Two reviews about oncolytic viruses

1) Oncolytic adenoviruses targeted to cancer stem cells by Joshua J Short and David T Curiel, Mol Cancer Ther 2009(Aug); 8(8): 2096-102 [Epub 2009(Aug 11)][PubMed Citation].

2) Targeting cancer-initiating cells with oncolytic viruses by Timothy P Cripe and 4 co-authors, including Patrick WK Lee, Mol Ther 2009(Aug 11) [Epub ahead of print][PubMed Citation].

[Found via CSC-related articles bookmarked in Connotea].

MicroRNA-181 and liver cancer

Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells by Junfang Ji and 15 co-authors, including Carlo M Croce and Xin Wei Wang, Hepatology 2009(Aug); 50(2): 472-80. [PubMed Abstract][Full text of author manuscript, available in PMC 2009(Aug 5)].

See also: EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features by Taro Yamashita and 15 co-authors, including Xin Wei Wang, Gastroenterology 2009(Mar); 136(3): 1012-24.e4 [Epub 2008(Dec 5)]. [PubMed Abstract].

And: New kids on the block: Diagnostic and prognostic microRNAs in hepatocellular carcinoma by Junfang Ji and Xin Wei Wang, Cancer Biology & Therapy 2009(Sep 15); 8(18) [Forthcoming].

Rak gene helps protect PTEN tumor suppressor

News release: Gene Prevents Destruction of Tumor Suppressor in Breast Cancer, The University of Texas M. D. Anderson Cancer Center, April 6, 2009. Excerpt from the end of the release:

"Recently, we found that Rak can prevent spontaneous DNA damage and has a critical role in suppressing cancer stem cells," he [Shiaw-Yih Lin] said. "So, we will expand our research efforts toward determining how Rak helps to maintain genomic integrity."

Other versions of this news release: Rak gene helps protect tumor suppressor in breast cancer, News-Medical.Net, April 7, 2009; Gene Helps Protect Tumor Suppressor In Breast Cancer, ScienceDaily, April 6, 2009.

The news releases are based on this article: Rak functions as a tumor suppressor by regulating PTEN protein stability and function by Eun-Kyoung Yim and 10 co-authors, including Shiaw-Yih Lin, Cancer Cell 2009(Apr 7); 15(4): 304-14 [PubMed Citation][Full text].

Inhibitory effects of omacetaxine on leukemic stem cells

Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice, by Yaoyu Chen and 5 co-authors, including Shaoguang Li, Leukemia 2009(Mar 26) [Epub ahead of print][PubMed Citation]. Examples of related news items:

Data suggesting that omacetaxine can eradicate leukemic stem cells may offer a breakthrough for CML, Physorg.com, March 26, 2009. Excerpt:

Data showing the ability of omacetaxine to kill leukemic stem cells in mouse models with drug-resistant chronic myelogenous leukemia (CML) are the subject of an advance online publication in the journal Leukemia, ChemGenex Pharmaceuticals Limited (ASX:CXS and NASDAQ:CXSP) announced today. The findings of this study provide new insights into the problem of minimal residual disease and may open the door to the development of a curative treatment strategy for some patients with CML. .....

Leukemic stem cell killer ‘omacetaxine’ help rises Chemgenex’s share, Stem Cell Research Blog, March 28, 2009. Excerpt:

ChemGenex Pharmaceuticals announced on March 26th, 2009 through online publication in the journal Leukemia, about the ability of omacetaxine to kill leukemic stem cells in mouse models with drug-resistant chronic myelogenous leukemia (CML). .....

Multipotent stromal cells as a Trojan horse?

Link between cancer stem cells and adult mesenchymal stromal cells: implications for cancer therapy by Christian Jorgensen, Regen Med 2009(Mar);4(2): 149-52 [PubMed Citation][Publicly accessible full text]. First paragraph:

A new concept has emerged in tumor biology suggesting that tumoral growth is derived from cancer stem cells (CSCs) present in the tumor. Moreover, these CSCs share common features with adult stem cells. In parallel, recent works have highlighted interactions between multipotent stromal cells (MSCs) and carcinoma, and the possible use of MSCs in cell-based anticancer therapies. Thus, translational research between fields of stem cells and tumor biology has changed our perception of carcinoma progression. The therapeutic implications are considerable and imply that to eradicate cancer we need to identify and target the CSCs as well as the MSCs that have migrated to the stroma.

Thanks to Alexey Bersenev, via Twitter/cells_nnm.

Neoplastic transformation of intestinal SC

Cancer stem cells: Can mutated stem cells produce tumours? by Nicola McCarthy, Nat Rev Cancer 2009(Feb); 9(2): 74 [full text accessible after free registration]. Last sentence:

Both papers indicate that a single mutation in normal intestinal stem cells can give rise to tumours, as has been suggested. It is interesting that, although LGR5 and PROM1 seem to mark similar stem cells in the small intestine, PROM1 does not mark colonic stem cells, whereas LGR5 does. This illustrates the need to clearly define markers and their limitations if we are to begin to understand the contribution of normal tissue stem cells and cancer stem cells to tumorigenesis.

The two papers referred to are these [neither are publicly accessible]:

1) Crypt stem cells as the cells-of-origin of intestinal cancer by Nick Barker and 9 co-authors, including Hans Clevers, Nature 2008(Dec 17) [Epub ahead of print][PubMed Citation].

2) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation by Liqin Zhu and 9 co-authors, including Richard Gilbertson, Nature 2008(Dec 17) [Epub ahead of print][PubMed Citation].

See also this blog post: Two articles linking normal intestinal SC to CSC, December 18, 2008.

Prognostic potential of CSC analysis in glioblastoma

Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme by Roberto Pallini and 10 co-authors, including Ruggero De Maria, Clin Cancer Res 2008(Dec 15); 14(24): 8205-12. PubMed Abstract:

PURPOSE: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients. EXPERIMENTAL DESIGN: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133(+) and CD133(+)/Ki67(+) cells in patient tumors. RESULTS: In vitro CSC generation and the presence of >/=2% CD133(+) cells in tumor lesions negatively correlated with overall (P = 0.0001 and 0.02, respectively) and progression-free (P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall (P = 0.007) and progression-free (P = 0.001) survival was observed among patients whose tumors contained CD133(+) cells expressing Ki67. Taking into account symptom duration, surgery type, age, O(6)-methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively. CONCLUSIONS: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133(+)/Ki67(+) cells are two considerable prognostic factors of disease progression and poor clinical outcome.

See also: Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme by Maurizio Martini and 5 co-authors, including Luigi Maria Larocca, Int J Cancer 2008(Dec 15); 123(12): 2955-60 [Epub 2008(Sep 3)][PubMed Citation].

[The full text of these articles isn't publicly accessible].

Articles about CSC in Stem Cells journal (Dec 2008)

Articles on CSC in the December 2008 (Vol 26, No 12) issue of the journal Stem Cells:

The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma by Germana Rappa, Oystein Fodstad, Aurelio Lorico, Stem Cells 2008; 26(12): 3008-17 [Epub 2008(Sep 18)][PubMed Citation].

Hedgehog Signaling Regulates Brain Tumor-Initiating Cell Proliferation and Portends Shorter Survival for Patients with PTEN-Coexpressing Glioblastomas by Qijin Xu and 4 co-authors, including John S Yu, Stem Cells 2008; 26(12): 3018-26 [Epub 2008(Sep 11)][PubMed Citation].

Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition by Christine E Eyler and 5 co-authors, including Jeremy N Rich, Stem Cells 2008; 26(12): 3027-36 [Epub 2008(Sep 18)][PubMed Citation].

Quantitative Mass Spectrometry Identifies Drug Targets in Cancer Stem Cell-Containing Side Population by Sebastian CJ Steiniger and 4 co-authors, including Kim D Janda, Stem Cells 2008; 26(12): 3037-46 [Epub 2008(Sep 18)][PubMed Citation].

Human T-Cell Lymphotropic Virus Type 1 Infection of CD34+ Hematopoietic Progenitor Cells Induces Cell Cycle Arrest by Modulation of p21cip1/waf1 and Survivin by Prabal Banerjee and 3 co-authors, including Gerold Feuer, Stem Cells 2008; 26(12): 3047-58 [Epub 2008(Sep 25)][PubMed Citation].

Identification of a Small Subpopulation of Candidate Leukemia-Initiating Cells in the Side Population of Patients with Acute Myeloid Leukemia by Bijan Moshaver and 9 co-authors, including , Gerrit Jan Schuurhuis, Stem Cells 2008; 26(12): 3059-67 [Epub 2008(Oct 2)][PubMed Citation].

OCT4 Spliced Variants Are Differentially Expressed in Human Pluripotent and Nonpluripotent Cells by Yaser Atlasi and 4 co-authors, including Peter W Andrews, Stem Cells 2008; 26(12): 3068-74 [Epub 2008(Sep 11)][PubMed Citation].

[These articles are not publicly accessible, unlike two interviews, with Alan Trounson and Rudolf Jaenisch, in the same issue of Stem Cells].

Two articles linking normal intestinal SC to CSC

1) Crypt stem cells as the cells-of-origin of intestinal cancer by Nick Barker and 9 co-authors, including Owen J Sansom and Hans Clevers, Nature 2008(Dec17) [Epub ahead of print]. Abstract:

Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells[reference 1]. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5+ cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.

See also: Tracking down bowel cancer stem cells by Kat Arney, Science Update Blog, Cancer Research UK, December 17, 2008. Excerpt:

More experiments need to be done before we know for sure whether stem cells play a vital role in human bowel cancer. For now, these results are a promising step in the right direction – and a confirmation that the stem cell theory may well hold true for at least one type of cancer.

If we can understand more about the molecular pathways that control cancer, we can start to design new, more effective ways to prevent and treat the disease.

2) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation by Liqin Zhu and 9 co-authors, including Richard J Gilbertson, Nature 2008(Dec17) [Epub ahead of print]. Abstract:

Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133)[reference 1]. What remains unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear LacZ reporter allele knocked into the Prom1 locus (Prom1^C-L), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1^+/C-L mice containing the Rosa26-YFP reporter allele showed that Prom1⁺ cells are located at the base of crypts in the small intestine, co-express Lgr5 [reference 2], generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Prom1 was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling[references 3, 4, 5]. Activation of endogenous Wnt signalling in Prom1^+/C-L mice containing a Cre-dependent mutant allele of beta-catenin (Ctnnb1^lox(ex3)) resulted in a gross disruption of crypt architecture and a disproportionate expansion of Prom1 cells at the crypt base. Lineage tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1⁺ cells in these mice, only 7% of tumour cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Prom1⁺ tumour cells.

See also: Molecular marker identifies normal stem cells as intestinal tumor source, News Release, St. Jude Children's Research Hospital, December 17, 2008. Excerpt:

Scientists at St. Jude Children’s Research Hospital have answered a central question in cancer biology: whether normal stem cells can give rise to tumors. Stem cells are immature cells that can renew themselves and give rise to mature differentiated cells that compose the range of body tissues. In recent years, researchers have developed evidence that cancers may arise from mutant forms of stem cells.