Identification of gastric cancer stem cells


A. Cldn18-IRES-CreERT2 driver that selectively introduces mutations into the gastric epithelium of mice. Researchers have developed a new mouse model (C18-ATK) that reproduces human metastatic gastric cancer by combining Wnt with the Kras or Trp53 mutations reported in human gastric cancer. This mouse model accurately reproduces advanced gastric cancer in humans and is an excellent model for gastric cancer research. An orthotopic transplantation model using gastric cancer organoids established from gastric cancer tissue of B.C18-ATK mice. By utilizing these porting models, the time required for analysis can be significantly reduced, enabling high-quality, large-scale analysis. The combination of C. Lgr5 + gastric cancer stem cell removal and the anticancer drug 5-fluorouracil significantly suppressed the progression of gastric cancer. It was suggested that by targeting Lgr5 + gastric cancer cells, which are also present in human gastric cancer, a breakthrough treatment for advanced gastric cancer could be developed.Credit: Kanazawa University

Researchers have succeeded in establishing a mouse model that develops gastric cancer that closely resembles advanced human gastric cancer. Using this model, they discovered gastric cancer stem cells, Lgr5 + gastric cancer cells, that are essential for the development, maintenance, and metastasis of cancer. This research is expected to provide an experimental system that enables detailed analysis of highly malignant gastric cancer and lead to the development of breakthrough treatments for advanced human gastric cancer.

About 1 million people are newly diagnosed with cancer every year in Japan. Gastric cancer is the third leading cause of death from cancer, with more than 40,000 Japanese dying each year.Chemotherapy using Anti-cancer agent Used for advanced users stomach cancerHowever, there is still no completely effective treatment. One reason is that there is no mouse model that can reproduce the development and malignant transformation of human gastric cancer in vivo. Therefore, the mechanism of gastric cancer development and malignant transformation has not been completely elucidated, and no effective treatment for malignant gastric cancer has been established.

Recently, the existence of Cancer stem cells It has been suggested as one of the causes of drug resistance exhibited by malignant cancer.Cancer trunk cell It has pluripotency and self-replication ability. Even if the surrounding cancer cells disappear after chemotherapy, the stem cells survive, regenerate the cancer cells, and cause the cancer to come back. However, the existence of cancer stem cells has not been clearly established so far, and detailed analysis of gastric cancer stem cells has not been performed.

Therefore, in order to develop an effective treatment for malignant gastric cancer, infiltration and metastasis in vivo are performed by establishing a mouse model that closely mimics human gastric cancer, taking into account the characteristics of existing gastric cancer stem cells. It is essential to elucidate the malignant mechanism that causes it. In gastric cancer tissue, including interactions with the surrounding microenvironment.

This study was conducted by an international research team consisting of scientists from the Department of Epithelial Stem Cell Biology, Cancer Research Institute, Kanazawa University and A * Star scientists from Singapore. The research team has newly established Cldn18-IRES-CreERT2 mice that can selectively induce mutations in the gastric epithelium. By mating these with mice that may induce mutations in the WNT and RAS signaling genes or the Trp53 gene (reported in the TCGA gastric cancer database), the team can recreate a human metastatic stomach. Succeeded in developing a mouse model of gastric cancer Cancer. By comparing and analyzing the gastric cancer tissue generated in these mice and the gastric cancer tissue of the patient in detail, it was confirmed that the characteristics and gene expression observed in advanced human gastric cancer were accurately reproduced.This shows their newly established gastric cancer Mouse model It can be a valuable resource for basic and preclinical studies of gastric cancer.In addition, the team developed an orthotopic transplant by orthotopic transplantation of organoids established from mouse gastric cancer tissue into the mouse stomach. model It reproduces the metastatic process of gastric cancer and enables highly reproducible large-scale and rapid analysis.

Through detailed analysis using these models, the team discovered that gastric cancer cells expressing the Lgr5 gene, which is known as a target gene for Wnt signaling, play an important role in the development and progression of gastric cancer. In addition, by investigating the contribution of Lgr5 + gastric cancer cells to gastric cancer metastasis using a drug that removes Lgr5 + gastric cancer cells in vivo, we found that Lgr5 + gastric cancer cells are actually gastric cancer stem cells essential for gastric cancer metastasis. I made it clear. In addition, they found that the use of the anticancer drug 5-fluorouracil in combination with Lgr5 + gastric cancer stem cell removal can effectively suppress the progression and metastasis of gastric cancer in vivo.

This study revealed that Lgr5 + gastric cancer stem cells play an important role in the development, progression, and metastasis of gastric cancer. In addition, it was clarified that the synergistic effect of anticancer drugs and gastric cancer stem cell removal can significantly suppress the progression and metastasis of gastric cancer. This result suggests that there is great clinical significance in the development of treatments targeting Lgr5 + gastric cancer cells, which are also present in human gastric cancer tissue.In addition, new gastric cancer mouse The model established by the team may be applicable to elucidate the mechanism of gastric cancer development, Progression, and metastasis, screening for new diagnostic and therapeutic agents, and preclinical studies.Further research may help develop effective treatments for metastatic gastric cancer by targeting the stomach. cancer Stem cells..

The latest information on gastric cancer treatment and research

For more information:
A. Fatehullah et al, a pool of Lgr5 + stem cells present in the tumor, promotes the establishment and progression of advanced gastric cancer. Nature cell biology (2021). DOI: 10.1038 / s41556-021-00793-9

Quote: Development of new gastric cancer model: https: // identified gastric cancer stem cells acquired on December 22, 2021 (December 2021) The 22nd). html

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