Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers1. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding β-catenin)1,2,3 or AXIN2 (encoding axin-2, also known as conductin)4. These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free β-catenin in the nucleus1,2,3. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer5. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development6,7,8,9,10. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.

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Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, and treatment of solid tumor stem cells.

Compositions and methods for treating and diagnosing cancer

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

/pdf/can-we-safely-target-the-wnt-pathway-1zo5ueh28x.pdf

Can we safely target the WNT pathway

Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Here we provide an overview of the promise and pitfalls of current drug development strategies striving to inhibit the Wnt pathway and present new opportunities for therapeutic intervention.

Mining the Wnt pathway for cancer therapeutics

Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease.

This application relates to proteins involved in the Wnt/frizzled signaling pathway. More specifically, it involves the role of these proteins in proliferative disorders.

Wnt and frizzled receptors as targets for immunotherapy in head and neck squamous cell carcinomas

Les diverses paires de recepteurs-ligands des familles Wnt et frizzled (Fzd) jouent un role important au cours du developpement embryonnaire, et peuvent donc etre surexprimees dans des cancers ayant pour origine des cellules immatures. Des etudes ont ete effectuees sur les niveaux d'ARNm et les niveaux d'expression de 5 genes Wnt (Wnt-1, 5a, 7a, 10b, 13) et 2 genes Fzd (Fzd-2, 5) presents dans 10 lignees cellulaires d'un carcinome spinocellulaire cervico-facial (HNSCC). De plus, des anticorps anti-Wnt-1 ont ete utilises pour etudier la voie de signalisation de Wnt/Fzd. Les resultats de ces etudes indiquent que les lignees cellulaires HNSCC surexpriment un ou plusieurs genes Wnt et Fzd, et le developpement et la survie d'une sous-population de HNSCC peut dependre de la voie Wnt/Fzd. Par consequent, les recepteurs Wnt et Fzd peuvent etre utilises comme cibles dans une immunotherapie contre ce cancer courant.

Sen Malini

Papers

Wnt and frizzled receptors as targets for immunotherapy in head and neck squamous cell carcinomas

Recepteurs wnt et frizzled utilises comme cibles en immunotherapie contre un carcinome spinocellulaire cervico-facial

Wnt und frizzled-rezeptoren als targets für die immuntherapie bei kopf-hals-plattenepithelkarzinomen