Category Archives: Stem Cells

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.

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].

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.

.....

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.

ISCO to Present Data on Progress of Human Parthenogenetic Stem Cell Differentiation into Functional Liver Cells at the Annual Meeting of the American Association for the Study of Liver Diseases

International Stem Cell Corporation (OTCBB:ISCO), http://www.internationalstemcell.com, will present data on its progress toward producing human liver cells from immune-matched patient-specific parthenogenetic stem cells at The Liver Meeting^®, the 61^st Annual Meeting of the American Association for the Study of Liver Diseases (ASSLD), in Boston, MA from October 29 – November 2, 2010.

ISCO will present to a number of the world's leading liver specialists, a new method of obtaining highly enriched cultures of differentiated cells from pluripotent human stem cells, based on a natural physiological process. A follow-on presentation will demonstrate that differentiation protocols previously developed for human embryonic stem cells can, with some modification, be effectively applied to human parthenogenetic stem cells. These findings will be presented as part of the 'Stem Cell Poster Session' on November 1, 2010, and are entitled, 'Hepatocyte-like cells derived from patient-specific human parthenogenetic stem cells possess functions of mature human hepatocytes including P450 activity" and, "Derivation of highly enriched populations of hepatocytes from various types of human pluripotent stem cells using a novel physiological method."

Commenting on these presentations, ISCO's CEO, Andrey Semechkin, PhD, said: "We are pleased our research team is able to present and discuss these important findings at this highly prestigious meeting of The American Association for the Study of Liver Diseases, one of the leading organizations in the U.S. specializing in the health of the liver and attended by more than 7,500 physicians and scientists."

ISCO's Director of Research and Therapeutic Development, Nikolay Turovets, PhD, stated, "Presenting these new discoveries at this meeting demonstrates the progress we have made towards producing hepatic cells using our parthenotes, and form part of our ongoing efforts to develop and publicize the unique benefits of our human parthenogenetic stem cell platform to the scientific community. Over the past year, our research group has also presented data to the International Society for Stem Cell Research (ISSCR), the 8th Annual Meeting and the Human SCNT Workshop conducted by the California Institute for Regenerative Medicine (CIRM) and the Medical Research Council (MRC)".

In addition, ISCO announced today the signing of an agreement with Explora BioLabs, a leading California-based CRO specializing in conducting high-quality pre-clinical in vivo studies. Based on the results presented at this conference, ISCO will be initiating a series of pre-clinical animal experiments to study the engraftment and in vivo maturation of these cells.

ISCO's Vice President, Simon Craw, PhD, said: "Demonstrating that our human parthenogenetic stem cells can truly differentiate into mature cells, as well as the initiation of these animal studies represents important achievements towards demonstrating the validity of creating a bank of immune-matched human pluripotent stem cells and their therapeutic derivatives that can be used in clinical studies and, ultimately, be a valuable health resource for the growing field of regenerative medicine."

ABOUT INTERNATIONAL STEM CELL CORPORATION (ISCO.OB)

International Stem Cell Corporation is a California-based biotechnology company focused on therapeutic and research products. ISCO's core technology, parthenogenesis, results in creation of pluripotent human stem cells from unfertilized oocytes (eggs). These proprietary cells avoid ethical issues associated with use or destruction of viable human embryos and, unlike most other major stem cell types, can be immune matched and be a source of therapeutic cells with minimal rejection after transplantation into hundreds of millions of individuals of differing racial groups. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary, Lifeline Cell Technology, and is developing a line of cosmeceutical products via its subsidiary, Lifeline Skin Care. ISCO is advancing novel human stem cell-based therapies where cells have been proven to be efficacious but traditional small molecule and protein therapeutics have not. More information is available on ISCO's website, http://www.internationalstemcell.com.

To subscribe to receive ongoing corporate communications please click on the following link: http://www.b2i.us/irpass.asp?BzID=1468&to=ea&s=0.

FORWARD-LOOKING STATEMENTS

Statements pertaining to anticipated developments and therapeutic applications, the potential benefits of collaborations, affiliations, and other opportunities for the company and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates,") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products and the management of collaborations, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, application of capital resources among competing uses, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company's business, particularly those mentioned in the cautionary statements found in the company's Securities and Exchange Commission filings. The company disclaims any intent or obligation to update forward-looking statements.

Key Words: Stem cells, parthenogenesis, biotechnology

International Stem Cell Corporation
Ken Aldrich, Chairman
1-760-940-6383
kaldrich@intlstemcell.com
or
Nikolay Turovets, PhD
nturovets@intlstemcell.com

International Stem Cell Corporation and Insight Bioventures India Structure Indian Affiliate to Develop Stem Cell-Based Eye Care Therapeutics for India and Produce Research Products for Asia

International Stem Cell Corporation (OTCBB: ISCO), http://www.internationalstemcell.com, and Insight Bioventures India Private Limited (IBVI), (http://www.insightbioventures.in) today announced that they have agreed on financial and structural terms for establishment of an Indian affiliate of ISCO (ISCO India). This is an important milestone in ISCO and IBVI's goal to facilitate development and commercialization of ISCO's stem-cell derived corneal tissue, CytoCor™, and retinal cells, CytoRet™, for treatment of blindness and severe vision impairment as well as cell systems for drug screening in India and establish a manufacturing base for ISCO's Lifeline Cell Technology^® (Lifeline) brand of cell culture media for commercialization throughout Asia.

IBVI is an experienced biomedical business developer that facilitated the earliest cell therapy guidelines with the regulatory agencies in India and is well connected with Indian research and clinical centers, corporations and government. IBVI has now partnered with MARG Group (http://www.marggroup.com), one of India's fastest-growing infrastructure developers with interest in ports, airports, power plants, commercial spaces, special export zones and other integrated infrastructures, to form 'Insight-MARG Biofund' (Biofund). The MARG Group is the lead facilitator of Biofund, the largest of its nature in India so far and with great possibility for being complemented by Indian government grants.

ISCO is a public US biopharmaceutical company that has pioneered the creation of a new class of stem cells, 'human parthenogenetic stem cells', with broad therapeutic application potential and ability to form non-rejected, immune matched therapeutic cells for millions of people. Two ISCO therapeutic programs from this platform are CytoCor and CytoRet that offer first-in-class opportunities to treat diseases in the front and the back of the eye where surgery and traditional small molecule and protein therapeutics are not options. ISCO also markets and sells cell culture research products through its Lifeline affiliate and international distributors, including in Asia. Lifeline is interested in leveraging its expertise to develop live human cell systems for drug screening in India.

G.R.K. Reddy, MARG Group's founder and chairman, says, 'MARG Group and IBVI have formed Biofund to leverage our resources and network of cutting-edge research and clinical institutes, corporate entities and government agencies in India. We believe ISCO India's unique combination of novel therapeutics to address large unmet medical needs and current and near-term research product businesses will be a first successful Biofund investment and set the stage for subsequent ventures.'

The agreed financial and structural terms will enable formation of ISCO India as a majority-owned Indian affiliate of ISCO, initially with laboratories in India's first clinical research facility (CRF) for stem cells and regenerative medicine in Hyderabad with the intent to relocate to India's first platinum-rated research center, MARG Science Park (http://www.margsciencepark.com), in Chennai. The park is a member of International Association of Sciences Parks (IASP) and has established networking and alliances with renowned institutes and organizations. The affiliate will be managed jointly by a team of experienced managers in India and ISCO executives.

ISCO expects that manufacturing of Lifeline media products and shipping of cell products from this central Indian base will be established to supply the growing network of Lifeline's Asian distributors with high-quality products in a cost-efficient fashion. In parallel, ISCO India intends to explore development of Lifeline cell systems for drug screening in India. On the therapeutic side, ISCO India will leverage the access to leading eye care researchers, patients and regulatory agencies in India and advance the CytoCor and CytoRet cellular ophthalmology programs towards the clinic and through safety-efficacy trials.

Central to the operation will be continued collaboration with the ophthalmology scientists and clinicians at Sankara Nethralaya (http://www.sankaranethralaya.org) in Chennai established last spring. ISCO India will also collaborate with the Centre for Cellular and Molecular Biology (CCMB, http://www.ccmb.res.in) in Hyderabad that was instrumental in the establishment of the CRF and will be a joint CRF tenant with ISCO India. Both institutions are respected worldwide for their research in cellular science and therapy.

According to Dr. Jayaraman Packirisamy, Executive Director of IBVI, 'As we launch Biofund, ISCO India will provide an opportunity to address large unmet medical needs while establishing an ecosystem for the well-educated work force, world-class research and development facilities and investors in India. By combining manufacturing of existing and development of new research products with well-defined therapeutic development, we create an attractive risk-reward profile that is rarely seen in our industry.'

Brian Lundstrom, ISCO's President, adds 'ISCO wishes to collaborate with leading research and clinical groups like CCMB and Sankara Nethralaya for our cellular ophthalmology programs. Moreover, we have to manufacture our Lifeline media in Asia and ship those with our primary human cells from an Asian location in order to supply that fast-growing market with the highest possible quality products in a cost-efficient manner. The combination of well-proven Indian research and clinical institutes, world-class facilities, and funding from the Insight-MARG Biofund provides ISCO with a unique way to advance our programs and businesses without additional US capital investment or issuance of equity shares.'

ABOUT INSIGHT BIOVENTURES INDIA

Insight Bioventures Private Limited (IBVI) is the Asian member of Insight Bioventures founded in 1997 to apply a multidimensional approach to value creation in the international life sciences community while placing client's interests first. IBVI operates through a team of experienced associates and partners from the pharmaceutical industry, academic research and the financial sector. The company maintains long-standing relationships with opinion leaders in different therapeutic areas that assist in evaluation and advancement of innovative product concepts and medical businesses. IBVI has made tissue engineering and cell therapy a major technology focus and works with recognized leaders in these areas, e.g. Sristi Biosciences and International Stem Cell Corporation. IBVI has partnered with strong Indian corporations and high net worth individuals to establish a dedicated 'Biofund' to finance the best novel technologies for Indian development and with potential to address large unmet medical needs in the Asian market. More information is available on IBVI's website: http://www.insightbioventures.in.

ABOUT INTERNATIONAL STEM CELL CORPORATION (ISCO.OB)

International Stem Cell Corporation is a California-based biotechnology company focused on therapeutic and research products. ISCO's core technology, parthenogenesis, results in creation of pluripotent human stem cells from unfertilized oocytes (eggs). These proprietary cells avoid ethical issues associated with use or destruction of viable human embryos and, unlike most other major stem cell types, can be immune matched and be a source of therapeutic cells with minimal rejection after transplantation into hundreds of millions of individuals of differing racial groups. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary, Lifeline Cell Technology, and is developing a line of cosmeceutical products via its subsidiary, Lifeline Skin Care. ISCO is advancing novel human stem cell-based therapies where cells have been proven to be efficacious but traditional small molecule and protein therapeutics have not. More information is available on ISCO's website.

To subscribe to receive ongoing corporate communications please click on the following link: http://www.b2i.us/irpass.asp?BzID=1468&to=ea&s=0.

FORWARD-LOOKING STATEMENTS

Statements pertaining to anticipated developments and therapeutic applications, the potential benefits of collaborations, affiliations, and other opportunities for the company and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates,") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products and the management of collaborations, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, application of capital resources among competing uses, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company's business, particularly those mentioned in the cautionary statements found in the company's Securities and Exchange Commission filings. The company disclaims any intent or obligation to update forward-looking statements.

Key Words: Stem cells, parthenogenesis, cornea, retina, research products, biotechnology, India

International Stem Cell Corporation
Brian Lundstrom, President
+1-510-220-5599
bl@intlstemcell.com
or
Insight Bioventures India Private Limited
Dr. Jayaraman Packirisamy, Executive Director
+91-98489-12260
jayaram@insightbioventures.in