TY - JOUR
T1 - Mesenchymal stem cells promote formation of colorectal tumors in mice
AU - Tsai, Kuoshu
AU - Yang, Shunghaur
AU - Lei, Yenping
AU - Tsai, Chihchien
AU - Chen, Hsinwei
AU - Hsu, Chihyuan
AU - Chen, Linglan
AU - Wang, Hseiwei
AU - Miller, Stephanie A.
AU - Chiou, Shihhwa
AU - Hung, Mienchie
AU - Hung, Shihchieh
N1 - Funding Information:
Funding Supported by the National Science Council (3111-B-039, 96-2627-B-010-009, 97-3111-B-010-001, and 99-3111-B-010-005-), Taipei Veterans General Hospital (V97C1-060, V98C1-009, and V98E1-002), the MD Anderson Cancer Center/China Medical University and Hospital Sister Institution Fund, and the National Yang-Ming University, Ministry of Education. This work was assisted in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital.
PY - 2011/9
Y1 - 2011/9
N2 - Background & Aims: Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation. Methods: Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation. Results: A small number (≤10) of unsorted, CD133, CD166-, epithelial cell adhesion molecule(EpCAM), or CD133/CD166-/EpCAM colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation. Conclusions: IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer.
AB - Background & Aims: Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation. Methods: Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation. Results: A small number (≤10) of unsorted, CD133, CD166-, epithelial cell adhesion molecule(EpCAM), or CD133/CD166-/EpCAM colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation. Conclusions: IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer.
KW - Cancer Stem Cells
KW - JAK2
KW - Marrow Stromal Cells
KW - Tumor Development
UR - http://www.scopus.com/inward/record.url?scp=80052122372&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2011.05.045
DO - 10.1053/j.gastro.2011.05.045
M3 - Article
AN - SCOPUS:80052122372
SN - 0016-5085
VL - 141
SP - 1046
EP - 1056
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -