Sunday, November 30, 2008

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 [], 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.

Thursday, November 27, 2008

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.

Monday, November 24, 2008

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.

Friday, November 21, 2008

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.

Thursday, November 20, 2008

c-Myc required for maintenance of glioma CSC

c-Myc is required for maintenance of glioma cancer stem cells by Jialiang Wang and 7 co-authors, including Jeremy N Rich, PLoS ONE 2008(Nov 20); 3(11): e3769. [PMCID: PMC2582454]. Abstract:

Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells.

Methodology/Principal Findings

Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G0/G1 phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice.


These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers.
The full text is openly accessible.

Monday, November 17, 2008

Liver progenitor cell population with CSC phenotype

Expansion of CD133 expressing liver cancer stem cells in liver specific PTEN deleted mice by C Bart Rountree, Wei Ding, Lina He, Bangyan Stiles, Stem Cells 2008(Nov 13). [Epub ahead of print]. PubMed Abstract:
Background: PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a lipid phosphatase that regulates mitogenic signaling pathways, and deficiency of PTEN results in cell proliferation, survival, and malignancy. Murine liver specific Pten deletion models develop liver malignancy by twelve months of age. Using this model, we describe a population of CD133+ liver cancer stem cells isolated during the chronic injury phase of disease progression and before primary carcinoma formation. Methods: We performed immunohistochemistry and flow cytometry isolation using livers from 3 and 6-monthold Pten(loxp/loxp); Alb-Cre+ mice (Mutants) and controls. CD133+CD45- non-parenchymal (NP) cells were analyzed for gene expression profile and protein levels. Single CD133+CD45- oval cells were isolated for clonal expansion and tumor analysis. Cultured and freshly isolated liver CD133+CD45- and CD133-CD45- NP cells were injected into immune-deficient and immune-competent mice. Results: In Mutant mice, the NP fraction increases in CD133+CD45- cells in 3 and 6-month Pten deleted animals compared to controls. Clone lines expanded from single CD133+CD45- cells demonstrated consistent liver progenitor cell phenotype, with bi-lineage gene expression of hepatocyte and cholangiocyte markers. CD133+ cells from expanded clone lines formed robust tumors in immune-deficient and immune-competent mice. Furthermore, freshly isolated CD133+CD45- NP liver cells from six month-old Mutants formed tumors invivo, and CD133-CD45- NP cells did not. Consistent with a cancer stem cell phenotype, CD133+ cells demonstrate resistance to chemotherapy agents compared to CD133- cells. Conclusions: CD133+CD45- non-parenchymal cells from chronic injury Pten(loxp/loxp); Alb-Cre+ mice represent a bi-potent liver progenitor cell population with cancer stem cell phenotype.
The full text of this article is openly accessible [PDF].

Press release from Celprogen Inc.

Celprogen Introduces an in vivo Model for Human Brain Cancer (Human Glioblastoma GBM) for Drug Discovery Applications, Business Wire, November 17, 2008. Excerpt:
Celprogen has established a Drug Discovery program to provide drug efficacy testing services to major Pharmaceutical firms for their potential drugs against Human Glioblastoma. The other in vivo cancer model systems in the pipe line at Celprogen are: breast cancer, prostate cancer, liver cancer, colon cancer, lung cancer and pancreatic cancer that are scheduled to be released as early as the beginning of second quarter 2009. These in vivo cancer model systems are being generated from already established Celprogen’s Cancer Stem Cells.
See also: Celprogen Launches Cancer Stem Cells, Medical News Today, January 25, 2008.

About Celprogen (located in San Pedro, California).

Sunday, November 16, 2008

News release about microRNAs

UCSF team moves in on mechanism in stem cell growth, possibly cancer, News Release, UCSF News Office, November 13, 2008. Excerpt:
In recent years, microRNAs have been implicated in cancer stem cells, cancer metastases, and even in psychological and metabolic diseases.
The news release is about this publication: Embryonic stem cell–specific microRNAs regulate the G1-S transition and promote rapid proliferation by Yangming Wang and 5 co-authors, including Robert Blelloch, Nat Genet 2008(Nov 2) [Epub ahead of print]. [PubMed Citation]. The article isn't freely accessible.

Friday, November 14, 2008

Monday Nov 17 deadline for Disease Team competition

Monday deadline for Canadians on CIRM's big Disease Team round by David Jensen, The California Stem Cell Report, November 12, 2008. Excerpt:
Canadian researchers have an urgent deadline to register for the competition for a piece of possibly as much as $210 million in team-funding in an international effort involving the California stem cell agency.
See also: CIRM/CSCC Joint Announcement: Disease Teams Awards, Cancer Stem Cell News, October 23, 2008.

The link to register for the Disease Team competition is:

Thursday, November 13, 2008

Chemokines in cancer and metastatic progression

The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis by Stefania Gelmini and 4 co-authors, including Elena Lazzeri, J Endocrinol Invest 2008(Sep); 31(9): 809-19 [PDF]. PubMed Abstract:
Chemokines exert their multifunctional role in several physiologic and pathologic processes through interaction with their specific receptors. Much evidence have revealed that metastatic spread tumor cells may use chemokinemediated mechanisms. In particular, an involvement of stromal cell-derived factor-1 (SDF-1) in growth of primary tumors and in metastatic process has been demonstrated. Indeed, it has been suggested that CXCR4 expression by tumor cells, plays a critical role in cell metastasis by a chemotactic gradient to organs expressing the ligand SDF-1. Moreover, CXCR4 overexpression correlated with poor prognosis in many types of cancer. In physiologic condition, SDF-1 also plays an essential role modulating stem cell proliferation, survival, and homing through its canonical receptor CXCR4. Recently, several studies have demonstrated the existence of a small subset of cancer cells which share many characteristics with stem cells and named cancer stem cells (CSC). They constitute a reservoir of self-sustaining cells with the ability to maintain the tumor growth. In particular, most of them express CXCR4 receptor and respond to a chemotactic gradient of its specific ligand SDF-1, suggesting that CSC probably represent a subpopulation capable of initiating metastasis. This review focuses on the role of SDF-1/CXCR4 axis in cancer and in the metastatic progression by tumoral cells, as well as the role of CSC in tumor pathogenesis and in metastatic process. A better understanding of migratory mechanism involving cancer cells and CSC provides a powerful tool for developing novel therapies reducing both local and distant recurrences.

Saturday, November 8, 2008

CD133 is a marker of bioenergetic stress in human glioma

CD133 is a marker of bioenergetic stress in human glioma by Corinne E Griguer and 6 co-authors, including G Yancey Gillespie, PLoS ONE 2008; 3(11): e3655. Epub 2008 Nov 5. PubMed Abstract:
Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.
Excerpts from the Discussion section of the full text (openly accessible):
Figure 7. Tumor progression model
Last paragraph:
We described here that hypoxia and modification of the bioenergetic status of glioma cells govern the regulation of CD133 at post-transcriptional level. Data presented here strongly indicated that changes in the cellular environment that results in alteration of mitochondrial function are responsible for the enhanced up-regulation of CD133 antigen in glioma cells, suggesting that CD133 expression in human glioma cells is not obligatory relative to the stem cell phenotype but rather, reveals the occurrence of a stress response.

Friday, November 7, 2008

ErbB2 induces Notch1 activity and function in breast cancer cells

ErbB2 induces Notch1 activity and function in breast cancer cells by Jaime Lindsay and 18 co-authors, including Richard G Pestell, Clinical and Translational Science 2008(Sep 10); 2(1): 107-115. Abstract:
The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed Notch (Notchfl/fl) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.
At present, the full text of this article is freely accessible.

For examples of news items about this article, see: Breast Cancer - Targeting A Protein Called Cyclin D1 May Block The Expansion Of Cancerous Stem Cells, Medical News Today, November 6, 2008, and, Therapy may block expansion of breast cancer cells, Science Centric, November 6, 2008.

OncoMed press release

OncoMed Pharmaceuticals press release, November 4, 2008 [PDF]. Excerpt:
OncoMed's lead anti-cancer stem cell antibody, OMP-21M18, entered human clinical studies earlier this year with the initiation of a Phase I trial in patients with advanced solid tumors. OMP-21M18 targets a major cancer stem cell pathway, and is a part of OncoMed's collaboration with GlaxoSmithKline. The Phase I clinical trial is designed to evaluate the safety of escalating doses of OMP-21M18 in patients with solid tumors who have received previous treatment. Pharmacokinetics and initial indications of efficacy will also be assessed. OMP-21M18 is the first anti-cancer stem cell antibody against this novel target critical to cancer stem cells growth and development.
For news items about this press release, see, for example: "OncoMed Pharmaceuticals Completes Series B Financing: Lead Cancer Stem Cell Product Candidate Enters Clinical Trials", November 4, 2008 in Yahoo! Finance and The Earth Times. See also: OncoMed raises $93M in add-on funding, Lisa Sibley, Silicon Valley/San Jose Business Journal, November 4, 2008.

Tuesday, November 4, 2008

Browsing the International Cancer Research Portfolio

The Canadian Cancer Research Alliance has joined the International Cancer Research Portfolio (ICRP). Excerpt from the ICRP website: "Cancer research funders from several countries have joined in a partnership to classify their research portfolios in a common manner". The partners in the ICRP currently include major funders in the US, the UK, and Canada.

The database can be searched in various ways. For example, an Advanced Search can be carried out for the exact phrase "cancer stem cells" in the titles and abstracts of awards made in Canada, by all of the participating Canadian funding organizations, in the years 2007-2008, for all types of cancer, all areas of research and all types of projects. The results obtained for this search:
11 Total Awards
Year = 2008; 2007
This exact phrase = cancer stem cells
Country = Canada
Funding Organization = Canada
For 6 these 11 awards, the funding organization was the Canadian Institutes of Health Research (CIHR). For the remaining 5, the funding organization was the National Cancer Institute of Canada (NCIC). (Note that, at present, some organizations in Canada that provide support for cancer-related research, but within a broader mandate, are not participants in the ICRP. These include some members of the Cancer Stem Cell Consortium: The Canada Foundation for Innovation (CFI), Genome Canada and The Stem Cell Network).

An analogous search can be carried out for the exact phrase "cancer stem cells" in the titles and abstracts of awards made in California, by all of the participating US funding organizations, in the years 2007-2008, for all types of cancer, all areas of research and all types of projects. The results obtained:
25 Total Awards
Year = 2008; 2007
State = California
This exact phrase = cancer stem cells
Country = United States
Funding Organization = United States
An analogous search, for awards made by funding organizations in the US, to all states in the US, yielded a total of 89 awards. Of these, those states receiving more than 2 awards were CA (25, see above); MA (13); NY (11); TX (11); MD (6) and PA (4).

An analogous search for awards made by funding agencies in the UK, to all of the UK, yielded a total of 3 awards.

Two publications on colorectal cancer stem cells

1) Colon cancer stem cells: implications for prevention and therapy by Emina H Huang and Max S Wicha, Trends Mol Med 2008(Nov); 14(11): 503-9. Epub 2008 Oct 17. Pubmed Abstract:
The recent identification of colon cancer tumor-initiating cells adds further support to the cancer stem cell hypothesis. Ongoing basic and translational research efforts are aimed at gaining an increased understanding of the biology of these cells, as well as methods of targeting them. In addition, the relationship between colon carcinogenesis and inflammatory conditions, such as longstanding colitis and inherited syndromes, might be linked to the effect of the processes on stem cells in the colon. This review summarizes current literature on colon cancer stem cells and proposes strategies aimed at targeting these cells for colon cancer prevention and therapy.
From the "Summary" section of the full text (not publicly accessible):
The identification of colon cancer tumor-initiating cells provides further support for the cancer stem cell hypothesis. Future therapy will be directed not only at these rare cells themselves but also at the microenvironment that regulates stem cell behavior. Furthermore, because cancers might originate from disregulation of normal stem cell homeostasis, strategies for cancer prevention might also target this cell population.
2) CD44 is of functional importance for colorectal cancer stem cells by Lei Du and 10 co-authors, including Quan Chen, Clin Cancer Res 2008(Nov 1); 14(21), 6751-60. Abstract:
Purpose: Both CD44 and CD133 were reported as putative markers for isolating colorectal cancer stem cells (CSC). It remains to be resolved if both of these markers are of functional importance for colorectal CSC.
Experimental Design: The expression of CD44 and CD133 in normal colonic tissues and primary colorectal cancer was assessed by immunohistochemistry in a series of 60 patients on tissue microarray sections. Both in vitro clonogenic and in vivo tumorigenic assay were applied to measure CSC activities from the cells isolated from patients. Lentiviral RNA interference was used to stably knock down CD44 or CD133 in colorectal cancer cells from patients.
Results: We found that CD44+ cells displayed clustered growth and they did not colocalize with CD133+ cells within colorectal cancer. As few as 100 CD44+ cells from a patients' tumor initiated a xenograft tumor in vivo. A single CD44+ cell from a tumor could form a sphere in vitro which has characteristic stem cell properties and was able to generate a xenograft tumor resembling the properties of the primary tumor. Knockdown of CD44, but not CD133, strongly prevented clonal formation and inhibited tumorigenicity in xenograft model.
Conclusions: These results indicate that CD44 is a robust marker and is of functional importance for colorectal CSC for cancer initiation.
From the "Translational Relevance" section of the full text (not publicly accessible):
Cancer stem cells (CSC) represent an exciting avenue for cancer study and novel target for drug discovery. In this study, we showed that CD44 was a robust colorectal CSC marker and it is of functional importance for colorectal CSCs using clinic samples and xenograft models. The expression of CD44 and CD133 was assessed in primary tumors and matched normal tissues of patients with colorectal cancer (CRC) by using immunohistochemistry and flow cytometric analysis. We found that CD133 and CD44 did not appear on the same region of tumor tissue and it is infrequent to detect that both markers coexisted in the same cell. Knockdown of CD44 expression by RNA interference or inhibition of its function by specific antibodies could significantly inhibit tumor initiation and development in nude mice. These results indicate that CD44 and its related signaling pathway could be a critical diagnostic and therapeutic target for CRC.

Saturday, November 1, 2008

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.