Cell of origin for human prostate cancer

Scientists at UCLA find cell of origin for human prostate cancer by Kim Irwin, UCLA Newsroom, July 29, 2010. Excerpts:

"Certainly, the dominant thought is that human prostate cancer arose from the luminal cells because the cancers had more features resembling luminal cells," said Witte, senior author of the study and a Howard Hughes Medical Institute Investigator. "But we were able to start with a basal cell and induce human prostate cancer, and now, as we go forward, this gives us a place to look in understanding the sequence of genetic events that initiates prostate cancer and defining the cell-signaling pathways that may be at work fueling the malignancy, helping us to potentially uncover new targets for therapy."

.....

The new human-in-mouse model system developed in the study was created by taking healthy human prostate tissue that will induce cancer once it is placed in mice, instead of taking malignant tissue that is already cancerous and implanting it. This model can now be used to evaluate the effectiveness of new types of therapeutics. By using defined genetic events to activate specific signaling pathways, researchers can more easily compare therapeutic efficacy. The new model, by deconstructing tissue and then reconstructing it, also will aid in analyzing how the cells change during cancer progression.

This news release is based on the publication: Identification of a Cell of Origin for Human Prostate Cancer by Andrew S Goldstein and 5 co-authors, including Owen N Witte, Science 2010(Jul 30); 329(5991): 568-71. [PubMed citation][FriendFeed entry][Twitter trackbacks via Topsy].

Prostate CSCs sensitive to gamma-tocotrienol?

Gamma-Tocotrienol Kills Prostate Cancer Stem Cells, PRNewswire, July 25, 2010. Excerpt:

The scientists found that low doses of gamma-tocotrienol cause apoptosis in the prostate cancer stem cells and suppress their colony formation capability. This results in a lower prostate cancer stem cell population (as defined by the protein markers CD133 and CD44). Further tests in mice models were conducted, where mice implanted with hormonal refractory prostate cancer cells were given gamma-tocotrienol orally. The results showed that gamma- tocotrienol not only reduced tumour size formed, but also decreased the incidence rate of tumour formation by 75%, as compared to the control group of mice, which had 100% tumour formation. These results strongly suggest that gamma-tocotrienol could be developed for prostate cancer prevention and treatment.

The news release by Davos Life Science is based on the publication:

Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population by Sze Ue Luk and 11 co-authors, including Ming-Tat Ling, Int J Cancer 2010(Jul 8) [Epub ahead of print][PubMed citation].

Comment:

See also a relevant patent application: (WO/2010/047663) Use of Tocotrienol Composition for the Prevention of Cancer.
Publication Date: 29.04.2010
Applicants: DAVOS LIFE SCIENCE PTE. LTD. [SG/SG]; 16 Tuas South Street 5 Singapore 637795 (SG) (All Except US).
LING, Ming Tat [CN/AU]; (AU) (US Only).
YAP, Wei Ney [MY/SG]; (SG) (US Only).
WONG, Yong Chuan [MY/CN]; (CN) (US Only).
YAP, Yee Leng, Daniel [MY/SG]; (SG) (US Only).

Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic SC

Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells by E Camilla Forsberg and 6 co-authors, including Irving L Weissman, PLoS One 2010(Jan 20);5(1):e8785. [Connotea bookmark][FriendFeed entry][Full text is publicly accessible (via Libre OA)]. PubMed Abstract:

Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem cells.

Twist modulates breast CSC

Potential new 'twist' in breast cancer detection, EurekAlert, December 4, 2009 [FriendFeed entry]. First paragraph:

Working with mice, scientists at Johns Hopkins publishing in the December issue of Neoplasia have shown that a protein made by a gene called "Twist" may be the proverbial red flag that can accurately distinguish stem cells that drive aggressive, metastatic breast cancer from other breast cancer cells.

Based on: Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression by Farhad Vesuna, Ala Lisok, Brian Kimble and Venu Raman, Neoplasia 2009(Dec); 11(12): 1318-28 [Abstract][OA full text PDF][DOAJ entry for Neoplasia].

Heterogeneity in the AML stem cell pool

Heterogeneity in the AML stem cell pool by Laura E Hays, Blood 2009(Nov 5); 114(19): 3976-7 [PubMed Citation][FriendFeed entry]. Excerpt:

To examine AML and stem cell diversity, Heuser and colleagues develop a novel murine model that closely mimics aggressive human AML and demonstrate an essential role of Stat5 in leukemic stem cell renewal.

Comment on: Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal by Michael Heuser and 14 co-authors, including Gerald Krystal and R Keith Humphries, Blood 2009(Nov 5); 114(19): 3983-93 [Epub 2009(Aug 10)][PubMed Citation].

Aurothiomalate being studied in a preclinical lung cancer model

Mayo Clinic researchers find lung cancer oncogene holds key to turning off cancer stem cells, News Release, Mayo Clinic, September 8, 2009. First two paragraphs:

Scientists at the Mayo Clinic campus in Florida have found that the lung cancer oncogene PKCiota is necessary for the proliferation of lung cancer stem cells. These stem cells are rare and powerful master cells that manufacture the other cells that make up lung tumors and are resistant to chemotherapy treatment.

Their study, published in the Oct. 1 issue of Cancer Research, also shows that an agent, aurothiomalate, being tested at Mayo Clinic in a phase I clinical trial substantially inhibits growth of these cancer stem cells.

The news release is about this publication: Atypical Protein Kinase C{iota} Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis by Roderick P Regala and 5 co-authors, including Alan P Fields, Cancer Res 2009(Sep 8) [Epub ahead of print][PubMed Citation]. The final paragraph of the full text:

Our present results show that aurothiomalate exhibits potent antiproliferative activity toward the tumor stem cell niche in a relevant preclinical lung cancer model. Future studies will be required to assess whether aurothiomalate has similar antiproliferative effects on human lung cancer stem cells isolated from primary human lung tumors.

Comment: The publication reports results that were obtained using a mouse model. The News Release states that a Phase I clinical trial is under way at the Mayo Clinic, but this trial isn't mentioned in the full text of the publication in Cancer Research. According to MedicineNet.com, aurothiomalate is a "gold-containing chemical (salt) used in treating rheumatoid arthritis".

Imatinib refractoriness of leukemia-initiating cells

Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder by Katherine I Oravecz-Wilson and 11 co-authors, including Sean J Morrison and Theodora S Ross, Cancer Cell 2009(Aug 4); 16(2): 137-48. Last sentence of the PubMed Abstract:

Although imatinib dramatically decreased disease burden, LICs persisted, demonstrating imatinib refractoriness of LICs.

Prom1-expressing cells not essential for gliomagenesis

Glioblastoma Formation from Cell Population Depleted of Prominin1-Expressing Cells, Elites TV, August 29, 2009. [Twitter entry].

This news item provides the abstract of an article (with the same title) by Kenji Nishide, Yuka Nakatani, Hiroshi Kiyonari and Toru Kondo, published in PLoS One 2009(Aug 31); 4(8): e6869. [PubMed Citation][Full text is publicly accessible (via Libre OA)]. Last sentence of the abstract:

Thus, our studies demonstrate that Prom1-expressing cells are dispensable for gliomagenesis in this mouse model.

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].

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].

Targeted therapy for AML stem cells

New Targeted Therapy Finds And Eliminates Deadly Leukemia Stem Cells, ScienceDaily July 3, 2009. [FriendFeed entry]. First paragraph:

New research describes a molecular tool that shows great promise as a therapeutic for human acute myeloid leukemia (AML), a notoriously treatment-resistant blood cancer. The study, published in the July 2nd issue of the journal Cell Stem Cell, describes exciting preclinical studies in which a new therapeutic approach selectively attacks human cancer cells grown in the lab and in animal models of leukemia.

The news release is about this article: Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells by Liqing Jin and 14 co-authors, including John E Dick and Richard B Lock, Cell Stem Cell 2009(Jul 2); 5(1): 31-42. [PubMed Citation].

Stem-like cells in benign tumours

Tumor 'Stem-like Cells' Exist In Benign Tumors, ScienceDaily, July 22, 2009. First paragraph:

Cancer stem-like cells have been implicated in the genesis of a variety of malignant cancers. Research scientists at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute have isolated stem-like cells in benign (pituitary) tumors and used these "mother" cells to generate new tumors in laboratory mice. Targeting the cells of origin is seen as a possible strategy in the fight against malignant and benign tumors.

Based on the publication: Isolation of tumour stem-like cells from benign tumours by Qijin Xu and 10 co-authors, including John S Yu, Br J Cancer 2009(Jul 21); 101(2): 303-11 [Epub 2009(Jun 30)]. Final section of PubMed Abstract:

CONCLUSION: This study for the first time indicates that stem-like cells are present in benign tumours. The conclusions from this study may have applications to understanding pituitary tumour biology and therapies, as well as implications for the notion of tumour-initiating cells in general.

Chemosensitization of AML

Another nail in the AML coffin by Camille N Abboud, Blood 2009(Jun 11); 113(24): 6045-6. Editorial [Full text is currently publicly accessible][PubMed Citation]. First paragraph:

In this issue of Blood, Nervi and colleagues and Zeng and colleagues independently report similar findings in both in vitro and in vivo AML models, showing chemosensitization by blocking CXCR4/CXCL12 (SDF-1{alpha}:stromal cell–derived factor 1) signaling using novel CXCR4 antagonist bicyclams, namely AMD3100 (plerixafor) and AMD3465.

Excerpt from the final paragraph:

Finally, while both reports open new avenues for overcoming in vivo drug resistance in AML, it is yet unclear whether durable complete remissions can ensue from this strategy. AML is indeed a very heterogenous disease, and successful eradication of leukemic stem/progenitor cells will require blocking multiple receptors/pathways ...

The two articles discussed in this editorial are:

1) Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100 by Bruno Nervi and 10 co-authors, including Timothy J Ley, and John F DiPersio, Blood 2009(Jun 11); 113(24): 6206-14 [Epub 2008(Dec 2)]. [PubMed Citation].

2) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML by Zhihong Zeng and 12 co-authors, Blood 2009(Jun 11); 113(24): 6215-24 [Epub 2008(Oct 27)]. [PubMed Citation][FriendFeed entry].

[Only the abstracts of these two articles are currently publicly accessible].

Presentation on miRNA replacement therapy

Mirna Therapeutics Presents Data at Keystone Symposium on MicroRNA and Cancer, Business Wire, June 15, 2009 [Entry in FriendFeed]. Excerpt:

The expression of miR-34 is reduced in a variety of cancers as well as in cancer stem cells, suggesting that miR-Rx34 may have broad applicability as an anti-cancer agent in miRNA replacement strategies.

Microtubule-associated kinase DCAMKL-1 a novel target for anti-CSC-based strategies?

Scientists discover stem cell protein linked to cancer growth, Kerentech, May 23, 2009. Excerpt:

Researchers have studied stem cell proteins for years, but Houchen and Anant said they not only found a new cancer protein, but discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.

The results of their research will be published in an upcoming issue of the journal Gastroenterology.

See also: Scientists Discover How Cancer Protein Works, News release, OU Cancer Institute. Excerpt:

The latest work involves a new stem cell protein. Houchen and Anant discovered that this protein was responsible for regulating a natural tumor suppressor. It is the first such evidence of a stem cell protein regulating a tumor suppressor. When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced or "knocked down," the level of tumor suppressor went up and the tumor stopped growing. Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.

The relevant publication is: Selective Blockade of DCAMKL-1 Results in Tumor Growth Arrest by a Let-7a MicroRNA-Dependent Mechanism by Sripathi M Sureban and 6 co-authors, including Shrikant Anant and Courtney W Houchen, Gastroenterology 2009(May 12) [PubMed Citation].

Another related publication from this group: Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice by Randal May and 5 co-authors, Stem Cells 2008(Mar); 26(3): 630-7 [Epub 2007 Nov 29]. [PubMed Citation][Full text is publicly accessible (via Gratis OA)].

Combined treatment to eliminate CSC in pancreatic cancer

Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer by Maria-Theresa Mueller and 13 co-authors, including Christopher Heeschen, Gastroenterology 2009(Jun 4). PubMed Abstract:

BACKGROUND & AIMS:: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSC), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mTOR, respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS:: We used in vitro and in vivo models of pancreatic cancer to examine the effects of a sonic hedgehog inhibition (cyclopamine / CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS:: Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSC to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS:: The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSC. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.

[Thanks to Alexey Bersenev].

Specific target gene found using CML mouse model

Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia by Yaoyu Chen, Yiguo Hu, Haojian Zhang, Cong Peng, Shaoguang Li, Nature Genetics 2009(June 7).

For a news release about this article, see: A lethal cancer knocked down by one-two drug punch, Genetic Engineering & Biotechnology News, June 7, 2009. Excerpts:

The researchers found that CML did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.

[Shaoguang] Li also treated mice with CML with Zileuton, an asthma medication that inhibits the Alox5 inflammation pathway, as well imatinib, commonly known as Gleevec, the most effective current leukemia medication. Imatinib effectively treated CML, but Zileuton was more effective. The two drugs combined provided an even better therapeutic effect.

[Thanks to Alexey Bersenov].

Cancer Stem Cells Generated by Cancer Outgrowth

Mouse Fibroblasts Lacking RB1 Function Form Spheres and Undergo Reprogramming to a Cancer Stem Cell Phenotype, by Yongqing Liu and 10 co-authors, including Douglas C Dean, Cell Stem Cell 2009(Apr 3); 4(4), 336-47. [Summary][Publicly accessible full text].

Examples of related news items:

Cancer stem cells generated by cancer outgrowth, Life Sciences World, April 2, 2009. First sentence:

Scientists have discovered that growing mouse skin cells in spheres can lead to generation of cells with properties of cancer stem cells, even without genetic manipulation of stem cell genes.

Cancer Stem Cells Generated by Cancer Outgrowth, Disabled World, April 2, 2009.

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). .....

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.