Journal
GUT
Volume 63, Issue 1, Pages 131-142Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2012-303715
Keywords
Cancer Prevention; Colonic Adenomas; Colonic Polyps; Colorectal Cancer
Categories
Funding
- A*STAR, Singapore
- Sharon D Lund foundation
- American Cancer Society
- Swedish Cancer Society
- Medical Faculty (Lund University)
- Soderberg Foundation
- Segerfalk Foundation
- Anna-Lisa and Sven-Erik Lundgren Foundation for Medical Research
- Knut and Alice Wallenberg Foundation
- Lund City Jubileumsfond
- John and Augusta Persson Foundation for Medical Research
- Maggie Stephens Foundation
- Gunnar Nilsson Cancer Foundation
- Inga-Britt and Arne Lundberg Foundation
- HJ Forssman Foundation for Medical Research
- Royal Physiographic Society
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Background Most colon cancers start with dysregulated Wnt/-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human -lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties of the complex and its biological context. Objective To investigate if HAMLET can be used for colon cancer treatment and prevention. Apc(Min/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human disease. Method HAMLET was given perorally in therapeutic and prophylactic regimens. Tumour burden and animal survival of HAMLET-treated and sham-fed mice were compared. Tissue analysis focused on Wnt/-catenin signalling, proliferation markers and gene expression, using microarrays, immunoblotting, immunohistochemistry and ELISA. Confocal microscopy, reporter assay, immunoprecipitation, immunoblotting, ion flux assays and holographic imaging were used to determine effects on colon cancer cells. Results Peroral HAMLET administration reduced tumour progression and mortality in Apc(Min/+) mice. HAMLET accumulated specifically in tumour tissue, reduced -catenin and related tumour markers. Gene expression analysis detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered -catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling -catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly prevented tumour development. Conclusions These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people carrying APC mutations, where colon cancer remains a leading cause of death.
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