Monday, October 13, 2008

The Year in Hormones and Cancer Lecture

COMMENTARY: The Year in Hormones and Cancer Lecture: Update of Estrogen plus Progestin Therapy for Menopausal Hormone Replacement Implicating Stem Cells in the Increased Breast Cancer Risk by Kathryn B. Horwitz, Mol Endocrinol 2008(Oct 9) [Epub ahead of print]. [PubMed Abstract]:
This transcript is based on my "The Year in Hormones & Cancer" lecture at ENDO 08 that reviewed current data surrounding hormone replacement therapy (HRT); the relationship between systemic estrogen plus progestin (E+P) treatment and increased breast cancer risk; and explored the hypothesis that women who "develop" breast cancer while on E+P had occult, undiagnosed disease before they started therapy. Beginning with recent HRT data focusing on E+P and its association with breast cancer to set the stage, the lecture then reviewed our newly published data that progestins expand breast cancer stem cells. Finally, the issues of occult or undiagnosed breast cancer in presumably healthy women, and of tumor dormancy in breast cancer survivors, were brought to bear on the discussion. Taken together, these apparently disparate themes allowed me to suggest the idea that systemic progestins have the ability to reawaken cancers that were presumed to be either nonexistent or cured. To avoid this potentially devastating outcome while retaining the benefits of E+P, I advocated the use of local progestin delivery methods, rather than the currently popular systemic routes.
The last two sentences of the "Conclusions" section in the (freely-accessible) PDF version of the full text:
There is considerable evidence for the presence of undetected, possibly undetectable, microdisease in a relatively substantial population of women - both in women who have no evidence of disease, as well as in women who have had breast cancer and are believed to be disease-free. I believe that systemic HRT, especially the progestin component, could be dangerous to such women.

Sunday, October 12, 2008

Stanford center for stem cell research

Lokey gives $75 million to create nation's largest stem cell research center at Stanford by Ruthann Richter (News Release, Office of Communication & Public Affairs, Stanford University Medical Center, October 6, 2008). Excerpts:
Lorry I. Lokey, the Business Wire founder and philanthropist, is giving $75 million to the Stanford University School of Medicine to help build what is expected to be the nation’s largest center for stem cell research, the medical school announced Oct. 6.
.....
His contribution will help build a new home for the Stem Cell Biology and Regenerative Medicine Institute, one of five major research institutes based in the medical school. Institute scientists are involved in the full array of stem cell research, including studies in both embryonic and adult cells, as well as work in cancer stem cells and in the development of disease-specific stem cell lines.
.....
“Scientists in the fields of stem cell and cancer research are on the brink of new discoveries that may soon affect the understanding and treatment of disease,” said Irving Weissman, MD, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of Stanford’s stem cell institute. “With this magnificent lead gift from Lorry Lokey, Stanford will have the facilities to lead those efforts.”

Weissman, who was the first to isolate stem cells in both mice and humans, said the availability of new space will attract key faculty to Stanford and spur collaborations with scientists from the around the world. The new center will include 60 laboratory benches for scientists who will visit Stanford for a month or a year at a time. Lokey said the prospect of bringing top research talent to Stanford is far more meaningful to him than any worldly goods his money could buy.

“I don’t want airplanes and boats and country club memberships,” he said. “I believe that if you fall into a lot of money like I did, you put it into the soil—you replenish the soil for next year’s crop.”
Found via MarketWatch, Oct 06, 2008.

Thursday, October 9, 2008

Translational research for medical interventions

Tracking the lag between promise and payoff by Janet D. Stemwedel, Adventures in Ethics and Science, October 2, 2008. This blog post isn't about cancer stem cells, but is of interest because it's focus is on translational research for medical interventions. Excerpts:
One of the reasons non-scientists see science as at all valuable is that scientific research may result in useful medical treatments. And one of the aspects of science that seems elusive to non-scientists is just how long it can take scientific research to bring those useful medical treatments about.
.....
The time interval between the first report on preparation, isolation, or synthesis (or the earliest patent) and the highly cited articles reporting successful clinical interventions -- between the report of findings with clinical potential and the determination via clinical trials that that promise is realized in a treatment -- is the "translational lag". (There is, of course, another lag that's harder to quantify this way -- that between the initial findings in the research lab and the publication of those findings.)
Contopoulos-Ioannidis et al. found that the median translational lag for the highly cited article[s] in their study was 24 years. That's a long time.
The blog post is based on this article: Life Cycle of Translational Research for Medical Interventions, by Despina G. Contopoulos-Ioannidis, George A. Alexiou, Theodore C. Gouvias, John P. A. Ioannidis, Science 2008(Sep 5); 321(5894): 1298-9 [PubMed Citation]. The article isn't freely accessible, and has no abstract. The brief Summary:
From the initial discovery of a medical intervention to a highly cited article is a long road, and even this is not the end of the journey.
An excerpt from the final section of the full text:
The following are some recommendations for improving the system, based on our analyses:
• Discovery of new substances and interventions remains essential, but proper credit and incentives should be given to accelerate the testing of these applications in high-quality, unbiased clinical research and the replication of claims for effectiveness.
• Multidisciplinary collaboration with focused targets and involving both basic and clinical sciences should be encouraged.
• Proof of effectiveness for new interventions requires large, robust randomized clinical trials.
• Translational efforts for common diseases should focus more on novel agents and new cutting-edge technologies; for these ailments, it is unlikely that genuine major benefits from interventions already known for a long time have gone unnoticed.
Comments: Of the 32 interventions highlighted in this study, only two were cancer-related:

1) Levamisole (with Fluorouracil): Colon cancer
• Date of highly cited study: 1990
• Date of first description of intervention: 1966
• Report of first human use: 1977
2) Tamoxifen: Breast cancer prevention
• Date of highly cited study: 1998
• Date of first description of intervention: 1964
• Report of first human use: 1971
For cancer stem cells, what might be an important first intervention to be described? Proof that the eradication of cancer stem cells from a patient's tumor is therapeutic?

Perhaps a clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression wouldn't be regarded as a "therapeutic intervention", but it's a key challenge for those doing research on cancer stem cells. See, for example, a review by Eric Lagasse, Gene Ther 2008(Jan); 15(2): 136-42 [PubMed Abstract]. Excerpt from the full text (not freely accessible):
[Remaining challenges] include the clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression and proof that the eradication of cancer stem cells from a patient's tumor is therapeutic.

Sunday, October 5, 2008

Cell fate in human multipotent colorectal cancer cells

Alpha2 Beta1 integrin regulates lineage commitment in multipotent human colorectal cancer cells by Susan C. Kirkland and Huijun Ying, J Biol Chem 2008(Oct 10); 283(41): 27612-19. The last sentence of the Abstract:
This study indicates that the collagen receptor alpha2beta1 integrin is a regulator of cell fate in human multipotent colorectal cancer cells.
This is an Author Choice (hybrid OA) article, licensed with a Creative Commons Attribution Non-Commercial License.

Thursday, October 2, 2008

Review article in Urologic Oncology

"Cancer stem cells"-Lessons from Hercules to fight the Hydra, by Felix Roman Moltzahn, Jens-Peter Volkmer, Daniel Rottke, Rolf Ackermann. Urol Oncol 2008 Sep 23. [Epub ahead of print]. Abstract:
Following the initial identification of hematopoietic tumor stem cells, such cells were also found in several solid tumor types. In urology, cancer stem cells have only been found in prostate tumors so far. The concept and detection of tumor stem cells rely heavily on findings derived from stem cell research. Therefore, in addition to identifying and characterizing urologic tumor stem cells, research in uro-oncology should also aim at better understanding the stem-cell biology of urologic organs. Insights in similarities and differences gleaned from these studies could be used to develop strategies for targeted destruction of tumor stem cells while sparing the physiological stem cells. The main target of future curative therapies in uro-oncology must therefore be the central, immortal head of the Hydra, the tumor stem cell.
Excerpt from the full text:
3. CSC definition
The tumor stem cell is the original cell of the tumor, responsible for tumorigenesis, tumor differentiation, tumor maintenance, and also for tumor spread and tumor relapse. This is analogous to a stem cell being the original cell of an organ, responsible for organogenesis and organ maintenance.
Unfortunately, the full text isn't freely-accessible. The publisher (Elsevier) permits the peer-reviewed postprint to be archived on authors' personal or authors' institution's server (see the SHERPA/RoMEO entry for Urologic Oncology). However, a Google search didn't reveal a freely-accessible version of this review.

Monday, September 29, 2008

Two blog posts about cancer stem cells

Two recent blog posts by Kevin Graham (thanks to Drew Lyall):

1) Meet Kevin Graham: Cancer stem cell researcher, Connecting for Kids, September 19, 2008. Excerpt:
Have you ever heard of tumour stem cells? Did you know that stem cell research is being used to search for a cure for brain tumours? Admittedly, these probably aren’t the first things that jump to your mind when you hear about stem cell research, but that’s exactly why we started this forum.
2) Stem cells, Cancer and Cancer Stem Cells, Connecting for Kids, September 24, 2008. Excerpt:
How do you target a cancer stem cell? This is one of the many ways in which stem cell research is paying off. Early indications are that normal stem cells and cancer stem cells share many of the same cellular processes. Research over the years has compiled an amazing amount of data about how normal stem cells function, information that is now being rapidly applied to cancer stem cells.
The right frame of both posts also includes links to brief profiles of three other stem cell researchers at the Hospital for Sick Children (SickKids) in Toronto: Janet Rossant (mammalian developmental biology and genetics), Peter Dirks (cancer stem cells of brain tumors) and Freda Miller (neuronal stem cells and neuronal growth, survival and apoptosis).

Thursday, September 25, 2008

Cancer stem cells in solid tumours: a review

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Jane E Visvader & Geoffrey J Lindeman, Nature Reviews Cancer 2008(Oct); 8(10): 755-68. Abstract:
Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.
This review is currently available free as a special feature to registered visitors to Nature Reviews Cancer. Registration is also free.