Portal de Periódicos da CAPES

Connecting Cancer to the Asymmetric Division of Stem Cells

2006; Cell Press; Volume: 124; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2006.03.004

1097-4172

Andreas Wodarz, Cayetano González,

Microtubule and mitosis dynamics

Two studies, one in this issue of Cell (Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar) and the other in Developmental Cell (Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar) show that the cell-fate determinant Brain Tumor (Brat) suppresses self-renewal in one of the daughter cells that arise from the asymmetric division of a neural stem cell. This work suggests a mechanism by which loss of polarity in stem cells may lead to tumorigenesis. Two studies, one in this issue of Cell (Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar) and the other in Developmental Cell (Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar) show that the cell-fate determinant Brain Tumor (Brat) suppresses self-renewal in one of the daughter cells that arise from the asymmetric division of a neural stem cell. This work suggests a mechanism by which loss of polarity in stem cells may lead to tumorigenesis. Nearly forty years ago, two years before the term "tumor suppressor" was coined, work in the fruit fly Drosophila provided the first example of a gene (lethal giant larvae, l(2)gl), whose loss of function resulted in tumor formation (Bilder, 2004Bilder D. Genes Dev. 2004; 18: 1909-1925Crossref PubMed Scopus (463) Google Scholar). Since then, the depth and scope of research in this field has established Drosophila as an excellent model organism for the comprehensive analysis of tumorigenesis. By now, dozens of genes have been identified whose inactivation produces tumors in a wide range of different tissues, including the imaginal discs, brain, hemolymph, and gonads. The grade of these tumors ranges from benign hyperplasias to malignant neoplasms. Among the best examples of the latter are the invasive neuroblastomas that are induced by mutations in disc large (dlg), scribble (scrib), l(2)gl, and brat. dlg, scrib, and l(2)gl are also required to maintain polarity in different cell types, including neuroblasts, the stem cells that give rise to the neoplasms that form in loss-of-function mutants for all three genes (Gateff, 1994Gateff E. Int. J. Dev. Biol. 1994; 38: 565-590PubMed Google Scholar, Bilder, 2004Bilder D. Genes Dev. 2004; 18: 1909-1925Crossref PubMed Scopus (463) Google Scholar). Therefore, as in mammalian epithelia, tumor progression and loss of polarity are highly correlated events in Drosophila neuroblastomas. Neuroblasts are polarized along their apical-basal axis. During mitosis, various mRNAs and proteins segregate to either the apical or the basal cytocortex (Figure 1) . After cytokinesis, apical proteins stay in the larger daughter and basal proteins end up in the smaller daughter, thus mediating the different fates of the two sisters: the larger daughter remains a neuroblast and retains the properties of a stem cell, whereas the smaller daughter is a so-called ganglion mother cell (GMC) that will divide one more time to generate a pair of neurons or glial cells (Wodarz and Huttner, 2003Wodarz A. Huttner W.B. Mech. Dev. 2003; 120: 1297-1309Crossref PubMed Scopus (145) Google Scholar). Recent work has shown that failure to express or to localize some of the basal proteins can trigger neoplastic transformation in Drosophila neuroblasts, thus establishing a causal relationship between compromised inheritance of cell-fate determinants and unrestrained growth of the mutant neuroblast lineage (Caussinus and Gonzalez, 2005Caussinus E. Gonzalez C. Nat. Genet. 2005; 37: 1125-1129Crossref PubMed Scopus (341) Google Scholar). Moreover, the ectopic expression of a constitutively active form of atypical protein kinase C (aPKC), an apically localized protein, leads to an increase in the number of brain neuroblasts, indicating that aPKC may promote self-renewal and inhibit neuronal differentiation (Lee et al., 2006bLee C.Y. Robinson K.J. Doe C.Q. Nature. 2006; 439: 594-598Crossref PubMed Scopus (252) Google Scholar). Which molecular mechanisms connect cell fate and the control of cell proliferation? This key question lies at the heart of understanding how loss of stem cell polarity may lead to cancer. A paper in this issue of Cell (Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar) and a related paper in Developmental Cell (Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar) provide an answer. They show that the tumor-suppressor protein Brat serves as a cell-fate determinant that segregates asymmetrically into the smaller daughter, the GMC. Two independent experimental approaches have revealed this new function of Brat. Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar identified a new mutant brat allele in a genetic screen for mutations that affect the number of neuroblasts in the central brain of Drosophila larvae. Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar isolated Brat as a binding partner of the Miranda (Mira) protein, which in neuroblasts functions as a cortical adaptor for the cell-fate determinant Prospero (Pros; Wodarz and Huttner, 2003Wodarz A. Huttner W.B. Mech. Dev. 2003; 120: 1297-1309Crossref PubMed Scopus (145) Google Scholar). Both papers show that Brat binds to the cargo binding domain of Mira and colocalizes with Mira at the basal cortex of dividing neuroblasts. The analysis of Brat localization in mira and pros mutants revealed that Mira is required for Brat localization whereas Pros is dispensable, consistent with Brat being a cargo of Mira. Loss of brat function leads to mild defects in the CNS during embryogenesis (Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar) but results in a dramatic increase in the number of neuroblasts in the larval brain and the concomitant loss of differentiated neurons (Gateff, 1994Gateff E. Int. J. Dev. Biol. 1994; 38: 565-590PubMed Google Scholar, Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar, Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar). Similar observations were made in the larval brains of flies bearing a pros loss-of-function mutation and in flies with loss of function mutations in genes that are required for proper segregation of Pros and Brat into the GMC (such as mira, l(2)gl, and partner of inscuteable [pins]; Caussinus and Gonzalez, 2005Caussinus E. Gonzalez C. Nat. Genet. 2005; 37: 1125-1129Crossref PubMed Scopus (341) Google Scholar, Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar, Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar). How could Pros and Brat exert their function in the GMC? Pros is a homeobox transcription factor that acts either as an activator or as a repressor of target-gene transcription, depending on the context. Consistent with the occurrence of supernumerary cell divisions, key cell cycle regulators like cyclin A, cyclin E, and string (cdc25) are among the target genes that are derepressed in pros mutants (Li and Vaessin, 2000Li L. Vaessin H. Genes Dev. 2000; 14: 147-151PubMed Google Scholar). In contrast, Brat has been shown to interact with RNA binding proteins by direct protein-protein interactions and to repress translation of specific mRNAs (Sonoda and Wharton, 2001Sonoda J. Wharton R.P. Genes Dev. 2001; 15: 762-773Crossref PubMed Scopus (264) Google Scholar). Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar now have found that one of the proteins downregulated by Brat in wild-type neuroblasts is the transcription factor Myc. Among the targets of Myc are many genes that are involved in the RNA-polymerase I-dependent transcription of rRNA and ribosome biosynthesis (Grewal et al., 2005Grewal S.S. Li L. Orian A. Eisenman R.N. Edgar B.A. Nat. Cell Biol. 2005; 7: 295-302Crossref PubMed Scopus (304) Google Scholar). In fact, overexpression of Myc leads to enlarged nucleoli and increased protein synthesis, which causes an increase in cell size (Grewal et al., 2005Grewal S.S. Li L. Orian A. Eisenman R.N. Edgar B.A. Nat. Cell Biol. 2005; 7: 295-302Crossref PubMed Scopus (304) Google Scholar). Consistent with these findings, brat mutant cells also have enlarged nucleoli (Frank et al., 2002Frank D.J. Edgar B.A. Roth M.B. Development. 2002; 129: 399-407PubMed Google Scholar, Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar), and there is evidence that GMCs in brat mutants increase in size and convert to ectopic neuroblasts (Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar). Together, these findings point to a dual function of the cell-fate determinants Brat and Pros as suppressors of self-renewal in the GMC, which also promote the terminal differentiation of the GMC daughters. This work indicates that compromised inheritance of cell-fate determinants contributes to unrestrained growth of the neuroblast lineage. Are studies in the fruit fly telling us anything relevant with respect to the formation of tumors in man? The hypothesis that some tumors may arise by the transformation of stem cells into cancer stem cells has recently gained much attention (Reya et al., 2001Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Nature. 2001; 414: 105-111Crossref PubMed Scopus (7878) Google Scholar). Stem cells possess an enormous developmental potential and have the unique ability to self-renew. These two features, essential for their normal behavior during development and adult tissue homeostasis, could make stem cells a major threat to the organism if the machinery that keeps them in check becomes defective. Is this a plausible mechanism of tumorigenesis? Exploiting Drosophila neuroblasts as model stem cells, three recent papers have clearly demonstrated that this is indeed the case (Caussinus and Gonzalez, 2005Caussinus E. Gonzalez C. Nat. Genet. 2005; 37: 1125-1129Crossref PubMed Scopus (341) Google Scholar, Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar, Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar). In addition, these papers show that keeping the self-renewal potential of stem cells at bay requires the tight control of the unequal segregation of cell-fate determinants in mitosis, a process that, in all likelihood, is as critical to human stem cells as it is to Drosophila neuroblasts. Furthermore, work in Drosophila has revealed a direct connection between loss of the cell-fate determinants Brat and Pros and the ectopic upregulation of specific target genes that in flies and in humans are known to control the cell cycle (Caussinus and Gonzalez, 2005Caussinus E. Gonzalez C. Nat. Genet. 2005; 37: 1125-1129Crossref PubMed Scopus (341) Google Scholar, Betschinger et al., 2006Betschinger J. Mechtler K. Knoblich J.A. Cell. 2006; (this issue)PubMed Google Scholar, Lee et al., 2006aLee C.-Y. Wilkinson B.D. Siegrist S.E. Wharton R.P. Doe C.Q. Dev. Cell. 2006; https://doi.org/10.1016/j.devcel.2006.01.017Abstract Full Text Full Text PDF Scopus (237) Google Scholar). It remains to be determined whether the human homologs of the Drosophila genes involved in the control of asymmetry and cell fate work in a similar way to prevent the generation of cancer in man. In any case, Drosophila is showing its worth when it comes to modeling fundamental processes that are relevant for understanding human diseases.