Signal amplification loops in chronic inflammation and Colon Cancer

The inflammatory gastrointestinal diseases Crohn’s disease, inflammatory bowel diseases (IBD), and ulcerative colitis (UC), are all known to be key risk factors in the development of colorectal cancer.  TNFα and IL-6 are two pro-inflammatory cytokines that signal to activate the NF-ĸB and STAT3 transcription factors, respectively.  Both pathways are known to play a role in the persistent inflammation that drives development of colitis-associated colorectal cancer.

Sphingosine-1-phosphate (S1P) is a lysophospholipid that is metabolized from phosphorylation of sphingosine by the kinases, SphK1 and SphK2, and signals through the G-protein coupled receptor sphingosine-1-phosphate receptor-1 (S1PR1).  The S1P-S1PR1 signaling pathway has been shown to activate STAT3 and induce expression of both IL-6 and S1PR1, driving a positive feedback loop leading to persistent STAT3 activation in tumor cells (Lee et. al., 2010).  S1P and SphK1 have also been shown to play a critical role in the NF-ĸB signaling pathway.  S1P was required for TRAF2 E3 ubiquitin ligase activity and activation of NF-ĸB by TNFα independently from the S1PR1 receptor pathway (Alvarez et. al., 2010).  SphK1 has also been linked to development of colorectal cancer.  SphK1 was highly expressed in human colons cancers as compared with normal mucosa, and SphK1-/- mice were less susceptible to azoxymethane induction of colon cancer (Kawamori, 2009).

In a study by Liang et al. in this month’s issue of Cancer Cell, the authors close these links between the TNFα/NF-ĸB, IL-6/STAT3, and SphK1/S1P pathways in chronic inflammation driven colorectal cancer.  In the dextran sodium sulfate (DSS) murine model of colitis driven tumorigenesis, deficiency of SphK2 led to a compensatory upregulation of SphK1 and S1P production, and exacerbated DSS driven colitis and subsequent tumorigenesis.  S1P-driven NF-ĸB activation was enhanced, as was production of TNFα, IL-6, and STAT3 activation in SphK2-/- mice, and the SphK1/S1P pathway primarily exerted its activities in colonic mucosa infiltrating immune cells.  FTY720, an antagonist of S1PR1 and SphK1, was able to inhibit the S1P positive-feedback loop and block persistent activation of STAT3 and NF-ĸB and production of IL-6.  Additionally, FTY720 inhibited the development of tumors in this colitis driven tumorigenesis murine model.

In summary, these studies show that SphK1 drives a feed-forward signal amplification loop that exacerbates inflammation and promotes tumorigenesis by production of S1P.  S1P then drives S1PR1 activation of STAT3 leading to further production of S1PR1, as well as activates NF-ĸB and induction of TNFα and IL-6 transcription, which further feed back on the NF-ĸB and STAT3 pathways, respectively.  Blocking this amplification loop by inhibiting S1PR1 and SphK1 may thus be a promising treatment strategy for colitis-associated colorectal cancer.



Further Reading:

Sphingosine-1-Phosphate Links Persistent STAT3 Activation, Chronic Intestinal Inflammation, and Development of Colitis-Associated Cancer.  Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang WC, Hait NC, Allegood JC, Price MM, Avni D, Takabe K, Kordula T, Milstien S, Spiegel S. Cancer Cell. 2013 Jan 14;23(1):107-20.

Sphingosine 1-Phosphate Is a Missing Link between Chronic Inflammation and Colon Cancer.  Pyne NJ, Pyne S. Cancer Cell. 2013 Jan 14;23(1):5-7.

STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors.  H. Lee H, Deng J, Kujawski M, Yang C, Liu Y, Herrmann A, Kortylewski M, Horne D, Somlo G, Forman S, Jove R, Yu H.. Nat. Med., 16 (2010), pp. 1421–1428.

Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2.  Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T, Milstien S, Spiegel S. Nature. 2010 Jun 24;465(7301):1084-8.

Role for sphingosine kinase 1 in colon carcinogenesis. T. Kawamori, T. Kaneshiro, M. Okumura, S. Maalouf, A. Uflacker, J. Bielawski, Y.A. Hannun, L.M. Obeid.  FASEB J., 23 (2009), pp. 405–414.

Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.  Rosen H. and Goetzl EJ.   Nature Reviews Immunology 5, 560-570, July 2005.

 Immunity, inflammation, and cancer.  S.I. Grivennikov, F.R. Greten, M. Karin.  Cell, 140 (2010), pp. 883–899.

Intestinal inflammation and cancer.  T.A. Ullman, S.H. Itzkowitz.  Gastroenterology, 140 (2011), pp. 1807–1816.