ASH 50th Anniversary Review by John Dick

Stem cell concepts renew cancer research by John E Dick, Blood 2008(Dec 15);112(13): 4793-4807. Abstract:

Although uncontrolled proliferation is a distinguishing property of a tumor as a whole, the individual cells that make up the tumor exhibit considerable variation in many properties, including morphology, proliferation kinetics, and the ability to initiate tumor growth in transplant assays. Understanding the molecular and cellular basis of this heterogeneity has important implications in the design of therapeutic strategies. The mechanistic basis of tumor heterogeneity has been uncertain; however, there is now strong evidence that cancer is a cellular hierarchy with cancer stem cells at the apex. This review provides a historical overview of the influence of hematology on the development of stem cell concepts and their linkage to cancer.

One of the most recent of the 50th Anniversary Reviews of the American Society of Hematology (ASH).

Understanding of bone marrow SC niche expanded

Detection of functional haematopoietic stem cell niche using real-time imaging by Yucai Xie, Tong Yin, Winfried Wiegraebe and 15 co-authors, including Ricardo A Feldman and Linheng Li, Nature 2008(Dec 3) [Epub ahead of print]. PubMed Abstract:

Haematopoietic stem cell (HSC) niches, although proposed decades ago, have only recently been identified as separate osteoblastic and vascular microenvironments. Their interrelationships and interactions with HSCs in vivo remain largely unknown. Here we report the use of a newly developed ex vivo real-time imaging technology and immunoassaying to trace the homing of purified green-fluorescent-protein-expressing (GFP(+)) HSCs. We found that transplanted HSCs tended to home to the endosteum (an inner bone surface) in irradiated mice, but were randomly distributed and unstable in non-irradiated mice. Moreover, GFP(+) HSCs were more frequently detected in the trabecular bone area compared with compact bone area, and this was validated by live imaging bioluminescence driven by the stem-cell-leukaemia (Scl) promoter-enhancer. HSCs home to bone marrow through the vascular system. We found that the endosteum is well vascularized and that vasculature is frequently localized near N-cadherin(+) pre-osteoblastic cells, a known niche component. By monitoring individual HSC behaviour using real-time imaging, we found that a portion of the homed HSCs underwent active division in the irradiated mice, coinciding with their expansion as measured by flow assay. Thus, in contrast to central marrow, the endosteum formed a special zone, which normally maintains HSCs but promotes their expansion in response to bone marrow damage.

Found via: Understanding Of Bone Marrow Stem Cell Niche Expanded, individualall.net Health News. Excerpt:

“EVISC technology will allow us to study HSC lineage commitment in vivo,” said Linheng Li, Ph.D., Investigator and senior author on the paper. “Furthermore, we will be able to use this technology to study leukemia (and other cancer) stem cells to better understand whether they use the same or different niches that normal stem cells use, and even to evaluate drug resistance and treatment responses. This is an exciting new avenue for our work.”

NV-128 potentially active against CSC

Novogen's NV-128 shows potential activity against cancer stem cells, Recent News, Novogen, December 1, 2008. Excerpts:

Pharmaceutical company Novogen Limited (ASX: NRT Nasdaq: NVGN) today announced that work performed in collaboration with a Yale University research team led by Associate Professor Gil Mor, MD, PhD, has revealed its novel mTOR inhibitor NV-128 has the potential to act against cancer stem cells in addition to rapidly proliferating cells in established solid tumours.

“Yale’s research team is finding that NV-128 has a high level of potency against cancer stem cells,” said Dr Gil Mor. “In fact, of the investigational therapies Yale has tried, NV-128 is one of the most exciting to us.”

.....

Structurally, NV-128 is an analogue of triphendiol and phenoxodiol, both of which are investigational drugs that have been licensed by Novogen to Marshall Edwards, Inc.

See also: Novogen: NV-128 potentially active against cancer stem cells, Biotech Daily, December 2, 2008.

And: Marshall Edwards' Phenoxodiol and Novogen's NV-128 Display Divergent Mechanisms of Action but Potent Synergistic Anti-Cancer Activity When Used in Combination, Marketwire, October 30, 2008.

And: Anti-tumor activity of phenoxodiol: from bench to clinic by Ayesha B Alvero and 6 co-authors, including Gil Mor, Future Oncol 2008(Aug); 4(4): 475-82. [PubMed Citation].

Published CIRM-sponsored CSC research

Found via: Stem Cell Research by CIRM Grantees:

Cancer
Mutation Revealed to Convert Blood Stem Cells to Cancer Stem Cells

CIRM-funded researcher: Wei Guo

Researchers at UC, Los Angeles discovered a series of mutations that can convert normal blood stem cells into cancer stem cells. It is believed that many types of cancer result from cancer stem cells created by such mutations. In this case the first mutation converted normal stem cells and then caused over expression of an oncogene, a cancer gene, resulting in a proliferation of leukemia stem cells and acute T-cell lymphoblastic leukemia in a mouse model. The team hopes that by studying these pathways they will find ways to block them with small molecule drugs and cure the often fatal disease. The study was published in the May 22, 2008 issue of Nature.

Related Information: Nature paper, UCLA press release, The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Funding grant summary

The published paper is: Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation by Wei Guo and 10 co-authors, including Hong Wu, Nature 2008(May 22); 453(7194): 529-33 Epub 2008 May 7. [PubMed Citation].

Guidelines for the Clinical Translation of SC

Guidelines for the Clinical Translation of Stem Cells, International Society for Stem Cell Research (ISSCR), December 3, 2008. Links are provided to the Guidelines [PDF], to Apppendix 1 (a Patient Handbook on Stem Cell Therapies) [PDF], to Appendix 2 (Additional Resources), to a Cell Stem Cell article summarizing the essential elements of the document [PubMed Citation] and to a joint ISSCR and Cell Stem Cell Press Release about the Guidelines.

For an article, in the same issue of Cell Stem Cell, that provides evidence that such Guidelines are needed, see: Stem Cell Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine by Darren Lau and 5 co-authors, including Timothy Caulfield, Cell Stem Cell 2008(Dec 4); 3(6): 591-4. PubMed Abstract:

Despite the immature state of stem cell medicine, patients are seeking and accessing putative stem cell therapies in an "early market" in which direct-to-consumer advertising via the internet likely plays an important role. We analyzed stem cell clinic websites and appraised the relevant published clinical evidence of stem cell therapies to address three questions about the direct-to-consumer portrayal of stem cell medicine in this early market: What sorts of therapies are being offered? How are they portrayed? Is there clinical evidence to support the use of these therapies? We found that the portrayal of stem cell medicine on provider websites is optimistic and unsubstantiated by peer-reviewed literature.

See also: Laws needed to protect patients from stem cell clinics' exaggerated claims: study by Sheryl Ubelacker, Canadian Press, December 3, 2008. The first sentence:

Canadians should be "very skeptical" of foreign clinics that use websites to promote stem cell therapies for a wide range of medical conditions, warn researchers, saying there is a dearth of scientific evidence to back up their claims.

Comments: The Guidelines contain no explicit mention of cancer SC. However, if one accepts the prediction that "diagnostic methods based on the detection of CSC’s will have the potential to address key limitations of current methods" [excerpt from Business Wire, April 26, 2007], then some attention needs to be paid to the known limitations of diagnostic methods. Two examples of relevant references:

1) Grading quality of evidence and strength of recommendations for diagnostic tests and strategies by Holger J Schünemann and 10 co-authors, including Gordon H Guyatt, BMJ 2008(May 17); 336(7653): 1106-10 [PubMed Citation]. Excerpt from the publicly-accessible Extract:

Inferring from data on accuracy that a diagnostic test or strategy improves patient-important outcomes will require the availability of effective treatment, reduction of test related adverse effects or anxiety, or improvement of patients’ wellbeing from prognostic information.

Excerpt from the full text:

Although recommendations on diagnostic testing share the fundamental logic of recommendations on treatment, they present unique challenges.

2) See also: Evaluation of clinical innovation: a gray zone in the ethics of modern clinical practice? by Johane Patenaude and 4 co-authors, J Gen Intern Med 2008(Jan); 23(Suppl 1): 27-31 [PubMed Citation]. Excerpt for the Conclusions section of the (publicly accessible) full text:

Innovation is a neglected area for ethics assessment. Further studies on a larger scale are necessary to review the concepts of experimental, innovative, and commonly accepted care.

Perhaps a subsequent version of the ISSCR Guidelines should include a section on diagnostic tests involving CSC?

Tumorigenic cells not rare in human melanoma

Efficient tumour formation by single human melanoma cells by Elsa Quintana and 5 co-authors, including Sean J Morrison, Nature 2008(Dec 4); 456(7222): 593-8. Abstract:

A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1–0.0001%) form tumours when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, the extent to which NOD/SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg ^-/-) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.

See also: U-M scientists probe limits of 'cancer stem-cell model'; Melanoma, the deadliest skin cancer, does not fit the model, News Release, University of Michigan, December 3, 2008.

Article in The Scientist

How to win the war against cancer by Frank L Douglas and Robert E Litan, The Scientist, November 5, 2008 [free registration is required]. Excerpt:

We now know from many areas of science -- including cancer research -- that collaborative research by investigators with different but complementary areas of expertise are more likely to crack difficult problems than "lone rangers" who work in isolation. With more cooperation and less competition in cancer research, the war against cancer is much more likely to be won.

Over the past month, this short opinion article has attracted a number of comments from readers. An example: "Competition vs. collaboration" by an anonymous poster, November 10, 2008. Excerpt:

Therefore big bucks should be spent by the NIH on big projects, but these projects should have a purely supportive role (core facilities, tissue banks, high-throughput assay systems, result databases) and the people involved should be paid enough to make up for decreased career opportunities, which working in such supportive roles would entail. Enticing people to collaborate just because there is money in collaborating is going to just result in a lot of people flocking around the trough and pretending they have some common goal, while in fact they will be doing disparate things under a makeshift common banner.

Another example of a comment: "Doubtful strategy" by Rainer Zahlten, November 7, 2008. Excerpt:

This "new" strategy is bound to fail. Why? Because enforced cooperation for the sake of obtaining research grants is counterproductive to a physiologic matching of research interests, including a viable chemistry between participating scientists.

Thanks to Lisa Willemse, who noticed this article.