Mesenchymal stem cells induce epithelial proliferation within the inflamed stomach.
Bone marrow-derived mesenchymal stem cells (MSCs) sustain cancer cells by creating a microenvironment favorable for tumor growth. In particular, MSCs have been implicated in gastric cancer development. There is extensive evidence suggesting that Hedgehog signaling regulates tumor growth. However, very little is known regarding the precise roles of Hedgehog signaling and MSCs in tumor development within the stomach. The current study tests that hypothesis that Sonic Hedgehog (Shh), secreted from MSCs, provides a proliferative stimulus for the gastric epithelium in the presence of inflammation. Red fluorescent protein-expressing MSCs transformed in vitro (stMSCs) were transduced with lentiviral constructs containing a vector control (stMSC(vect)) or short hairpin RNA (shRNA) targeting the Shh gene (stMSC(ShhKO)). Gastric submucosal transplantation of wild-type MSCs (wtMSCs), wild-type MSCs overexpressing Shh (wtMSC(Shh)), stMSC(vect), or stMSC(ShhKO) cells in C57BL/6 control (BL/6) or gastrin-deficient (GKO) mice was performed and mice analyzed 30 and 60 days posttransplantation. Compared with BL/6 mice transplanted with wtMSC(Shh) and stMSC(vect) cells, inflamed GKO mice developed aggressive gastric tumors. Tumor development was not observed in mouse stomachs transplanted with wtMSC or stMSC(ShhKO) cells. Compared with stMSC(ShhKO)-transplanted mice, within the inflamed GKO mouse stomach, Shh-expressing stMSC(vect)- and wtMSC(Shh)-induced proliferation of CD44-positive cells. CD44-positive cells clustered in gland-like structures within the tumor stroma and were positive for Patched (Ptch) expression. We conclude that Shh, secreted from MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation.
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Jessica M
JM
Donnelly
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Amy
A
Engevik
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Rui
R
Feng
Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Chang
C
Xiao
Department of Pathology Wright State University, Health Sciences, Dayton, Ohio; Veterans Affairs Medical Center, Cincinnati, Ohio; and.
Gregory P
GP
Boivin
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Jing
J
Li
Department of Medicine, Division of Gastroenterology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
JeanMarie
J
Houghton
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; yana.zavros@uc.edu.
Yana
Y
Zavros
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000172:deficiency; D005756:Gastritis / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology
D005755:Gastrins; D053823:Hedgehog Proteins; C465570:Shh protein, mouse
CD44; Sonic Hedgehog; cancer stem cells; inflammation