Category Archives: Stem Cell Therapy

Critical molecular pathways in cancer stem cells of chronic myeloid leukemia by Y Chen, C Peng, C Sullivan, D Li and S Li, Leukemia 2010(Sep); 24(9): 1545-54. Epub 2010 Jun 24. [Connotea bookmark][PubMed citation][Full text]. The abstract of this OA review:

Inhibition of BCR-ABL with kinase inhibitors in the treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) is highly effective in controlling but not curing the disease. This is largely due to the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for disease relapse. This stem cell resistance is not associated with the BCR-ABL kinase domain mutations resistant to kinase inhibitors. Development of curative therapies for CML requires the identification of crucial molecular pathways responsible for the survival and self-renewal of LSCs. In this review, we will discuss our current understanding of these crucial molecular pathways in LSCs and the available therapeutic strategies for targeting these stem cells in CML.

Insights into the stem cells of chronic myeloid leukemia by I Sloma, X Jiang, A C Eaves and C J Eaves, Leukemia 2010(Sep 23). [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.

Surprise breast cancer source by Jennifer Welsh,TheScientist.com, September 2, 2010. First paragraph:

Some breast cancer tumors may not originate from stem cells as previously believed, according to a study published in the September 3rd issue of Cell Stem Cell. The discovery is an important step in the development of treatments for these cancers.

This news story is based on the publication: BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells by Gemma Molyneux and 11 co-authors, including Matthew J Smalley, Cell Stem Cell 2010(Sep 3); 7(3): 403-417. OA article [Full text] [PubMed citation].

A commentary: Cancer Cell of Origin: Spotlight on Luminal Progenitors by Christine L Chaffer and Robert A Weinberg, Cell Stem Cell 2010(Sep 3); 7(3): 271-272. [PubMed citation].

Tumor-Initiating Cells Are Rare in Many Human Tumors by Kota Ishizawa and 16 co-authors, including Benjamin G Neel and William Matsui, Cell Stem Cell 2010(Sep 3); 7(3): 279-282. [FriendFeed entry][PubMed citation]. Abstract:

Tumor-initiating cells (TICs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be relatively rare in most human cancers. Recent data in melanoma indicate that the frequency of TICs increases dramatically via more permissive xenotransplantation conditions, raising the possibility that the true frequency of TICs has been greatly underestimated in most human tumors. We compared the growth of human pancreatic, non-small cell lung, and head and neck carcinomas in NOD/SCID and NSG mice. Although TIC frequency was detected up to 10-fold higher in NSG mice, it remained low (<1 in 2500 cells) in all cases. Moreover, aldehyde dehydrogenase-positive (ALDH(+)) and CD44(+)CD24(+) cells, phenotypically distinct cells enriched in TICs, were equally tumorigenic in NOD/SCID and NSG mice. Our findings demonstrate that TICs are rare in these cancers and that the identification of TICs and their frequency in other human malignancies should be validated via primary tumors and highly permissive xenotransplantation conditions.

Do we have to kill the last CML cell? DM Ross, TP Hughes and JV Melo, Leukemia 2010(Sep 16) [Epub ahead of print][FriendFeed entry][PubMed citation][Full text]. The abstract of this OA review:

Previous experience in the treatment of chronic myeloid leukaemic (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR; no detectable BCR-ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemic, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemic cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemic clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML.

Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens by Kristen M Smith and 16 co-authors, including David R Kaplan, EMBO Mol Med 2010(Aug 18) [Epub ahead of print][Full text]. Abstract:

Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies.

See also: New Twist on Drug Screening to Treat Common Childhood Cancer, ScienceDaily, August 18, 2010. Excerpt:

A study led by scientists at The Hospital for Sick Children (SickKids) reveals a new method of identifying drugs to treat children suffering from fatal cancers for which an effective treatment has not been found. Rather than developing a new drug from scratch, which is a complicated and time-consuming process, they tried a different approach: in the lab, they tested existing drugs on cancer stem cells from young patients with neuroblastoma, one of the common cancers of infants and children.

A related blog post is: High-throughput cancer stem cell-based screening assay for therapeutic compounds by Alexey Bersenev, Stem Cell Assays, August 19, 2010 [FriendFeed entry].

1) Cancer Stem Cells in Pancreatic Cancer by Qi Bao and 6 co-authors, including Karl-Walter Jauch and Christiane J Bruns, Cancers 2010(Aug 19); 2(3): 1629-41. [Full text PDF][Scribd entry][Part of the Special Issue Pancreatic Cancer]. Abstract:

Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer.

2) The Emerging Role of the Phosphatidylinositol 3-Kinase/ Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cell Biology by Alberto M Martelli and 4 co-authors, including James A McCubrey, Cancers 2010(Aug 18); 2(3): 1576-96. [Part of the Special Issue Cancer Stem Cells].

Comment: Review #2 is the first paper that has been published in the special issue on Cancer Stem Cells. As of August 20, 17 more contributions to this special issue are planned. Review #1, although about CSCs, is a contribution to a separate special issue on Pancreatic Cancer.

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein by Marcus Järås and 10 co-authors, including Thoas Fioretos, Proc Natl Acad Sci USA 2010(Aug 30). OA article. [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.

Adult lung stem cells, vital to injury repair, associated with poor cancer prognosis, News release, UCLA Newsroom, August 17, 2010. Excerpts:

Adult stem cells that are vital for airway repair in the lung but that persist in areas where pre-cancerous lesions are found are associated with a poor prognosis in patients who develop cancer, even those with early-stage disease, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.

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In this study, Gomperts and her team screened around 900 tumors removed from patients with non-small cell lung cancer at UCLA and the University of Texas' MD Anderson Cancer Center, looking to see whether the adult stem cells could be found in the tumor. In her lab, Gomperts is now studying the pre-cancerous lesions where the adult stem cells persist in an attempt to uncover the cascade of molecular events that may transform these cells into lung cancer stem cells.

The news release is based on this publication: Presence of a Putative Tumor-Initiating Progenitor Cell Population Predicts Poor Prognosis in Smokers with Non–Small Cell Lung Cancer by Aik T Ooi and 19 co-authors, including Brigitte N Gomperts, Cancer Res 2010(Aug 15); 70(16): 6639-48. [PubMed citation][Full text]. Abstract:

Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC.

Therapeutic implications of colon cancer stem cells by Eros Fabrizi and 3 co-authors, including Lucia Ricci-Vitiani, World J Gastroenterol 2010(Aug 21); 16(31): 3871-7. OA review. [FriendFeed entry][PubMed citation]. Abstract:

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.