Awards for Connie Eaves and John Dick

Canadian stem cell researchers Eaves and Dick to receive hematology awards, Michael Rudnicki, Stem Cell Network blog, July 31, 2009. Excerpts:

Connie Eaves, PhD, of the BC Cancer Agency, University of British Columbia in Vancouver, will be presented with the Henry M. Stratton Medal, which honors an individual whose well-recognized contributions to hematology have taken place over a period of several years. Dr. Eaves will receive this award for her remarkable achievements in the area of stem cell biology for more than two decades. Dr. Eaves has been on the cutting edge of adapting or introducing technologies related to stem cell biology, especially her ground-breaking techniques of using the long-term culture system as means of understanding the proliferative and renewal properties of normal and malignant primitive human hematopoietic stem cells.

John E. Dick, PhD, of the University Health Network in Toronto, will be recognized with the E. Donnall Thomas Lecture and Prize for his pioneering research into the development of human leukemia, which has transformed the view of how leukemia progresses. This prize, named after a Nobel Prize laureate and past Society president, recognizes pioneering research achievements in hematology.

These summaries were obtained from: Six Researchers to Receive Prestigious Awards From the American Society of Hematology, Press Release, American Society of Hematology, July 13, 2009.

Comment: Very appropriate recognition of accomplishments in hematological research that have included important contributions to cancer research.

CD133 and poorer prognosis in locally advanced colon cancer

Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB by Chun-Yan Li and 11 co-authors, including Xiao-Shi Zhang, J Transl Med 2009(Jul 7); 7: 56. [Full text via Libre OA][PMC version of the full text][PubMed Abstract] Final paragraph of the Abstract:

CONCLUSION: The fact that a higher percentage CD133+ cells were strongly associated with a poorer prognosis in patients with locally advanced colon cancer implicated that CD133+ cancer cells contribute to the tumor progression, and the overpopulation hypothesis of cancer stem cell seems reasonable.

Leukemia SC cloak themselves to avoid detection

Leukemia cells evade immune system by mimicking normal cells, Stanford study shows by Krista Conger, News Release, Stanford University Medical Center, July 23, 2009. First sentence:

Human leukemia stem cells escape detection by co-opting a protective molecular badge used by normal blood stem cells to migrate safely within the body, according to a pair of studies by researchers at Stanford University Medical School.

See also: Molecule Helps Leukemia Cells Hide From Immune System, Drugs.com, July 23, 2009. First sentence:

Leukemia stem cells cleverly cloak themselves to avoid detection by a person's immune system, according to a pair of studies by researchers at Stanford University Medical School.

And: Leukemia cells evade immune system by mimicking normal cells, Stanford studies show, EurekAlert, July 23, 2009.

The two articles upon which the news releases are based:

1) CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis by Siddhartha Jaiswal, Catriona H M Jamieson and 7 co-authors, including Irving L Weissman, Cell 2009(Jul 23); 138(2): 271-85. [PubMed Citation].

2) CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells by Ravindra Majeti and 7 co-authors, including Irving L Weissman, Cell 2009(Jul 23); 138(2): 286-99. [PubMed Citation][FriendFeed entry].

Tissue Factor and CSC

Tissue Factor and Cancer Stem Cells. Is There a Linkage? by Chloe Milsom and 5 co-authors, including Janusz Rak, Arterioscler Thromb Vasc Biol 2009(Jul 23) [Epub ahead of print]. PubMed Abstract. Last sentence:

We propose that both tumor cell-associated and host-related TF could influence the properties of CSCs, and that agents targeting the TF/PAR system may represent a hitherto unappreciated therapeutic opportunity to control cancer progression by influencing the CSC/TIC compartment.

A neurosurgeon's guide to CSC

A neurosurgeon's guide to stem cells, cancer stem cells, and brain tumor stem cells by Samuel H Cheshier and 5 co-authors, including Irving L Weissman, Neurosurgery 2009(Aug); 65(2): 237-49. PubMed Abstract:

Stem cells and their potential applications have become the forefront of scientific, political, and ethical discourse. Whereas stem cells were long accepted as units of development and evolution, it is now becoming increasingly clear that they are also units of oncogenesis. Although the field of stem cell biology is expanding at an astounding rate, the data attained are not readily translatable for the physicians who may eventually deliver these tools to patients. Herein, we provide a brief review of stem cell and cancer stem cell biology and highlight the scientific and clinical implications of recent findings regarding the presence of cancer-forming stem cells in brain tumors.

Review in special issue of Chemical Reviews

Cancer Stem Cells: A New Theory Regarding a Timeless Disease by Bedabrata Sarkar, Joseph Dosch and Diane M Simeone, Chem Rev 2009(Jul); 109(7): 3200-8.[PubMed Citation]. Excerpt from the full text of this review:

5 Conclusions

The discovery of CSCs in several types of solid tumors over the past few years represents a major paradigm shift in the field of oncology and is likely to change our understanding of the process of tumorigenesis. The existence of cancer stem cells also has direct therapeutic implications. Most current systemic therapies have been found ineffective in the treatment of solid tumors, and this may be due, at least in part, to increased resistance of the cancer stem cells. Selective pressure provided by treatment of the tumor with chemotherapy or ionizing radiation may allow for the survival and enrichment of a resistant CSC population, with subsequent reconstitution of the primary tumor with cells that will not be responsive to further treatment cycles. It will be important to understand how cancer stem cells are different from the rest of the tumor cell population in order to develop effective targeted therapeutics to this resistant cancer cell population, with the goal of improvement in patient outcomes.

This article is part of the 2009 Cancer Chemotherapeutics special issue of Chemical Reviews.

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.

Translation of knowledge about CSC into clinical use

Radiation Therapy Oncology Group Translational Research Program Stem Cell Symposium: Incorporating Stem Cell Hypotheses into Clinical Trials. Authors: Wendy A Woodward, Robert G Bristow, Michael F Clarke, Robert P Coppes, Massimo Cristofanilli, Dan G Duda, John R Fike, Dolores Hambardzumyan, Richard P Hill, Craig T Jordan, Luka Milas, Frank Pajonk, Walter J Curran, Adam P Dicker, Yuhchyau Chen. Int J Radiat Oncol Biol Phys 2009(Aug 1); 74(5): 1580-91 [Epub 2009(Jun 17)]. PubMed Abstract:

At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. This report summarizes the major topics discussed and the future directions that research should take. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use.

CD133 expression has high prognostic impact for colon cancer

The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer by David Horst and 6 co-authors, including Thomas Kirchner and Andreas Jung, J Pathol 2009(Jun 25) [Epub ahead of print] PubMed Abstract:

In colon cancer, CD133 has recently been used to enrich for a subset of tumour cells with tumour-initiating capabilities and was therefore suggested to mark colon cancer stem cells. However, this molecule has surprisingly been shown to lack functional importance for tumour initiation itself. Herein, we investigated whether CD133 may be relevant for colon cancer metastasis in patients, and as metastasis requires several additional biological characteristics besides tumour initiation, we examined the effects of knocking down CD133 expression in colon cancer cell lines on proliferation, migration, invasion, and colony formation. We demonstrate that high CD133 expression correlates strongly with synchronous liver metastasis in a matched case-control collection, while siRNA-mediated knock down of this factor has no significant effect on the mentioned biological characteristics. Thus, we conclude that CD133 expression is a marker with high prognostic impact for colon cancer, while it seems to have no obvious functional role as a driving force of this malignancy.

Video from Stanford about CSC

Cancer Stem Cells: The Origin of Cancer. Video (Runtime: 00:48:26) produced by Stanford University Medical Center, February 11, 2009. Description:

Irving Weissman, professor of developmental biology at Stanford University Medical Center, addresses what cancer stem cells are, how they maintain themselves and why they may be resistant to some current treatments. Weissman also talks about the "don't eat me" signal and how it relates to the growth of certain types of cancer cells. Find out how Stanford scientists and clinicians are working to identifying cancer stem cells in many types of tumors and how they have used that information to develop new therapeutic strategies.

Comment: Captions are available for this video. If viewed using QuickTime, the captions will be visible when the video is launched. (Unfortunately, the captions haven't been copyedited by the speaker, and contain some errors).

Alloreactive NK cells detect and target leukemic SCs

Human acute myeloid leukemia CD34+CD38– stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells by Ulrich Langenkamp and 6 co-authors, including Aleksandra Wodnar-Filipowicz, Haematologica 2009(Jul 16) [Epub ahead of print][FriendFeed entry][Early version of the full text PDF]. PubMed Abstract:

The concept of tumor immunosurveillance has raised prospects for natural killer (NK) cell-based immunotherapy of human cancer. The cure of acute myeloid leukemia (AML) may depend on eradication of leukemic stem cells (LSCs), the self-renewing component of leukemia. Whether NK cells can recognize and lyse LSCs is not known. To develop strategies that effectively target AML-LSCs, we investigated anti-leukemic effects of human alloreactive single KIR(+) NK cells. NK effectors with KIR specificity mismatched with respect to HLA class I allotype of target cells effectively recognized AML-LSCs defined phenotypically as CD34(+)CD38(-), while healthy bone marrow-derived CD34(+)CD38(-) hematopoietic stem cells were spared, as demonstrated by cytotoxicity and hematopoietic colony-forming assays. The HDAC inhibitor valproic acid augmented the activating NKG2D ligand-dependent lysis of AML-CD34(+)CD38(-) LSCs. These results show that alloreactive NK cells have the potential to detect and target LSCs, and thus to improve the treatment outcome in AML.

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].

Partnership to develop new colon cancer drugs

Ontario joins top researchers, Pfizer, to develop new colon cancer drugs by Amy Fuller, Canadian Press (via Winnipeg Free Press), July 15, 2009. (See also the same news release, via Yahoo News). First two paragraphs:

The fight against colon cancer got an infusion of funds Wednesday as the Ontario government and leading medical research centres joined with the world's largest pharmaceutical research company to develop new drugs.

Pfizer, a New York-based company with 1,400 employees across Canada, is partnering with the Ontario Cancer Institute and the Ontario Institute for Cancer Research in a $6.9-million collaboration over three years.

See also: Pfizer Gives $5.4M for Ontario Cancer Research Project, GenomeWeb Daily News, July 16, 2009. [Free registration required][Twitter entry]. Excerpts:

Pfizer Global Research and Development will collaborate with two Ontario institutes to discover and validate targets that could be used to diagnose, predict, or treat colorectal cancer.

.....

Ben Neel, who is director of OCI and is serving as a principal investigator on the project, said in a statement that the collaboration will "join the world class genomics and informatics programs at OICR, cutting edge research in cancer stem cell biology and functional genomics at OCI/PMH and the world's largest pharmaceutical company in a concerted effort to bring new therapies to colon cancer patients worldwide."

More on immune based therapies for the treatment of cancers

ImmunoCellular Therapeutics Retains Services of Torrey Pines Institute for Molecular Studies and Renowned Immunologist to Evaluate Lead Product Candidate, Business Wire, July 14, 2009. Excerpts:

ImmunoCellular Therapeutics, Ltd. (OTCBB: IMUC), a clinical-stage biotechnology company that is developing immune based therapies for the treatment of brain and other cancers, announced today that it has retained the services of the Torrey Pines Institute for Molecular Studies in San Diego, CA, to evaluate the immunogenicity of peptides to target cancer stem cells (CSC’s) relating to the Company’s lead product candidate ICT-121. The evaluation will be conducted by Dr. Clemencia Pinilla, a specialist in immune response mechanisms and their role in the prevention and cause of human disease with over 100 publications and multiple patents to her credit.

.....

ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs.

Relevant links: Profile of Clemencia Pinilla, of the Torrey Pines Institute for Molecular Studies in San Diego, California; and, Opinion: A Stem of Hope for Cancer Treatments by Manish Singh (President and CEO of IMUC), Genetic Engineering & Biotechnology News, June 12, 2009. [Previous blog post: Bright future for CSC therapies?, June 14, 2009].

Note that it is important that CSC-targeted vaccination "should not lead to immune reaction to normal cells that may express common antigens". For a recent publication from which this quotation is taken, see: Antigen-Specific T Cell Response from Dendritic Cell Vaccination Using Cancer Stem-like Cell-Associated Antigens by Qijin Xu and 8 co-authors, including John S Yu, Stem Cells 2009(Apr 23) [Epub ahead of print][PubMed Citation]. (John S Yu is Chief Scientific Officer and Chairman of the Board of IMUC, see: Our Team - IMUC).

For some background about immune based therapies for the treatment of cancer, see: Cancer Vaccines by Preeti Gokal Kochar, ProQuest Discovery Guide, January 2006.

See also: Connotea bookmarks matching tag CD133.

Differentially expressed genes in cell lines of differing lymphatic metastatic ability

Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment by Terlika S Pandit and 11 co-authors, including Ann F Chambers and Alan B Tuck, Int J Oncol 2009(Aug); 35(2): 297-308. [FriendFeed entry]. PubMed Abstract:

Although lymphatic dissemination is a major route for breast cancer metastasis, there has been little work to determine what factors control the ability of tumor cells to survive, establish and show progressive growth in a lymph node environment. This information is of particular relevance now, in the era of sentinel lymph node biopsy, where smaller intranodal tumor deposits are being detected earlier in the course of disease, the clinical relevance of which is uncertain. In this study, we compared differentially expressed genes in cell lines of high (468LN) vs. low (468GFP) lymphatic metastatic ability, and related these to clinical literature on genes associated with lymphatic metastatic ability and prognosis, to identify genes of potential clinical relevance. This approach revealed differential expression of a set of genes associated with 'cancer stem cell-like' properties, as well as networks of genes potentially associated with survival and autonomous growth. We explored these differences functionally and found that 468LN cells have a higher proportion of cells with a cancer stem cell-like (CD44+/CD24-) phenotype, have a higher clonogenic potential and a greater ability to survive, establish and grow in a foreign (lymph node and 3D Matrigel) microenvironment, relative to 468GFP cells. Differentially expressed genes which reflect these functions provide candidates for investigation as potential targets for therapy directed against early lymphatic metastasis.

Lecture on stem cells and cancer

The 2009 Summer Symposium of the David H. Koch Institute for Integrative Cancer Research of MIT was on Understanding Metastasis. The Symposium was held on June 19, 2009. One of the lectures in the morning session was on "Stem cells and cancer", by Sean Morrison (University of Michigan) [FriendFeed entry]. A video (35 min) of the lecture can be accessed via the program. One example of a noteworthy slide is the one that's shown for 10 seconds, from 28:38 to 28:48 (entitled: "Nobody has yet tested which cells actually contribute to disease in patients"), in which it's pointed out that the "Fate of cells within patients is unclear ...".

Another lecture, at the same Symposium, addresses this issue (within the context of the theme of the Symposium, "Understanding Metastasis"). It's "Monitoring the fate of cancer cells during metastasis", by Ann Chambers (Regional Cancer Center, London, Ontario). A video (25 min) of her lecture can also be accessed via the program.

CSC as a future avenue of research on breast cancer

Neoadjuvant chemotherapy for early breast cancer by J Sven D Mieog‌ and Cornelis JH van de Velde‌, Expert Opin Pharmacother 2009(Jun); 10(9): 1423-34. [PubMed Citation][ResearchGATE entry][FriendFeed entry]. Last sentence of the abstract:

In the near future, intraoperative fluorescent imaging and targeting of cancer stem cells will become important avenues of research.

Gordon Conference on Stem Cells and Cancer

The 2009 second Gordon Conference on Stem Cells and Cancer is scheduled for September 13-18, 2009, at Les Diablerets Conference Center, Les Diablerets, Switzerland. Chair: Maarten Van Lohuizen. Vice Chair: Catriona Jamieson. "Applications for this meeting must be submitted by August 23, 2009". [Program][FriendFeed entry].

The first Gordon Conference on Stem Cells and Cancer was held on September 9-14, 2007, at Big Sky Resort, Big Sky, MT, USA.

Therapeutic monoclonal antibody targeting of AML-LSCs

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

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.

This news release is about the 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 Abstract:

Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+)CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.