Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression Journal Article
| Authors: | Till, J. E.; Yoon, C.; Kim, B. J.; Roby, K.; Addai, P.; Jonokuchi, E.; Tang, L. H.; Yoon, S. S.; Ryeom, S. |
| Article Title: | Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression |
| Abstract: | Gastric adenocarcinoma is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases that are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of gastric adenocarcinoma tumorigenesis based on KrasG12D expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model that displays a median survival of 76 days. Tumors occur throughout the stomach, with metastases documented in lymph nodes, lung, and liver. Mice otherwise identical but retaining one wild-type Cdh1 allele exhibited longer survival with only 20% penetrance of invasive tumors and no apparent lung or liver metastases. Notably, increased RAS activity and downstream MAPK signaling was observed in stomachs only when E-cadherin was absent. This model offers a valuable tool to investigate gastric adenocarcinoma subtypes where RAS/MAPK pathway activation and E-cadherin attenuation are common. ©2017 AACR. |
| Keywords: | mitogen activated protein kinase; cancer survival; controlled study; protein expression; survival rate; genetics; nonhuman; liver neoplasms; lymph node metastasis; lymphatic metastasis; adenocarcinoma; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; animal tissue; gene expression; protein targeting; lung neoplasms; animal experiment; animal model; enzyme activation; pathology; protein p53; uvomorulin; mice, inbred c57bl; physiology; carcinogenesis; cell lineage; c57bl mouse; lung tumor; tumor suppressor gene; genetic engineering; liver tumor; tumor suppressor protein p53; upregulation; oncogene k ras; stomach adenocarcinoma; beta catenin; protein p21; proto-oncogene proteins p21(ras); stomach neoplasms; knockout mouse; stomach tumor; secondary; mapk signaling; humans; human; male; female; priority journal; article; fizzy related protein; fzr1 protein, mouse; kras2 protein, mouse; gastric carcinogenesis; stomach parietal cell; cdh1 proteins |
| Journal Title: | Cancer Research |
| Volume: | 77 |
| Issue: | 19 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-10-01 |
| Start Page: | 5349 |
| End Page: | 5359 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-17-0061 |
| PUBMED: | 28760854 |
| PROVIDER: | scopus |
| PMCID: | PMC5626624 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2017 -- Source: Scopus |
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