Distinct populations of tumor-initiating cells

Distinct populations of tumor-initiating cells derived from a tumor generated by rat mammary cancer stem cells by Ileana Zucchi and 13 co-authors, including Benjamin G Neel and Renato Dulbecco, Proc Natl Acad Sci USA 2008(Nov 4); 105(44): 16940–45, published ahead of print October 28, 2008. This is an Open Access Article [PDF]. PubMed Abstract:

Tumors derived from rat LA7 cancer stem cells (CSCs) contain a hierarchy of cells with different capacities to generate self-renewing spheres and tubules serially ex vivo and to evoke tumors in vivo. We isolated two morphologically distinct cell types with distinct tumorigenic potential from LA7-evoked tumors: cells with polygonal morphology that are characterized by expression of p21/(WAF1) and p63 and display hallmarks of CSCs and elongated epithelial cells, which generate tumors with far less heterogeneity than LA7 CSCs. Serial transplantation of elongated epithelial cells results in progressive loss of tumorigenic potential; tumor heterogeneity; CD44, E-cadherin, and epithelial cytokeratin expression and increased alpha-smooth muscle actin I and vimentin expression. In contrast, serial transplantation of LA7 CSCs can be performed indefinitely and results in tumors that maintain their heterogeneity, consistent with self-renewal and multilineage differentiation potential. Collectively, our data show that polygonal cells are CSCs, whereas epithelial elongated cells are lineage-committed progenitors with tumorigenic potential, and suggest that tumor progenitors, although lacking indefinite self-renewal potential, nevertheless may make a substantial contribution to tumor development. Because LA7 cells can switch between conditions that favor maintenance of pure CSCs vs. differentiation into other tumor cell types, this cell system provides the opportunity to study factors that influence CSC self-renewal and differentiation. One factor, p63, was identified as a key gene regulating the transition between CSCs and early progenitor cells.

CD133+ cells within osteosarcoma cell lines

Detection and characterization of CD133+ cancer stem cells in human solid tumours by Virginia Tirino and 8 co-authors, including Gianpaolo Papaccio, PLoS ONE 2008(Oct 21); 3(10): e3469. PubMed Abstract:

BACKGROUND: Osteosarcoma is the most common primary tumour of bone. Solid tumours are made of heterogeneous cell populations, which display different goals and roles in tumour economy. A rather small cell subset can hold or acquire stem potentials, gaining aggressiveness and increasing expectancy of recurrence. The CD133 antigen is a pentaspan membrane glycoprotein, which has been proposed as a cancer stem cell marker, since it has been previously demonstrated to be capable of identifying a cancer initiating subpopulation in brain, colon, melanoma and other solid tumours. Therefore, our aim was to observe the possible presence of cells expressing the CD133 antigen within solid tumour cell lines of osteosarcoma and, then, understand their biological characteristics and performances. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, using SAOS2, MG63 and U2OS, three human sarcoma cell lines isolated from young Caucasian subjects, we were able to identify and characterize, among them, CD133+ cells showing the following features: high proliferation rate, cell cycle detection in a G2\M phase, positivity for Ki-67, and expression of ABCG2 transporters. In addition, at the FACS, we were able to observe the CD133+ cell fraction showing side population profile and forming sphere-clusters in serum-free medium with a high clonogenic efficiency. CONCLUSIONS: Taken together, our findings lead to the thought that we can assume that we have identified, for the first time, CD133+ cells within osteosarcoma cell lines, showing many features of cancer stem cells. This can be of rather interest in order to design new therapies against the bone cancer.

The full text of this article is openly accessible.

Single-cell cloning of colon cancer stem cells

Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity by Louis Vermeulen and 8 co-authors, including Jan Paul Medema, Proc Natl Acad Sci USA 2008( Sep 9);105(36): 13427-32. PubMed Abstract:

Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.

Two articles about brain tumor initiating cells

Hedgehog signaling regulates brain tumor initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas by Qijin Xu, Xiangpeng Yuan, Gentao Liu, Keith L Black, John S Yu, Stem Cells 2008(Sep 11) [Epub ahead of print][PubMed Citation].

SOX2 silencing in glioblastoma tumor initiating cells causes stop of proliferation and loss of tumorigenicity by Rosaria Maria Rita Gangemi and 9 co-authors, including Giorgio Corte, Stem Cells 2008(Oct 23) [Epub ahead of print][PubMed Citation].

Neither of these articles is openly accessible.

UK/CIRM collaboration agreement

State, United Kingdom team for stem cell work by Bernadette Tansey, SFGate, October 21, 2008. Excerpts:

California's stem cell funding institute is teaming up with its United Kingdom counterpart to support research collaborations between scientists, the two government agencies said Monday.

.....

Under the new agreement, teams that include United Kingdom and California scientists will be able to file joint grant applications to the state's stem cell funding institute and the United Kingdom's Medical Research Council. For teams that win grants, the California institute will fund the work of the California members and the research council will pay for the research conducted in the United Kingdom.

.....

The state stem cell funding institute announced similar agreements in June with the Australian state of Victoria and Canada's Cancer Stem Cell Consortium. Victoria pledged $100 million to the effort.

Found via: UK, CIRM ink collaboration agreement by David Jensen, California Stem Cell Report, October 22, 2008.

See also: UK and California agree to collaborate on stem cell research by Monya Baker, The Niche, October 21, 2008. The first two paragraphs:

California’s stem cell funding agency signed a memorandum of understanding with the United Kingdom, expediting collaborations between scientists in the two locations.

Robert Klein, chair of the California Institute of Stem Cell Research and Lord Paul Drayson, UK’s Minister for Science, met in the San Francisco airport to sign the four-page document.

CIRM/CSCC Joint Announcement: Disease Teams Awards

The Cancer Stem Cell Consortium and the California Institute for Regenerative Medicine Announce Plans to Collaborate on Disease Team Awards, News & Media, Cancer Stem Cell Consortium.

At the BIO 2008 Conference in June, the Canadian Minister of Health, the Honourable Tony Clement, and the Governor of the State of California, Arnold Schwarzenegger announced a partnership between Canada's Cancer Stem Cell Consortium (CSCC) and the California Institute for Regenerative Medicine (CIRM) for international collaboration to advance cancer stem cell research.

It is proposed that one of the first initiatives to be launched by the CSCC will be a collaboration between Canadian and Californian scientists through CIRM's upcoming Disease Team Research Awards Competition, which will support multi-disciplinary teams of scientists in pursuit of therapies for specific diseases. The goal is to fund the work of Disease Teams that would result in a cell based therapy or a therapy derived from stem cell assays for a particular disease or serious injury. It is anticipated that the RFA for the Disease Team Research Awards will be issued by CIRM in February 2009 with funding announced before the end of the year. Successful proposals will include a description of milestones on a path to an Investigational New Drug filing at the end of the four-to-five year grant.

CIRM and the CSCC have been working to finalize the details of the collaboration, with approval to be requested later this year from their respective governing bodies. In advance of the formal approval and announcement, the organizations wish to alert the Canadian and Californian scientific communities of this potential opportunity and to encourage teams of Canadian and Californian scientists to initiate activities towards the development of Disease Teams focusing on cancer stem cells. Successful projects, co-led by Canadian and California scientists, will be co-funded by the CSCC and CIRM, with Canadian scientists funded by the CSCC and Californian scientists funded by CIRM. Support for Canadian scientists will primarily be for operating funds and will not include support for major infrastructure or facilities.

Canadian scientists proposing to collaborate with Californian colleagues in a joint Disease Team application must register with the CSCC as soon as possible and no later than November 17, 2008. Applications for funding will be reviewed by CIRM's Grants Working Group as part of the Disease Team Research Awards Competition.

To register to submit an application please contact:
Cindy L. Bell, Ph.D.
Interim Executive Director
Cancer Stem Cell Consortium
http://www.cancerstemcellconsortium.ca
Phone: 613-751-4460 ext 118
cbell@genomecanada.ca

Making an anti-leukemia drug better

Making an Anti-leukemia Drug Better, Ivanhoe's Medical Breakthroughs, October 21, 2008. The first sentence:

A recent discovery suggests the best way to treat leukemia may be to rely on a combination of targeted drugs rather than a single miracle drug.

The drug is imatinib.

The news item is based on: AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells by Liang L Zhou and 9 co-authors, including Xiaoyan Jiang, J Exp Med 2008(Oct 20): jem.20072316. [Epub ahead of print]. PubMed Abstract:

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin(-)CD34(+) human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL-inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2-STAT5. Moreover, we identified an AHI-1-BCR-ABL-JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.

See also: Giving imatinib a hand, Amy Maxmen, J Exp Med 2008(Oct 20): jem.20511iti5