Prevention and treatment of colon cancer by peroral administration of HAMLET (human α-lactalbumin made lethal to tumour cells).
BACKGROUND
Most colon cancers start with dysregulated Wnt/β-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human α-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.


METHODS
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/β-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 β-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 β-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling β-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.
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, , Lund, Sweden.
Manoj
M
Puthia
Petter
P
Storm
Aftab
A
Nadeem
Sabrina
S
Hsiung
Catharina
C
Svanborg
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D053208:Kaplan-Meier Estimate; D007768:Lactalbumin / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009829:Oleic Acids / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D047368:Tumor Burden
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005819:Genetic Markers; C506422:HAMLET complex, human; D009829:Oleic Acids; D007768:Lactalbumin
Cancer Prevention; Colonic Adenomas; Colonic Polyps; Colorectal Cancer