The distortion of growth factor signalling is the most important prerequisite in tumour progression. Transforming growth factor-beta (TGFbeta) signalling regulates tumour progression by a tumour cell-autonomous mechanism or through tumour-stroma interaction, and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Such inherent complexity of TGFbeta signalling results in arduous, but promising, assignments for developing therapeutic strategies against malignant tumours. As numerous cellular context-dependent factors tightly maintain the balance of TGFbeta signalling and contribute to the regulation of TGFbeta-induced cell responses, in this Review we discuss how they maintain the balance of TGFbeta signalling and how their collapse leads to tumour progression.

TGFβ signalling: a complex web in cancer progression

Neural stem cells (NSCs) yield both neuronal and glial progeny, but their differentiation potential toward multiple region-specific neuron types remains remarkably poor. In contrast, embryonic stem cell (ESC) progeny readily yield region-specific neuronal fates in response to appropriate developmental signals. Here we demonstrate prospective and clonal isolation of neural rosette cells (termed R-NSCs), a novel NSC type with broad differentiation potential toward CNS and PNS fates and capable of in vivo engraftment. R-NSCs can be derived from human and mouse ESCs or from neural plate stage embryos. While R-NSCs express markers classically associated with NSC fate, we identified a set of genes that specifically mark the R-NSC state. Maintenance of R-NSCs is promoted by activation of SHH and Notch pathways. In the absence of these signals, R-NSCs rapidly lose rosette organization and progress to a more restricted NSC stage. We propose that R-NSCs represent the first characterized NSC stage capable of responding to patterning cues that direct differentiation toward region-specific neuronal fates. In addition, the R-NSC-specific genetic markers presented here offer new tools for harnessing the differentiation potential of human ESCs.

/pdf/human-es-cell-derived-neural-rosettes-reveal-a-functionally-3z8q1jqkcf.pdf

Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage

The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion.

Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.

/pdf/epigenetics-and-cancer-46s3gs8mpv.pdf

Epigenetics and cancer.

Evi-1 encodes a zinc-finger protein that may be involved in leukaemic transformation of haematopoietic cells. Evi-1 has two zinc-finger domains, one with seven repeats of a zinc-finger motif and one with three repeats, and it has characteristics of a transcriptional regulator. Although Evi-1 is thought to be able to promote growth and to block differentiation in some cell types, its biological functions are poorly understood. Here we study the mechanisms that underlie oncogenesis induced by Evi-1 by investigating whether Evi-1 perturbs signalling through transforming growth factor-beta (TGF-beta), one of the most studied growth-regulatory factors, which inhibits proliferation of a wide range of cell types. We show that Evi-1 represses TGF-beta signalling and antagonizes the growth-inhibitory effects of TGF-beta. Two separate regions of Evi-1 are responsible for this repression; one of these regions is the first zinc-finger domain. Through this domain, Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signalling, thereby suppressing the transcriptional activity of Smad3. These results define a new function of Evi-1 as a repressor of signalling through TGF-beta.

The oncoprotein Evi-1 represses TGF-Beta signalling by inhibiting Smad3

Retroviral activation of Evi-1 gene expression is one of the most common transforming events in murine myeloid leukemias. To evaluate the role of the EVI1 gene in human acute myelogenous leukemia (AML), leukemic blasts or cell lines from 116 patients were examined. In eight patients the EVI1 gene was expressed and all but one had cytogenetically detectable translocations of chromosome 3q26 where the EVI1 gene has been localized. To identify breakpoints, a restriction map that spans 1700 kilobases (kb) of the EVI1 locus was developed by pulsed-field gel electrophoresis. In one case, t(3;3)(q21;q26), a rearrangement was localized to 170-330 kb 5' of the gene. In a second case, t(3;3)(q21;q26), there was a rearrangement 13 kb 5' of the gene. This rearrangement was cloned and shown to be due to the fusion of sequences from 3q21-22 with the EVI1 locus. In the third case, ins(3)-(q21q25q27), there was a rearrangement that mapped 150 kb downstream from the 5' end of the gene.

M H Whittaker

Papers

Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26.