In addition to changes in the Rho isoforms all

In addition to changes in the Rho isoforms, all Rac isoforms, including the constitutively active splice variant of Rac1, Rac1b, are overexpressed in various tumors and accumulating evidence indicates that they play an important role in the metastatic potential of cancer Celecoxib (Chan et al., 2005, Fritz et al., 1999, Jordan et al., 1999, Orgaz et al., 2014, Zhou et al., 2013). Similarly, overexpression of Cdc42 occurs in several human tumors (Fritz et al., 1999, Orgaz et al., 2014). Cdc42 is involved in activation of signaling that regulates cell polarity, cytoskeletal remodeling, cell migration, and cell proliferation, and as such, Cdc42 can be regarded as pro-oncogenic (Stengel & Zheng, 2011). Nonetheless, this does not appear to be the case in the pediatric tumor neuroblastoma, where overexpression of N-Myc, an important inverse prognostic marker, is associated with a deletion of the chromosomal region that contains the Cdc42 gene, resulting in a reduction in Cdc42 expression (Valentijn et al., 2005). In neuroblastoma cells, expression of active Cdc42 is required for differentiation, suggesting that Cdc42 likely functions as a tumor suppressor in neuroblastoma. However, on the contrary, there are also indications that expression of Cdc42 correlates with undifferentiated neuroblastoma (Lee, Craig, Romain, Qiao, & Chung, 2014). Thus, the exact role of Cdc42 in tumor progression appears, at least for neuroblastoma, to be complicated and context dependent. In a similar fashion as with the Rho isoforms, deregulation of Rac and Cdc42 occurs primarily at the level of activation. Examples of a deregulated Rac and Cdc42 GEF activity in cancers include the GEFs Tiam1, Vav2 and Trio, of which overexpression correlates with poor prognosis and enhanced metastatic behavior (Chen et al., 2012, Menacho-Marquez et al., 2013, Patel et al., 2007, Schmidt and Debant, 2014). The kinase effectors of Rac and Cdc42 belong to the P21-activated kinase (PAK) family, which are often overexpressed in tumors and are inversely correlated with survival (Chow et al., 2012, Radu et al., 2014). For example, PAK1 exhibits overexpression or hyperactivation in 50% of breast tumors (Ong et al., 2011) while it is overexpressed in invasive prostate cancer cells compared to noninvasive cells (Goc et al., 2013).
Rho protein networks in epithelial-to-mesenchymal transition For carcinoma cells to metastasize, the transformed cells need to lose their cell-cell contacts and adopt a more motile, migratory phenotype, a process commonly known as EMT. Normal epithelial cells are organized as two-dimensional layers with close contacts with neighboring cells and an apicobasal polarity axis. During EMT, epithelial cells lose their cell-cell adhesion complexes, rearrange their cytoskeleton and lose their apicobasal polarity. Actin dynamics during EMT are regulated by Rho proteins and the conversion from apicobasal polarity to front-rear polarity also involves Rho proteins. EMT is a key mechanism during normal development of organs and tissues, but over the past decade, the occurrence of EMT has become a well-documented event during tumor progression (Thiery, Acloque, Huang, & Nieto, 2009). Elucidating the exact molecular signature that drives this behavior is key to developing new therapeutic strategies to target EMT in cancer. During embryogenesis, tumors such as neuroblastoma develop from the neural crest; an ectodermal cell population consisting of multipotent stem cells (Fort & Theveneau, 2014). In the neural crest of Xenopus, depletion of RhoV (an atypical Rho protein closely related to Rac and Cdc42) inhibits expression of EMT regulatory transcription factors, whereas overexpression of RhoV enhances the expression of such factors (Guemar et al., 2007). Similarly, inhibition of Rac1 or PAK1 inhibition results in an almost complete repression of EMT transcription factors in Xenopus (Bisson, Wedlich, & Moss, 2012), indicating that RhoV, Rac1, Cdc42, and their downstream effector PAK1, are required for EMT during development of the neural crest.