Activated Wnt/ß-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model

Abstract

This study demonstrates that in malignant melanoma, elevated levels of nuclear ß-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of ß-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/ß-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear ß-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/ß-catenin signaling.differentiation ͉ prognosis ͉ metastasis ͉ WNT5A ͉ B16 model ͉ microarray M alignant melanoma accounts for Ͻ5% of all skin cancers, yet is responsible for 80% of skin cancer deaths (1). The outlook for patients with metastatic melanoma remains quite bleak, with a 5-year survival rate of only 5%-15% that has not changed significantly over decades despite intensive efforts to develop an effective therapy. Although the molecular mechanisms underlying the formation and progression of melanoma remain unresolved, recent studies have implicated Wnt signal transduction pathways in melanoma biology (2), raising the question of whether this insight can be used to develop a therapy.

MicroRNA-146a Suppresses Metastatic Activity in Brain Metastasis

“…Moreover, its target genes are used in the prognosis and disease-free survival of cancer patients (Giles et al, 2003). In contrast to earlier reports, β-catenin was associated with good prognosis and increased overall survival (Chien et al, 2009;Gould Rothberg et al, 2009) and its reduced expression was linked to cancer progression including metastasis in melanoma (Maelandsmo et al, 2003). In this regard, Arozarena et al (2011) recently reported that MITF, a melanoma-specific protein, opposes the function of β-catenin in melanoma.…”

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

“…However, recent studies have suggested that canonical WNT/β-catenin signaling can also elicit tumor-suppressive effects within a subset of cancers. For example, activation of WNT/β-catenin signaling suppressed melanoma tumor cell growth in mouse xenografts and was associated with increased survival in a subset of medulloblastoma, prostate, and ovarian cancers (8,27). Moreover, WNT/β-catenin activation also induces differentiation of melanoma and glioblastoma cells in vitro (8,28).…”

“…For example, activation of WNT/β-catenin signaling suppressed melanoma tumor cell growth in mouse xenografts and was associated with increased survival in a subset of medulloblastoma, prostate, and ovarian cancers (8,27). Moreover, WNT/β-catenin activation also induces differentiation of melanoma and glioblastoma cells in vitro (8,28). In ERMS, APC mutation and nuclear β-catenin localization are rather uncommon, suggesting that this pathway is inactive in most ERMS (29).…”

“…For example, acute promyelocytic leukemia (APL) was nearly universally lethal before the introduction of all-trans-retinoic acid-induced differentiation therapy, which now has cure rates approximating 80% (6). Differentiation therapy in solid tumors has garnered renewed interest over the past decade (7)(8)(9)(10), yet description of these approaches in sarcomas is only now being appreciated. In two studies, peroxisome proliferator-activated receptor γ agonists were able to induce differentiation in a subset of patients with liposarcoma and myxoid liposarcoma, respectively (11,12), suggesting that differentiation therapy will be possible in sarcoma.…”

Suppression of Casein Kinase 1α in Melanoma Cells Induces a Switch in β-Catenin Signaling to Promote Metastasis

“…In malignant melanoma, there are contradictory results about the role of β-catenin in tumor progression. Whereas several studies propose that an increased nuclear translocation and activity of β-catenin in melanoma cells promote tumor proliferation (23,24), others found recently that elevated levels of nuclear β-catenin correlate with improved survival from melanoma (25) and that β-catenin downregulation promotes metastasis formation in mice (26). Surprisingly, very little is known about the factors regulating nuclear translocation and activity of β-catenin in melanoma cells.…”