About promyelocytic leukaemia protein (PML)

Stemming out of a new PML era? A review by Paolo Salomoni, Cell Death Differ 2009(Jun 12) [Epub ahead of print][Entry in FriendFeed] PubMed Abstract:

The promyelocytic leukaemia protein PML is a growth and tumour suppressor inactivated in acute promyelocytic leukaemia (APL). Recent evidence indicates that PML plays a tumour-suppressive role in cancer of multiple histological origins. However, it is only very recently that PML growth-suppressive functions have been implicated in regulating physiological processes and tissue homoeostasis. In particular, it has been shown that PML is one of the key cell-cycle regulators controlling stem cell function in multiple tissues, from the blood to the brain. As a consequence, PML loss has an impact on tissue development and maintenance of stem cell pools. In addition, new data suggest that PML regulates self-renewal in cancer stem cells. Finally, the oncogenic fusion protein PML/RARalpha, contrary to the conventional view, appears to hijack growth-suppressive pathways to promote transformation of haematopoietic stem cells and to maintain the APL stem cell niche. Overall, these findings not only represent a change in paradigm in the field of PML/APL research, but also contribute to the understanding of fundamental mechanisms underlying stem cell function in vivo. The main objective of this review is to critically discuss the very recent literature on the role of PML in stem cells and tumour-initiating cells. Ultimately, it aims to propose new avenues of investigation.Cell Death and Differentiation advance online publication, 12 June 2009; doi:10.1038/cdd.2009.63.

MicroRNAs play roles in glioma stem-like cell behavior?

A review: MicroRNAs and glioblastoma; the stem cell connection by Jakub Godlewski and 4 co-authors, including Sean E Lawler, Cell Death Differ 2009(Jun 12) [Epub ahead of print][Entry in FriendFeed] PubMed Abstract:

Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.Cell Death and Differentiation advance online publication, 12 June 2009; doi:10.1038/cdd.2009.71.

Bright future for CSC therapies?

Opinion: A Stem of Hope for Cancer Treatments, Manish Singh, Genetic Engineering & Biotechnology News, June 12, 2009. Excerpts:

Three Attack Strategies
Investigations currently in progress target cancer stem cells using one of three approaches: small molecules, mAbs, or vaccines. Small molecule therapies work by perturbing the signaling pathway of cancer stem cells to put brakes on tumorogenesis. mAbs, on the other hand, are focused on recognizing certain markers that are highly expressed on CSCs but not on normal cells or normal stem cells. Lastly, active immunotherapy utilizes the native immune system to recognize and destroy cancer stem cells while leaving normal cells intact. While a few companies have been started de novo to focus on these programs, a number of existing compounds are also being tested for their effect on cancer stem cells.

.....

Our understanding of stem cells is in its infancy today, but there can be no doubt about their potential to solve some of the most complicated health problems in both regenerative medicine as well as cancer. Regenerative medicine is much more complicated due to several stages of development that the stem cells have to undergo to regenerate tissue. However, it may be easier to find therapeutic application in cancer, where the goal is to capture and destroy these tumor-initiating stem cells. Based on several encouraging clinical and preclinical studies combined with significant interest from large pharma to acquire these early-stage assets even before they enter the clinic, a bright future may be in store for cancer stem cell therapies.

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].

Updates sent to Twitter, May 31-June 6

Updates about CSC sent to Twitter during May 31-June 6:

About a Phase I clinical trial of ICT-107, a dendritic cell-based vaccine for glioblastoma (ASCO Abst#2032) [June 5]: http://is.gd/P1qU

Glioma Stem Cells: Better Flat Than Round: http://bit.ly/LXNmt - about Cell Stem Cell 2009(June 5;4(6):568-80 [June 4]: http://is.gd/Oyts

[See also: Cancer stem cell studies could open the door to personalized, targeted treatments for brain cancers, News release, The Hospital for Sick Children, June 4, 2009].

Most Common Brain Cancer May Originate In Neural Stem Cells: http://is.gd/MkH2 - based on (PubMed citation) [June 2]: http://bit.ly/jQDeD
[PubMed Citation].

Targeting breast cancer stem cells in mice: http://bit.ly/kylXn - based on (OA full text) [June 2]: http://is.gd/Mk3a
[Full text is publicly accessible (via Libre OA)].

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells, Cancer Cell 2009(Jun 2) [June 1]: http://is.gd/LQbJ
[PubMed Citation].