Generation of "CSC"

Human Adult Stem Cells as the Target Cells for the Initiation of Carcinogenesis and for the Generation of "Cancer Stem Cells" by James E Trosko, International Journal of Stem Cells 2008(Nov); 1(1): 8-26 [PDF]. Abstract:

The inference to stem cells has been found in ancient myths and the concept of stem cells has existed in the fields of plant biology, developmental biology and embryology for decades. In the field of cancer research, the stem cell theory was one of the earliest hypotheses on the origin of a cancer from a single cell. However, an opposing hypothesis had it that an adult differentiated somatic cell could "de-differentiate" to become a cancer cell. Only within the last decade, via the "cloning" of Dolly, the sheep, did the field of stem cell biology really trigger an exciting revolution in biological research. The isolation of human embryonic stem cells has created a true revolution in the life sciences that has led to the hope that these human stem cells could lead to (a) basic science understanding of gene regulation during differentiation and development; (b) stem cell therapy; (c) gene therapy via stem cells; (d) the use of stem cells for drug discovery; (e) screening for toxic effects of chemicals; and (f) understand the aging and diseases of aging processes.

Comment: A wide-ranging review, in a new journal [ijstemcell.com], by one of the pioneers in studies of radiation-induced damage to the DNA of mammalian cells [example of a 1965 publication]. Some more information about this new journal is available here.

Clonal origins of relapsed ALL

Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia by Charles G Mullighan and 6 co-authors, including James R Downing, Science 2008(Nov 28); 322(5906): 1377-80. PubMed Abstract:

Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 pediatric patients with ALL. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs), with the CNAs acquired at relapse preferentially affecting genes implicated in cell cycle regulation and B cell development. Most relapse samples lacked some of the CNAs present at diagnosis, which suggests that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies revealed that cells corresponding to the relapse clone were often present as minor subpopulations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment, and they point to new targets for therapeutic intervention.

Two advance online CSHSQB articles

1) Role of "Cancer Stem Cells" and Cell Survival in Tumor Development and Maintenance by Jerry Adams and 5 co-authors, including Andreas Strasser, Cold Spring Harb Symp Quant Biol 2008(Nov 6) [Epub ahead of print]. PubMed Abstract:

One critical issue for cancer biology is the nature of the cells that drive the inexorable growth of malignant tumors. Reports that only rare cell populations within human leukemias seeded leukemia in mice stimulated the now widely embraced hypothesis that only such "cancer stem cells" maintain all tumor growth. However, the mouse microenvironment might instead fail to support the dominant human tumor cell populations. Indeed, on syngeneic transplantation of mouse lymphomas and leukemias, we and other investigators have found that a substantial proportion (>10%) of their cells drive tumor growth. Thus, dominant clones rather than rare cancer stem cells appear to sustain many tumors. Another issue is the role of cell survival in tumorigenesis. Because tumor development can be promoted by the overexpression of prosurvival genes such as bcl-2, we are exploring the role of endogenous Bcl-2-like proteins in lymphomagenesis. The absence of endogenous Bcl-2 in mice expressing an Em, u-myc transgene reduced mature B-cell numbers and enhanced their apoptosis, but unexpectedly, lymphoma development was undiminished or even delayed. This suggests that these tumors originate in an earlier cell type, such as the pro-B or pre-B cell, and that the nascent neoplastic clones do not require Bcl-2 but may instead be protected by a Bcl-2 relative.

2) Neural and Cancer Stem Cells in Tumor Suppressor Mouse Models of Malignant Astrocytoma by S Alcantara Llaguno and 3 co-authors, including Luis F Parada, Cold Spring Harb Symp Quant Biol 2008(Nov 6) [Epub ahead of print]. PubMed Abstract:

Malignant astrocytomas are highly invasive brain tumors that portend poor prognosis and dismal survival. Mouse models that genetically resemble the human malignancy provide insight into the nature and pathogenesis of these cancers. We previously reported tumor suppressor mouse models based on conditional inactivation of human astrocytoma-relevant genes p53, Nf1, and Pten. These mice develop, with full penetrance, varying grades of astrocytic malignancy that recapitulate the human condition histologically and molecularly. Our studies indicate a central role for neural stem cells and stem-cell-like cancer cells in tumor initiation and progression. These mouse models thus represent powerful tools for investigating various aspects of tumor development that otherwise cannot be explored in humans. Further studies will provide a better understanding of the biology of these tumors and will hopefully pave the way for more effective therapeutic approaches for these devastating diseases.

2008 Speaker Interviews are freely accessible, but the articles are not.

CSC and chemoradiation resistance

Cancer stem cells and chemoradiation resistance by Hideshi Ishii and 6 co-authors, including Masaki Mori, Cancer Sci 2008(Oct); 99(10): 1871-77. PubMed Abstract:

Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multistepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by antiapoptotic signaling. CSCs mimic normal adult stem cells by demonstrating resistance to toxic injuries and chemoradiation therapy. Moreover, they might be responsible for tumor relapse following apparent beneficial treatments. Compared with hematopoietic malignancies, conventional therapy regimes in solid tumors have improved the overall survival marginally, illustrating the profound impact of treatment resistance. This implies that the present therapies, which follow total elimination of rapidly dividing and differentiated tumor cells, need to be modified to target CSCs that repopulate the tumor. In this review article, we report on recent findings regarding the involvement of CSCs in chemoradiation resistance and provide new insights into their therapeutic implications in cancer.

[SHERPA/RoMEO entry for Cancer Science]

CSC research programs: Sheila K Singh

Sheila K Singh, McMaster Stem Cell and Cancer Research Institute. Excerpt:

Dr. Singh's research program is centred on the study of cancer stem cells. She recently identified an abnormal stem cell that may drive the formation of brain tumours. Using the cell surface protein CD133, Dr. Singh has characterized a rare subpopulation of brain tumour cells that exclusively generate a replica of the patient's tumour and exhibit self-renewal ability in vivo through serial retransplantation.

Her research program will focus on further molecular and genetic characterization of the brain tumour initiating cell (BTIC), and the molecular signalling pathways that are dysregulated in this cell to allow for brain tumorigenesis.

See also: Identification of human brain tumour initiating cells by Sheila K Singh and 8 co-authors, including Peter B Dirks, Nature 2004(Nov 18); 432(7015): 396-401 [PubMed Citation][Google Scholar].

Re articles published in Nature: please note the current NPG author licence policy. Excerpt:

When a manuscript is accepted for publication in an NPG journal, authors are encouraged to submit the author's version of the accepted paper (the unedited manuscript) to PubMedCentral or other appropriate funding body's archive, for public release six months after publication.

Charity event in Australia to support CSC research

Charity Auction: Sydney Harbour Cruise.
Bids close: Nov 26, 2008, 6:55 PM.
In support of cancer stem cell research. Source: Angie Cleone.

Collaboration toward purification and analysis of CSCs

Cyntellect to Collaborate with U of Florida on Cancer Stem Cells, PRNewswire, November 20, 2008. See also: Caitlyn Borst, Press Release, Cyntellect, Inc., November 20, 2008 [PDF]. Excerpt:

Cyntellect, a privately-held lifesciences company leading the development and commercialization of live cell analysis, manipulation and purification systems, announced today that it has entered a research collaboration agreement with the University of Florida Interdisciplinary Center for Biotechnology Research. The agreement will focuson a variety of research areas including the purification and analysis of cancer stem cells (CSCs), rare cells which are believed to be directly involved in propagating cancers.