Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells

Correct spatio-temporal regulation of Wnt5a signaling is required for normal developmental morphogenesis, and defects in this pathway are linked to tumorigenesis. The precise role of Wnt5a signaling in cancer has, however, been a matter of controversy. Loss of Wnt5a signaling is related to development of lymphoid malignancies, whereas constitutively active Wnt5a signaling is involved in invasion or metastasis of several cancers. Interestingly, recent studies in Drosophila and mouse have revealed that disrupted cell polarity might contribute to invasion/metastasis of cancers. Wnt5a activates the planar cell polarity (PCP) pathway, partly through the receptor tyrosine kinase Ror2. Here, we review developments in our understanding of the molecular mechanisms underlying Wnt5a signaling, with an emphasis on the role of Ror2 in cancer. We also propose a model where the outcomes of normal and aberrant Wnt5a/Ror2 signaling depend on cell/tissue-tropic contexts.