Wnt-signaling and senescence: A tug of war in early neoplasia?

Abstract

Studies of early neoplasia have revealed fundamental molecular pathways that drive tumorigenesis. Despite this progress, synthesis of principles of tumorigenesis that span tissue types has lagged. Such forays into the 'comparative anatomy' of cancer can stimulate new models and refine key questions. We envision commonality of pathways important in formation of two early benign neoplasms that are found in different tissues and which are not generally thought to be similar: dysplastic nevi of the skin and intestinal aberrant crypt foci. We propose that these neoplasms result from an ongoing 'tug of war' between the tumor suppression barrier posed by cellular senescence and the tumor-promoting activity of Wnt-signaling. Whether or not such neoplasms progress to malignancy or persist in a benign state for many years might be largely determined by the outcome of this tug of war and its modulation by other genetic and epigenetic alterations, such as inactivation of p16(INK4a).

Figure 1. The canonical Wnt signaling pathway

Canonical Wnt ligands bind to their cognate transmembrane receptors, comprised of a Frizzled family member and the LRP5/6 co-receptor. Signaling through Dishevelled inhibits GSK3-mediated phosphorylation of b-catenin. Phosphorylation is promoted by two associated proteins, APC and axin. Phosphorylated b-catenin is targeted for degradation. Thus, Wnt ligands act to stabilize the cytoplasmic pool of b-catenin. B-catenin translocates to the cell nucleus where it binds to the TCF family of DNA-binding proteins. This complex activates transcription of genes, including proliferation-promoting genes such as c-jun, cyclin D1 and c-myc. Aqua: activators, red: inhibitors.

Figure 2. A tug-of-war between Wnt signaling and senescence

The red/green bar depicts the hypothetical continuum between a cell harboring an activated oncogene in an irreversible senescent state (green right) and a cell en route to transformation, when that oncogene is combined with other epigenetic and genetic alterations (red left). Benign clonal hyperproliferations, such as nevi and ACF, populate the middle of this continuum. The blue three-way arrows indicate the relative magnitude of senescence-promoting signals and senescence-suppressing Wnt signals, and the consequence of these signals for cell proliferation. When senescence-promoting signals predominate (top), a cell that acquires an activated oncogene will enter a senescent state. Such cells likely have a low risk of giving rise to cancer and generally remain undetected. When senescence-promoting signals are more balanced by senescence-suppressing Wnt signals, a cell will transiently proliferate and undergo clonal expansion to form a visible benign nevus (from a melanocyte) or ACF (from a colonic epithelial cell). Eventually, proliferative expansion will be arrested by senescence, although the tug-of-war between senescence and Wnt-signaling might prevent some cells from becoming irreversibly senescent. Such cells are likely to be at risk of neoplastic transformation, particularly if other genetic and epigenetic alterations accumulate. The greater the senescence-suppressing Wnt signals, the higher the risk of transformation (bottom blue arrows).