown that the ability to achieve the transformation of alveolar and tubular cells is related to the K-ras gene mutation subtype, where K-ras G12D can cause this transformation, while K-ras G12D mutant mice do not.

　　[Method of Modeling]

　　The K-Ras gene knockout mouse model utilizes LoxP/Cre specific recombination resection technique to activate the pancreatic specific promoter Pdx-1 to activate K-ras G12D, and all mice specifically produce various stages of PanIN, which is the K-ras C12D mouse PanIN model. In this model, except for K-ras gene mutations that can be detected, there are no mutations or deletions of P16, P53, or Smad4. The cell proliferation rate of this PanIN in vitro culture is similar to that of primary pancreatic cancer, and it can form colonies seen under light microscope in soft agar, and the colonies increase with the extension of culture time, suggesting that PanIN cells have the biological characteristics of malignant transformed tumor cells to a certain extent.

　　2. K-Ras gene mutation and P53 gene mutation gene targeting mouse pancreatic cancer model After mating K-ras C12D mice with inactivated mutant P53 R172H mice, all mice can specifically produce invasive pancreatic duct cell carcinoma (PDA) in a short period of time and metastasize to liver, lung and abdominal cavity, which is the K-ras G12D/P53 R172H mouse PDA model.

　　3. The K-ras G12D mice, a pancreatic cancer model in which K-Ras gene mutation cooperates with P16 gene mutation gene targeting mice, mate with P16 deficient mice. All mice can also specifically produce PDA, and die within 11 weeks, often metastasize to duodenum, kidney and other organs, and can also metastasize to liver and lung. This is the K-ras G12D/P16 deficient mouse PDA model.

　　4. The pancreatic cancer model of K-Ras gene mutation and DPC4 gene targeting mutation mice mated K-ras G12D mice with Smad4 deficient mice. The synergistic effect of the two does not directly lead to the occurrence of invasive pancreatic cancer, but leads to mucinous cystic lesions, which can finally progress to pancreatic cancer only under the condition of P53/P16 gene mutation.

　　【 Model Features 】 Currently, PanIN histological classification is mainly obtained through time controlled transgenic or gene targeting techniques, and it is difficult to obtain such morphological basis in clinical practice. Gene modified pancreatic cancer animal models are essentially very similar to human pancreatic cancer models, and the mode of metastasis is the most similar to human tumor metastasis. It can be used to study the early stage of tumor formation, so as to study the pathogenesis of early pancreatic cancer and the effect of intervention therapy.

　　According to the progression of PanIN pathological morphology, the evaluation and application of the model can be divided into PanlN-1A PanIN-1B、 PanIN-2、PanIN-3。 The specific classification criteria are as follows: PanIN-1A refers to lesions with mucus cell proliferation, no nipple formation, and mild atypical lesions; Papillary ductal epithelial hyperplasia and/or adenomatous hyperplasia, with mild atypical hyperplasia referred to as PanIN-1B; The polarity of the cell nucleus disappears and there is a phenomenon of multinucleation. Grade 2 ductal epithelial tumor like hyperplasia, moderate atypical, is PanIN-2; Cell polarity generally disappears, nuclear atypia. But the basement membrane is still intact, and the grade 3 ductal epithelial tumor like hyperplasia, which is severe atypical, is PanlN-3 (also known as carcinoma in situ).