WNT Signaling and Colorectal Cancer
- 669 Downloads
The WNT signaling pathway is a critical mediator of tissue homeostasis and repair, and frequently co-opted during tumor development. Almost all colorectal cancers (CRC) demonstrate hyperactivation of the WNT pathway, which in many cases is believed to be the initiating and driving event. In this short review, we provide a focused overview of recent developments in our understanding of the WNT pathway in CRC, describe new research tools that are enabling a deeper understanding of WNT biology, and outline ongoing efforts to target this pathway therapeutically.
KeywordsColorectal cancer CRC Wnt APC Beta-catenin RSPO
EMS is supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM07739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. LED is supported by a K22 Career Development Award from the NCI/NIH (CA 181280-01), with funding from the Starr Cancer Consortium (I8-A8-030) and NIH/NCI (5R01CA195787-02).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.• van de Wetering M, Francies HE, Francis JM, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161(4):933–45. This paper demonstrated the potential to establish living repositories of patient-derived organoid cultures and use them to prospectively identify drug sensitivities and new driver mutations in CRC.Google Scholar
- 27.Barker N, Ridgway R, van Es J, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2008.Google Scholar
- 29.• Dow LE, O’Rourke KP, Simon J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell. 2015;161(7):1539–52. This paper defined the importance of sustained Apc loss for driving tumorigenesis in the colon. Specifically, that restoring normal levels of Apc is sufficient to revert even advanced carcinomas to normal epithelium.Google Scholar
- 51.• Storm EE, Durinck S, de Sousa e Melo F, et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature. 2016;529(7584):97–100. This paper demonstrated that antibodies targeting RSPO3 were sufficient to halt tumor growth in xenografts of CRCs carrying PTPRK-RSPO3 fusions. This example implies RSPO fusions are a driving event in CRC and highlights a potential therapeutic approach.Google Scholar
- 54.Hilkens J, Timmer NC, Boer M, et al. RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. Gut. 2016.Google Scholar
- 59.•• Drost J, van Jaarsveld RH, Ponsioen B, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521(7550):43–7. This study, along with Matano et al. (Ref 36) demonstrated the ability to sequencially and specifically manipulate genomic loci in cultured human organoids. This enabled the authors of both studies to recapitulate the proposed sequence of oncogenesis in the colon (The Vogelgram) and highlight the stepwise transition to CRC.Google Scholar