Monday, August 31, 2009

Two publications about colorectal cancer

The Key to Stopping Colon Cancer? Med Tech Sentinel, August 30, 2009. Excerpt:
Scientists in Switzerland may have found a way to inhibit the growth of colon cancer in humans, says a new study published in EMBO Molecular Medicine. Researchers in Geneva discovered that by blocking a particular biological pathway, they could prevent the growth of tumors, metastatic lesions, and cancer stem cells. The Hedgehog-GL1 (HH-GL1) pathway appears to be crucial in the progression of colon cancer to an incurable, late stage. Cells use HH-GL1 to communicate with each other to determine position, growth and survival.
See also: 'Hedgehog' pathway may hold key to anti-cancer therapy, EurekAlert, August 26, 2009.

These news reports are about the publication: Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion by Frédéric Varnat and 6 co-authors, including Ariel Ruiz i Altaba, EMBO Molecular Medicine 2009(Aug 27) [Epub ahead of print][Abstract][Full text].

Another excerpt from The Key to Stopping Colon Cancer? (Med Tech Sentinel, August 30, 2009):
Earlier this month, scientists in North Carolina found another genetic target that may be useful in treating colorectal cancer. The pseudokinase ERBB3 is closely related to epidermal growth factor receptor (EGFR), which is already a target of several drugs used to treat colorectal cancer. Scientists found that genetically blocking ERBB3 was effective at preventing the disease in mice with colon cancer. In human colon cancer cells, removing ERBB3 caused a dramatic increase in cell death.
About the publication: Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium by Daekee Lee and 8 co-authors, including David W Threadgill, J Clin Invest 2009(Aug 17) [Epub ahead of print][PubMed Citation][Full text].

Friday, August 28, 2009

Globe & Mail article on CSCs

Cancer stem cells spur hope, skepticism by Jill Colvin, The Globe and Mail, August 27, 2009. [WebCite cache][Twitter entry][FriendFeed entry]. Excerpt:
Ontario Cancer Institute researcher John Dick, arguably the world's leading authority in the field, first identified stem cells in leukemia in the 1990s. Today, few doubt they play a key role in blood cancers.
In addition to this comment about the crucial contributions of John Dick, research on brain-tumour stem cells by Samuel Weiss is noted. There's also mention of the MIT and Harvard joint venture, Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening, published in Cell 2009(Aug 13). [See also this post in CSC News, August 14, 2009].

The criticisms by Scott Kern (such as: The fuzzy math of solid tumor stem cells: a perspective) of application the CSC hypothesis to colon, breast, or lung cancer are outlined. There's also a comment attributed to Richard Hill:
The hypothesis also hinges on the assumption that these cells are rare. Otherwise, traditional cancer therapies that shrink tumours would be killing them, too, and there would be no need to develop specialized treatments.
The "game-changing paper" by a team led by Sean Morrison, Efficient tumour formation by single human melanoma cells is also discussed. [See another post in CSC News, December 3, 2008, about this paper]. This research supports the view that "... stem cells may be key for some kinds of cancers and not for others".[This paper has attracted much attention. See, for example, Cancer Stem Cells May Not Be the Supervillains We Thought by Alexis Madrigal, Wired Science, December 3, 2008].

The article in The Globe & Mail ends with a paragraph about the hope that "new drug combinations that target all cell types" [associated with tumors] will be found, and a quote from William Hahn: "Whether the hypothesis is correct or incorrect in its full-blown beauty is really not important in the end" . [What really matters, from a clinical perspective, is whether or not efforts to target CSCs, in addition to other kinds of cells associated with tumors, will lead to improved outcomes for patients].

The article has already attracted some comments from readers.

Disclosure: I'm a co-author of some early papers about the CSC hypothesis, such as: J Natl Cancer Inst 1983(Jan); 70(1): 9-16.

Thursday, August 27, 2009

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].

Review of current knowledge on pancreatic CSC

Role of cancer stem cells in pancreatic ductal adenocarcinoma by Gregory Sergeant, Hugo Vankelecom, Lies Gremeaux and Baki Topal, Nat Rev Clin Oncol 2009(Aug 18) [Epub ahead of print]. PubMed Abstract:
As our understanding of pancreatic cancer evolves, evidence is growing to support a role for cancer stem cells in this devastating disease. Cancer stem cells constitute a distinct subpopulation in the tumor and are considered to drive both tumorigenesis and metastasis; these cells are thought to be highly resistant to standard treatment modalities. Here we review the current knowledge on pancreatic cancer stem cells and the implementation of cancer stem cell markers as prognostic or predictive biomarkers. We also discuss prospects for the use of cancer stem cells as targets for future therapeutic regimens in pancreatic cancer.

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

Sunday, August 23, 2009

Ovarian CSCs play a role in tumor neovascularization?

Stem-like Ovarian Cancer Cells can Serve as Tumor Vascular Progenitors by Ayesha B Alvero and 8 co-authors, including Gil Mor, Stem Cells 2009(Aug 5) [Epub ahead of print]. PubMed Abstract:
Neovascularization is required for solid tumor maintenance, progression, and metastasis. The most described contribution of cancer cells in tumor neovascularization is the secretion of factors, which attract various cell types to establish a microenvironment that promote blood vessel formation. The cancer stem cell hypothesis suggests that tumors are composed of cells that may share the differentiation capacity of normal stem cells. Similar to normal stem cells, cancer stem cells (CSCs) have the capacity to acquire different phenotypes. Thus, it is possible that CSCs have a bigger role in the process of tumor neovascularization. In this study, we show the capacity of a specific population of ovarian cancer cells with stem-like properties to give rise to xenograft tumors containing blood vessels, which are lined by human CD34+ cells. In addition, when cultured in high-density Matrigel, these cells mimic the behavior of normal endothelial cells and can form vessel-like structures in 24h. Microscopic analysis showed extensive branching and maturation of vessel-like structures in 7 days. Western blot and flow cytometry analysis showed that this process is accompanied by the acquisition of classical endothelial markers, CD34 and VE-cadherin. More importantly, we show that this process is VEGF-independent, but IKKbeta-dependent. Our findings suggest that anti-angiogenic therapies should take into consideration the inherent capacity of these cells to serve as vascular progenitors.

Mitogen independence of glioblastoma SCs

Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens by John J P Kelly and 11 co-authors, including Gregory Cairncross, Ian F Parney and Samuel Weiss, Stem Cells 2009(Aug 1); 27(8): 1722-33. [Epub 2009(Apr 23)][ResearchGATE Citation][PubMed Citation].

Thursday, August 20, 2009

Cancer can arise through de-differentiation?

Tumor suppressor pulls double shift as reprogramming watchdog, Press Release, Salk Institute for Biological Studies, August 9, 2009. Excerpts:
A collaborative study by researchers at the Salk Institute for Biological Studies uncovered that the tumor suppressor p53, which made its name as "guardian of the genome," not only stops cells that could become cancerous in their tracks but also controls somatic cell reprogramming.
"There's been a decade-old idea that cancer arises through the de-differentiation of fully committed and specialized cells but eventually it was discarded in favor of the currently fashionable cancer stem cell theory," says [Geoffrey] Wahl. "Now, that we know that p53 prevents de-differentiation, I believe it is time to reconsider the possibility that reprogramming plays a role in the development of cancer since virtually all cancer cells lose p53 function in one way or another."
See also: Cancer, stem cells linked in Salk study by Bradley J Fikes, North County Times, August 9, 2009. Excerpts:
A widely accepted theory of how cancer arises has been challenged by a study led by scientists at the Salk Institute.
When the p53 gene is removed, normal cells can be reprogrammed into stem cells with a tenfold greater success rate, the study found.
If the link is confirmed by other researchers, it would undermine a popular hypothesis that cancers arise from "cancer stem cells," caused by genetic changes in stem cells, [Juan Carlos Izpisúa] Belmonte said. Instead, he suggested, cancer could begin when normal cells spontaneously reprogram themselves, for reasons yet unknown, beginning the process that results in a cancerous tumor.
Based on this publication: Linking the p53 tumour suppressor pathway to somatic cell reprogramming by Teruhisa Kawamura and 7 co-authors, including Geoffrey M Wahl and Juan Carlos Izpisúa Belmonte, Nature 2009(Aug 9) [Epub ahead of print][PubMed Citation].

Saturday, August 15, 2009

Antitumor activity of anti-DLL4 antibodies

Data Published in Cell Stem Cell Demonstrates Potent Anti-Cancer Activity for OncoMed Pharmaceuticals Lead Antibody, Health Informer, August 7, 2009. Subtitle: Targeting Cancer Stem Cells Dramatically Reduces Tumor Growth and Recurrence in Preclinical Models. First paragraph:
OncoMed Pharmaceuticals, Inc. announced the publication in Cell Stem Cell of data demonstrating potent anti-cancer activity in colon and breast cancer models for the company’s first product candidate, OMP-21M18, underlining the therapeutic potential of targeting cancer stem cells to treat solid tumors. OMP-21M18 is currently in Phase 1 clinical testing.
The publication: DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency by Timothy Hoey and 14 co-authors, including Michael F Clarke, John Lewicki and Austin Gurney, Cell Stem Cell 2009(Aug 7); 5(2): 168-77. [PubMed Citation][FriendFeed entry].[Full text of this "Featured Article", via Gratis OA][Full text PDF].

Examples of other links to the News Release: [ (PDF)][Medical News Today][Genetic Engineering & Biotechnology News].

Friday, August 14, 2009

Identification of selective inhibitors of breast CSCs in mice

New method takes aim at aggressive cancer cells, News Release, Whitehead Institute for Biomedical Research, August 13, 2009. First paragraph:
A multi-institutional team of Boston-area researchers has discovered a chemical that works in mice to kill the rare but aggressive cells within breast cancers that have the ability to seed new tumors.
See also: First compound that specifically kills cancer stem cells found, ScienceBlog, August 13, 2009. Other news releases: [Medical News Today][ScienceDaily][EurekAlert].

A commentary: A screen for cancer killers by Elie Dolgin, Nature News, August 13, 2009. [FriendFeed entry]. First paragraph:
A new approach for identifying drugs that specifically attack cancer stem cells, the cellular culprits that are thought to start and maintain tumour growth, could change the way that drug companies and scientists search for therapies in the war against cancer.
Another commentary, Drug screening on cancer stem cells by Monya Baker (The Niche, August 14, 2009) includes links to the commentary by Elie Dolgin (see above) and to an article by Nicholas Wade (The New York Times, August 13, 2009).

The research publication that's attracting this attention is: Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening by Piyush B Gupta and 6 co-authors, including Robert A Weinberg and Eric S Lander, Cell 2009(Aug 13) [Epub ahead of print].[Twitter entry][FriendFeed entry].[Abstract].

Thursday, August 13, 2009

Molecular link connecting breast cancer SCs with normal SCs

Stanford scientists find common trigger in cancer and normal stem cell reproduction, EurekAlert, August 6, 2009. First paragraph:
Researchers at Stanford University School of Medicine have discovered, for the first time, a common molecular pathway that is used by both normal stem cells and cancer stem cells when they reproduce themselves.
See also: Common Trigger In Cancer And Normal Stem Cell Reproduction Found, ScienceDaily, August 7, 2009. About the article:

Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells by Yohei Shimono and 14 co-authors, including Michael F Clarke, Cell 2009(Aug 7); 138(3): 592-603. [FriendFeed entry][PubMed Citation]. Summary:
Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells invitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs invivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells.
For a commentary, see the latter part of: Breast cancer stem cells resemble healthy stem cells, resist chemotherapy by Monya Baker, The Niche, August 10, 2009.

On CSC and therapeutic sensitivity studies

If cancer stem cells are resistant to current therapies, what’s next? by Paola Marcato‌, Cheryl A Dean‌, Carman A Giacomantonio‌ and Patrick WK Lee‌, Future Oncol 2009(Aug); 5(6): 747-50. [Twitter entry][FriendFeed entry][PubMed Citation]. Excerpts from the final portion of this Editorial:
Thus far, oncolytic viruses as a class of novel cancer therapeutics appear to kill CSCs with the same efficiency as non-CSCs [references]. Therefore, the characteristics that make CSCs resistant to current therapies do not limit the ability of the viral-based therapies to infect and kill these cells. Of further interest is the possibility of engineering oncolytic viruses to specifically kill tumor cells that express CSC markers.
We conclude that with increasing evidence that CSCs are potent initiators of cancer and have an intrinsic resistance to current therapies, scientists and clinicians will need to rethink traditional end points, such as tumor regression, as the major indicator of the efficacy of anticancer therapies, new and old.

Tuesday, August 11, 2009

CSC, brain cancer and the STAT3 gene

STAT3 Gene Regulates Cancer Stem Cells in Brain Cancer, News Release, Tufts University, August 10, 2009. First paragraph:
In a study published online in advance of print in Stem Cells, Tufts researchers report that the STAT3 gene regulates cancer stem cells in brain cancer. Cancer stem cells have many characteristics of stem cells and are thought to be the cells that drive tumor formation. The researchers report that STAT3 could become a target for cancer therapy, specifically in Glioblastoma multiforme (GBM), a type of malignant and aggressive brain tumor.
See also: [Newswise][Insciences][EurekAlert][Medical News Today].

These News Releases are about this article: STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells by Maureen M Sherry and 4 co-authors, including Brent H Cochran, Stem Cells 2009(Aug 5) [Epub ahead of print]. [PubMed Citation].

Friday, August 7, 2009

Gene signatures in residual breast cancers after conventional therapy

Gene Signature of Breast Cancer Stem Cells Revealed, Genetic Engineering & Biotechnology News, August 4, 2009. First paragraph:
A consortium of researchers have identified the gene expression patterns of breast cancer stem cells that remain post treatment with either chemotherapy or antihormone treatments. They report that this gene signature differs from those linked to the bulk of epithelial cells in the tumor.
Based on: Gene signature for cancer stem cells may provide drug targets, Glenna Picton, News Release, Baylor College of Medicine, August 4, 2009.

See also: Gene signature for cancer stem cells may provide drug targets, Science Centric, August 4, 2009. First paragraph:
A subset of tumour cells that remain after a woman with breast cancer undergoes treatment with either anti-cancer or anti-hormone therapy shows a 'gene signature' that could be used to define targets for developing new drugs against the disease, said a consortium of researchers led by Baylor College of Medicine. The report appears in the current issue of the Proceedings of the National Academy of Sciences.
The report referred to in the above excerpt is an Open Access publication: Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features by Chad J Creighton and 22 co-authors, including Michael T Lewis, Jeffrey M Rosen and Jenny C Chang, Proc Natl Acad Sci USA 2009(Aug 3). [Epub ahead of print].[Abstract][Early version of OA full text].

Wednesday, August 5, 2009

Human bladder tumor-initiating cells

Scientists discover bladder cancer stem cell by Krista Conger, News Release, Stanford University, August 3, 2009. First paragraph:
Researchers at Stanford's School of Medicine have identified the first human bladder cancer stem cell and revealed how it works to escape the body's natural defenses.
See also: Stanford scientists discover bladder cancer stem cell, EuekAlert, August 3, 2009. And: Scientists Discover Bladder Cancer Stem Cell, ScienceDaily, August 4, 2009. [FriendFeed entry].

The news releases are based on this Open Access publication: Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells by Keith Syson Chan and 11 co-authors, including Irving L Weissman, Proc Natl Acad Sci USA 2009(Aug 4) [Epub ahead of print]. [Abstract][Early version of OA full text].

A post about another recent publication from Stanford: Leukemia SC cloak themselves to avoid detection (July 28, 2009).

Tuesday, August 4, 2009

Luminal progenitor cells in breast cancer

A new progenitor cell population in breast cancer, Nature Asia-Pacific, August 3, 2009. First paragraph:
Some breast cancers are thought to arise from mammary stem cells that mutate, but a study published in this week's Nature Medicine indicates that luminal cells that line the mammary ducts may also be tumor progenitors.
This Research Highlight is based on the publication: Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers by Elgene Lim and 20 co-authors, including kConFab, Jane E Visvader and Geoffrey J Lindeman, Nat Med 2009(Aug 2) [Epub ahead of print]. Final sentence of the PubMed Abstract:
Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors.
See also: Breast cancer discovery heralds diagnosis hope by Nick Miller,, August 3, 2009. Excerpt:
The breakthrough research came from the study of a unique collection of breast cancer tissue donated by Australian women.
And: Stem cell 'daughters' lead to breast cancer, EurekAlert, August 2, 2009. [FriendFeed entry]. Note to anyone who might find this title confusing: The word 'daughters' refers to cells that are produced by stem cells, not to the 'daughters' of patients!