Epigenetic elements such as microRNA have been shown to regulate stem cell morphogenesis and embryonic development. More recenty, microRNAs have been implicated in cancer-initiating events. In the September 26th online edition of Nature, Ma et al. from the Whitehead Institute at MIT, published their findings on the identification of a unique microRNA, miR-10b, which appears to mediate cancer metastasis. By conducting a genome-wide scan of metastatic breast cancers, the investigators found that miR-10b was highly expressed in 9 out of 18 patients. Comparing the level of expression of miR-10b in breast cancer cells, the researchers found it was expressed 50 times greater in cells from invasive tumors in contrast to cells from non-invasive breast cancers. In mouse footpad implantation experiments, the investigators found that by overexpressing miR-10b in non-invasive breast cancer cells, they were able to convert them into highly metastatic tumor-forming cells. The researchers further noted that the transcription factor, Twist, induces miR-10b expression which subsequently inhibits the translation of mRNA encoding the homeobox D-10 (HoxD10) gene. It was also shown that inhibiting HoxD10 expression upregulates the expression of the pro-metastatic gene, RHOC. In metastatic cells overexpressing miR-10b, the researchers showed that increasing the level of HoxD10 caused these cancer cells to lose their metastatic capacity. The authors also found that increased levels of miR-10b in breast carcinomas correlated with clinical progression.

Investigators from the Univ. of California, San Diego School of Medicine, Y. Cao et al., reported in the September 21st online edition of PNAS their findings on the NFκB signaling pathway in breast and mammary cancer. The study focused on preventing the activation of IκB kinase (IKKα), whose activity is required for cyclin D1 induction and proliferation of the lobuloalveolar epithelial cells. With mouse knock-in experiments of the mutant form of IKKα and exposure to known breast carcinogens, the investigators found that inhibiting IKKα activity retarded tumor development. The experimental data suggested that IKKα mutation not only inhibited tumors from forming, but also prevented carcinoma cells with the ErbB2/Her2 phenotype from self-renewing and forming secondary tumors. The authors concluded that "IKKα is not only a regulator of mammary epithelial proliferation, but is also an important contributor to ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells." It was also noted that IKKα may be a novel target for treating ErbB2-positive breast cancer.

University of Pittsburgh scientists J. B. Pollett et al. reported in the September 9th issue of Stem Cells the results of their study on a proposed mechanism in which muscle-derived stem cells (MDSCs) can become neoplastic as a result of concurrent differentiation signals. The investigators hypothesized that germ-line determination occurs very early during development and that extracellular signaling can alter a cell's fate that can result in oncogenesis. With MDSCs, the researchers found that 25% of the cells committed to an ostegenic lineage concomitantly receiving extrinsic differentiation signals could form tumors if implanted into mice. Similarly, using MDSCs that were committed to a myogenic lineage, it was also observed that 25% of these cells would form tumors if exposed to BMP4 for 4 days prior to implantation. In another set of experiments, it was found that if siRNA to MyoD1 was used to block the MDSCs from induction into the myogenic lineage, it blocked the MDSC transformation. The authors concluded that the "MDSC populations can undergo concomitant signal-induced transformation and that the initial stages of transformation may be due to changes in the balance between the inherent nature of the cell and extrinsic signaling pathways."

In our April 30th post, we noted that scientists from Stanford University had reported on their observations of asymmetric strand segregation of DNA in muscle stem cells. Their experimental results supported the "immortal strand hypothesis" of John Cairns, where older strands of DNA are retained by the self-renewing daughter stem cell following mitosis. Cairns' hypothesis underscores how the harmful effects of mutations during cell division are limited to the newly synthesized strands of DNA which are passed on to the lineage committed daughter cell, thereby reducing the risks of cancer if the terminally differentiated cells carried the mutations. However, researchers from the University of Michigan, M. J. Kiel et al., reported in the August 29th online edition of Nature that in their model system of murine hematopoietic stem cells (HSCs) asymmetric segregation does not occur. The investigators used BrdU injected into newborn mice, mice treated with cyclophosphamide and granulocyte colony-stimulating factor. BrdU labeling of the DNA occurred for 4-10 days followed by 70 days without BrdU. In each group of mice, the researchers found that less than 6% of the HSCs retained the BrdU label and less than 0.5% of all hematopoietic cells retained the label. The investigators concluded that BrdU "had poor specificity and poor sensitivity as an HSC marker. Using other labels such 5-chloro-2-deoxyuridine and 5-iodo-2-deoxyuridine for measuring DNA synthesis in their experiments, the investigators observed that individual HSCs in culture did not undergo asymmetric strand segregation. The authors concluded that the "immortal strand hypothesis" does not appear to be a general property of adult stem cells.