The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extra nodal metastasis using a unique humanized orthotopic mouse model

Margolin, David A., Myers, Tamara, Zhang, Xin, Bertoni, Danielle M., Reuter, Brian A., Obokhare, Izi, Borgovan, Theodor, Grimes, Chelsea, Green, Heather, Driscoll, Tiffany, Lee, Chung-Gi, Davis, Nancy K. and Li, Li (2015) The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extra nodal metastasis using a unique humanized orthotopic mouse model. FASEB Journal, 29 8: 3571-3581. doi:10.1096/fj.14-268938


Author Margolin, David A.
Myers, Tamara
Zhang, Xin
Bertoni, Danielle M.
Reuter, Brian A.
Obokhare, Izi
Borgovan, Theodor
Grimes, Chelsea
Green, Heather
Driscoll, Tiffany
Lee, Chung-Gi
Davis, Nancy K.
Li, Li
Title The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extra nodal metastasis using a unique humanized orthotopic mouse model
Journal name FASEB Journal   Check publisher's open access policy
ISSN 1530-6860
0892-6638
Publication date 2015-08
Year available 2015
Sub-type Article (original research)
DOI 10.1096/fj.14-268938
Open Access Status Not Open Access
Volume 29
Issue 8
Start page 3571
End page 3581
Total pages 11
Place of publication Bethesda, Maryland, United States
Publisher Federation of American Societies for Experimental Biology
Collection year 2016
Language eng
Formatted abstract
Colorectal cancer (CRC) is the second-most common cause of cancer-related mortality. The most important prognostic factors are lymph node (LN) involvement and extranodal metastasis. Our objective is to investigate the interactions between CD133+CXCR4+ (CXC receptor 4) colorectal cancer tumor-initiating cells (Co-TICs) and the LN stromal microenvironment in human CRC extranodal metastasis. We established a unique humanized orthotopic xenograft model. Luciferase-tagged CRC cell lines and human cancer cells were injected intrarectally into nonobese diabetic/SCID mice. Mesenteric LN stromal cells, stromal cell line HK, or CXCL12 knockdown HK (HK-KD-A3) cells were coinoculated with CRC cells. Tumor growth and metastasis were monitored by bioluminescent imaging and immunohistochemistry. We found that this model mimics the human CRC metastatic pattern with CRC cell lines or patient specimens. Adding LN stromal cells promotes CRC tumor growth and extranodal metastasis (P < 0.001). Knocking down CXCL12 impaired HK cell support of CRC tumor formation and extranodal metastasis. When HK cells were added, sorted CD133+CXCR4+ Co-TICs showed increased tumor formation and extranodal metastasis capacities compared to unseparated and non-Co-TIC populations. In conclusion, both Co-TIC and LN stromal factors play crucial roles in CRC metastasis through the CXCL12/CXCR4 axis. Blocking Co-TIC/LN-stromal interactions may lead to effective therapy to prevent extranodal metastasis.—Margolin, D. A., Myers, T., Zhang, X., Bertoni, D. M., Reuter, B. A., Obokhare, I., Borgovan, T., Grimes, C., Green, H., Driscoll, T., Lee, C.-G., Davis, N. K., Li, L. The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extranodal metastasis using a unique humanized orthotopic mouse model.
Keyword Cancer stem cell
Intrarectal injection
Xenograft
HK cell
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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