TY - JOUR
T1 - Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche
AU - Hayakawa, Yoku
AU - Ariyama, Hiroshi
AU - Stancikova, Jitka
AU - Sakitani, Kosuke
AU - Asfaha, Samuel
AU - Renz, Bernhard W.
AU - Dubeykovskaya, Zinaida A.
AU - Shibata, Wataru
AU - Wang, Hongshan
AU - Westphalen, Christoph B.
AU - Chen, Xiaowei
AU - Takemoto, Yoshihiro
AU - Kim, Woosook
AU - Khurana, Shradha S.
AU - Tailor, Yagnesh
AU - Nagar, Karan
AU - Tomita, Hiroyuki
AU - Hara, Akira
AU - Sepulveda, Antonia R.
AU - Setlik, Wanda
AU - Gershon, Michael D.
AU - Saha, Subhrajit
AU - Ding, Lei
AU - Shen, Zeli
AU - Fox, James G.
AU - Friedman, Richard A.
AU - Konieczny, Stephen F.
AU - Worthley, Daniel L.
AU - Korinek, Vladimir
AU - Wang, Timothy C.
N1 - Funding Information:
This research was supported by NIH grants U54CA126513, R01CA093405, R01CA120979, and R01DK052778 and by the Clyde Wu Family Foundation (T.C.W.). Y.H. was supported by Mitsukoshi Health and Welfare Foundation, JSPS Postdoctoral Fellowships for Research Abroad, and the Uehara Memorial Foundation. J.S. and V.K. were supported by the Czech Science Foundation grant numbers P305/11/1780 and 14-33952S.
Funding Information:
We thank Dr. Anil Rustgi, Dr. Kenneth Olive, Dr. Terry Yamaguchi, Dr. Leonard H. Augenlicht, Dr. Carrie Shawber, and Dr. Richard J. Miller for providing the mice; Ms. Kristie Gordon for assisting in the fluorescence-activated cell sorting (FACS) analysis; Mr. Adam White and Ms. Theresa Swayne for producing the 3D images; Dr. Rani Sellers, Ms. Barbara Cannella, and Ms. Supreet Kainth for assisting with the in situ hybridization; Ms. Ashlesha Muley and Mr. Tao Su for technical assistance; Ms. Wendy Beth Jackelow (Medical & Scientific Illustration) for creating schematic images; and Dr. James R. Goldenring for providing DMP-777. This research was supported by NIH grants U54CA126513, R01CA093405, R01CA120979, and R01DK052778 and by the Clyde Wu Family Foundation (T.C.W.). Y.H. was supported by Mitsukoshi Health and Welfare Foundation, JSPS Postdoctoral Fellowships for Research Abroad, and the Uehara Memorial Foundation. J.S. and V.K. were supported by the Czech Science Foundation grant numbers P305/11/1780 and 14-33952S.
PY - 2015/12/14
Y1 - 2015/12/14
N2 - The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1+ stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12+ endothelial cells and Cxcr4+ gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.
AB - The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1+ stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12+ endothelial cells and Cxcr4+ gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.
UR - http://www.scopus.com/inward/record.url?scp=84954214835&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2015.10.003
DO - 10.1016/j.ccell.2015.10.003
M3 - Article
C2 - 26585400
AN - SCOPUS:84954214835
VL - 28
SP - 800
EP - 814
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -