RAGE signaling significantly impacts tumorigenesis and hepatic tumor growth in murine models of colorectal carcinoma.
BACKGROUND
The receptor for advanced glycation end-products (RAGE) is a cell surface receptor implicated in tumor cell proliferation and migration. We hypothesized that RAGE signaling impacts tumorigenesis and metastatic tumor growth in murine models of colorectal carcinoma.


METHODS
Tumorigenesis: Apc (1638N/+) mice were crossed with Rage (-/-) mice in the C57BL/6 background to generate Apc (1638N/+)/Rage (-/-) mice. Metastasis: BALB/c mice underwent portal vein injection with CT26 cells (syngeneic) and received daily soluble (s)RAGE or vehicle. Rage (-/-) mice and Rage (+/+) controls underwent portal vein injection with MC38 cells (syngeneic). Rage (+/+) mice underwent portal vein injection with MC38 cells after stable transfection with full-length RAGE or mock transfection control.


RESULTS
Tumorigenesis: Apc (1638N/+)/Rage (-/-) mice had reduced tumor incidence, size, and histopathologic grade. Metastasis: Pharmacological blockade of RAGE with sRAGE or genetic deletion of Rage reduced hepatic tumor incidence, nodules, and burden. Gain of function by transfection with full-length RAGE increased hepatic tumor burden compared to vector control MC38 cells.


CONCLUSIONS
RAGE signaling plays an important role in tumorigenesis and hepatic tumor growth in murine models of colorectal carcinoma. Further work is needed to target the ligand-RAGE axis for possible prophylaxis and treatment of primary and metastatic colorectal carcinoma.
DiNorcia
Joseph
J
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Moroziewicz
Dorota N
DN
Ippagunta
Nikalesh
N
Lee
Minna K
MK
Foster
Mark
M
Rotterdam
Heidrun Z
HZ
Bao
Fei
F
Zhou
Yu Shan
YS
Yan
Shi Fang
SF
Emond
Jean
J
Schmidt
Ann Marie
AM
Allendorf
John D
JD
D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000503:physiopathology; D017127:Glycation End Products, Advanced; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
Nat Rev Immunol. 2004 Aug;4(8):641-8
15286730
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
J Clin Invest. 2001 Oct;108(7):949-55
11581294
Nature. 2009 Jan 1;457(7225):102-6
19122641
Nat Rev Immunol. 2005 Oct;5(10):749-59
16175180
Carcinogenesis. 2010 Mar;31(3):334-41
20028726
Am J Pathol. 2005 Mar;166(3):751-60
15743787
Nature. 2008 Jul 24;454(7203):436-44
18650914
J Clin Invest. 2008 Jan;118(1):183-94
18079965
Virchows Arch. 2005 Apr;446(4):411-5
15789216
Annu Rev Immunol. 2010;28:367-88
20192808
Gut. 2006 Feb;55(2):234-42
16118352
Mol Cell Biochem. 2010 Apr;337(1-2):251-8
19876719
Carcinogenesis. 2008 Oct;29(10):2035-43
18689872
Oncol Rep. 2003 Mar-Apr;10(2):445-8
12579287
J Clin Oncol. 2007 Oct 10;25(29):4575-80
17925551
J Clin Invest. 1995 Sep;96(3):1395-403
7544803
Am J Pathol. 2003 Apr;162(4):1123-37
12651605
Nat Med. 1998 Sep;4(9):1025-31
9734395
Nature. 2000 May 18;405(6784):354-60
10830965
J Leukoc Biol. 2009 Sep;86(3):505-12
19477910
Int J Cancer. 2003 May 10;104(6):722-7
12640679
J Clin Invest. 2003 Apr;111(7):959-72
12671045
Pathol Res Pract. 2008;204(7):479-90
18538487
J Clin Invest. 1996 Jan 1;97(1):238-43
8550841
Curr Mol Med. 2007 Dec;7(8):777-89
18331236
J Leukoc Biol. 2009 Sep;86(3):599-607
19584311
Cell Commun Signal. 2009 May 08;7:12
19426472
Nature. 2006 May 25;441(7092):431-6
16724054
Dis Colon Rectum. 2007 Aug;50(8):1230-40
17587138
Circulation. 1997 Oct 7;96(7):2262-71
9337199
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8969-73
8090754