The X Factor
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RESEARCH HIGHLIGHTS ANGIOGENESIS BREAST CANCER Showing the way home The X factor within the tumour parenchyma near to blood vessels, implying that the Recent research from the groups cells migrated out of the vessel into of David Livingston and Shridar the tumour tissue. Ganesan indicates that X chromo- Adhesion proteins, such as some abnormalities might func- integrins, are known to home haemat- tion in the development of both opoietic cells to the bone marrow, so sporadic and familial (BRCA1- could the same mechanism be used to negative) basal-like breast cancer. guide CD34+ cells to neovasculature? Evidence indicates that loss All circulating CD34+ cells expressed selection for of BRCA1 function disrupts the α β significant levels of integrin 4 1. the increased maintenance of the normal inactive When fluorescently labelled CD34+ expression X chromosome — BRCA1-mutant cells were injected with anti-α β anti- cell lines and cancers no longer have 4 1 of a select bodies into nude mice bearing breast markers of a normal inactivated X carcinomas, or into nude mice bearing number of X- chromosome. In addition, a loss of lung carcinomas, no CD34+-cell chromosomal X-inactivation markers has been arrest was seen. Antagonists of other genes is noted in breast cancers that are more integrins did not prevent arrest. likely to fail hormone treatment — a α β likely to be To investigate whether 4 1 characteristic of basal-like cancers promotes the participation of CD34+ a common (BLCs). So, joint first authors cells in blood vessel formation, characteristic Andrea Richardson and Zhigang Varner and colleagues isolated of BLC. Wang asked whether similar X murine bone-marrow-derived pro- chromosome abnormalities were genitor cells, which had previously common in sporadic cases of BLC. Circulating bone-marrow-derived been shown to participate in blood- progenitor cells are known to home vessel formation, from enhanced to actively remodelling tissues, such green fluorescent protein (EGFP) PROSTATE CANCER as a developing tumour. However, the mice. These cells expressed high α β + mechanisms that are involved have levels of integrin 4 1. EGFP cells been unclear. Judy Varner and col- not only homed to tumours but also α β + leagues now report that integrin 4 1 formed EGFP blood vessels at the Switching roles promotes homing of these progenitor tumour periphery — both properties α β cells to the tumour neovasculature, were inhibited by anti- 4 1 antibod- Prostate cancer invariably progresses α β and that the cells also actively partici- ies. In addition, the integrin 4 1 from androgen-dependent to pate in tumour growth. ligands, vascular cell adhesion mol- androgen-independent growth, First, human CD34+ progenitor ecule and fibronectin, were expressed causing resistance to anti-androgen cells were labelled with a fluorescent in tumour endothelium, primarily at therapy. Zhu et al. have now shown that dye and injected into the tail vein of the tumour periphery. infiltrating macrophages contribute to nude mice implanted with mouse This work identifies integrin this process by releasing signals that α β convert selective androgen-receptor breast carcinoma spheroids on mam- 4 1–ligand binding as a key mary fat pads. Real-time intravital mechanism regulating progenitor modulators (SARMs) from antagonists microscopy was used to track the cell homing to target tissues. It also to agonists of the androgen receptor. CD34+ cells and showed that within shows that once at the target site the Nuclear hormone-receptors such as the androgen receptor a few minutes they were circulating cells can differentiate into endothelial bind both their normal in the tumour vasculature and, a few cells. Antagonists of these bone- hormone ligands and various minutes later, they were arresting in marrow-derived progenitors, or of modulators (SARMs in blood vessels at the tumour periph- integrin α β or its ligands, could 4 1 the case of the androgen ery, but not in the tumour centre, form a useful part of anti-angiogenic receptor). The conformation surrounding normal fat pad or tumour therapy. of the receptor is determined uninvolved mouse skin. These results Ezzie Hutchinson both by its interactions with discount non-specific leakage from ligands and modulators, and by tumour vessels because, if that were ORIGINAL RESEARCH PAPER Jin, H. et al. the conformation of the promoter. so, you would expect to find CD34+ A homing mechanism for bone marrow-derived The receptor conformation, in turn, cells in central tumour vessels as well. progenitor cell recruitment to the neovasculature. governs the assembly of regulatory J. Clin. Invest. 116, 652–662 (2006) CD34+ progenitor cells were also seen 256 | APRIL 2006 | VOLUME 6 www.nature.com/reviews/cancer © 2006 Nature Publishing Group RESEARCH HIGHLIGHTS Analysis for markers of X global increase in the level of inactivation in 18 sporadic BLCs X-chromosomal-encoded RNAs. versus 20 high-grade non-basal-like However, gene-expression data IN BRIEF breast cancers demonstrated that indicated that a small subset of X- most (15 of 18) of the BLCs no chromosomal genes were overex- MELANOMA longer had a normal inactivated pressed, and further investigations UV causation of melanoma in Xiphophorus is X chromosome, whereas only 2 of led the authors to conclude that dominated by melanin photosensitized oxidant the 20 non-BLCs demonstrated selection for the increased expression production this loss. Furthermore, 4 familial of a select number of X-chromo- BRCA1–/– breast cancers also somal genes is likely to be a common Wood, S. R. et al. Proc. Natl Acad. Sci. USA 103, 4111–4115 (2006) demonstrated a loss of markers of characteristic of BLC. The wavelengths of sunlight that cause melanoma in humans, X inactivation. Surprisingly, almost BLC represents a highly aggres- and the mechanisms by which they function, remain unknown. Graham Timmins and colleagues show that the spectrum of all of the sporadic BLCs tested were sive form of breast cancer that wavelengths that cause melanoma in the Xiphophorus fish wild-type for BRCA1 and expressed often fails conventional treatment. strongly correlates with the spectrum that causes reactive- a functional, nuclear-localized Although mechanistically there melanin-radical formation. This indicates that melanin oxidation protein. Therefore, loss of BRCA1 is still much to learn about the by light has a central role in causing melanoma and might cannot explain the inactivated-X- X-chromosome abnormalities provide a surrogate approach to studying melanoma causation chromosome abnormalities in these that are present in human BLC, in humans. sporadic tumours. understanding these pathogenic HYPOXIA Further characterization of the mechanisms might provide new sporadic BLC and BRCA1–/– cases therapeutic treatments for both Hypoxia-induced energy stress regulates mRNA indicated that these tumours have sporadic and familial BLC. translation and cell growth X-chromosome changes that prob- Nicola McCarthy Liu, L. et al. Mol. Cell 21, 521–531 (2006) ably lead to increased amounts of Hypoxia is an innate feature of solid tumour biology. Liu et al. non-silenced X-chromosomal DNA. ORIGINAL RESEARCH PAPER Richardson, A. L. demonstrate that hypoxia downregulates protein synthesis So, do these tumours arise because of et al. X chromosomal abnormalities in basal-like through several pathways. Hypoxia-induced energy starvation an increased expression of proteins human breast cancer. Cancer Cell 9, 121–132 activates the AMP-protein kinase (AMPK)–tuberous sclerosis (2006) complex 2 (TSC2)–RHEB–mammalian target of rapamycin (mTOR) whose genes are normally silenced FURTHER READING Turner, N., Tutt, A. & pathway, inhibiting mTOR and its effectors that promote mRNA on the inactivated X chromosome? Ashworth, A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nature Rev. Cancer 4, 814–819 (2004) translation. Mutation of TSC2 disrupts this pathway, conferring RNA analyses demonstrated no a growth advantage on hypoxic cells. Hypoxia also inhibits two other key regulators of mRNA translation: eEF2 (through AMPK activation) and eIFα (through endoplasmic-reticulum stress). factors on promoters, thereby affecting then showed that TAB2 binds to a ONCOGENES the transcriptional output and whether conserved domain in the N-terminus there is hormone-induced growth. The of the androgen receptor. The authors c-Myb is an essential target for homeobox mediated negative effect of SARMs is dependent propose that IL-1β activates MEKK1, transformation of hematopoietic cells on the nuclear receptor co-repressor which can then be recruited to the Hess, J. et al. Blood 28 Feb 2006 (doi:10.1182/blood-2005-12-5014) (NCOR) complex, which binds the NCOR complex by TAB2. This causes HOXA genes in combination with MEIS1 are leukaemogenic, N-terminal of the receptor when the dismissal of the complex so that but the mechanism that underlies their transforming function the receptor is in its SARM-induced SARMs no longer have an antagonistic is unclear. Robert Slany and colleagues present evidence conformation. effect on the receptor; instead, they that Myb is an essential, but not sufficient, target for HOXA9/ The authors observed that cause activation. MEIS1-mediated transformation of haematopoietic cells. Myb macrophages were associated with Now that the mechanistic basis of expression is upregulated in response to Hoxa9 and Meis1 nearly all of the cancerous regions androgen-independent growth is overexpression in primary haematopoietic cells. Furthermore, of prostate samples.