Abstract LB-267: Role of keratin-19 positive stem cells in gastric tumorigenesis.
Authors: Asfaha Samuel , Hayakawa Yoku , Lukin Dana , Ericksen Russell , Muley Ashlesha , Yu Rain , Worthley Daniel L. , Westphalen Christoph B. , Stokes Sarah , von Burstin Johannes , Rustgi Anil K. , Wang Timothy C. 
Published: August 2014

Tumors are postulated to arise from tissue stem or progenitor cells. In the stomach, keratin 19 (K19) is thought to mark a potential progenitor cell within the gastric isthmus. To examine the contribution of tissue stem cells to the origin of gastric cancer, we generated a new K19-BAC-CreER transgenic line to study the lineage of K19+ cells and determine whether K19+ might mark both normal and cancer initiating gastric progenitors. K19-BAC-CreER mice were crossed to a ROSA26r(LacZ or GFP) reporter line. The offspring were induced with tamoxifen and studied in a MNU model of antral carcinogenesis. In separate experiments, K19CreER/ROSA26r mice were crossed to LSL-Kras mice to examine the contribution of the K19 lineage to a genetic model of gastric dysplasia. Tamoxifen-induced X-gal labeling occurred in ~10-30% of corpus pit and antral glands. The labeling persisted for greater than 52 weeks, consistent with K19 marking long-lived gastric stem cells. In K19CreER/ROSA26r mice treated with MNU there was a dramatic increase in the labeling of contiguous GFP/X-gal positive glands, consistent with K19+ stem cell expansion and crypt fission. To test whether K19+ progenitor cells labeled by tamoxifen during MNU treatment contribute to the origin of gastric tumors, we examined the pattern of X-gal lineage tracing in antral tumors. Interestingly, when K19+ cells were labeled by tamoxifen during MNU carcinogenesis, tumors originated from both K19-Cre recombined and non-recombined cells, suggesting that MNU stimulated the K19+ progenitor cell to give rise to multiple K19+ daughter cells that contribute to the tumor. In a genetic model of cancer, when oncogenic Kras was expressed in K19+ progenitors, gastric dysplasia was detected as early as 3 months following tamoxifen induction. In summary, K19 marks corpus, as well as, antral stem cells located in the isthmus (above the crypt base), and these K19+ cells serve as cancer initiating cells in both carcinogen and genetic models of gastric tumorigenesis. Kras or MNU-induced division of K19+ cells, evidenced by contiguous crypt labeling and suggestive of symmetric cell division, appears to be an initiating event. Gastric tumors are polyclonal with multiple K19+ cancer stem cells contributing to antral tumors. Thus K19+ stem cells appear relevant for normal homeostasis as well as the development of gastric cancer.

Citation Format: Samuel Asfaha, Yoku Hayakawa, Dana Lukin, Russell Ericksen, Ashlesha Muley, Rain Yu, Daniel L. Worthley, Christoph B. Westphalen, Sarah Stokes, Johannes von Burstin, Anil K. Rustgi, Timothy C. Wang. Role of keratin-19 positive stem cells in gastric tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-267. doi:10.1158/1538-7445.AM2013-LB-267