Category Archives: Stem Cells

By Suling Liu, Hasan Korkaya, and Max S. Wicha | April 1, 2012

Inthe 30-year battle waged since the initiation of the war on cancer, there have been substantial victories, with cures for childhood malignancies among the most important. Our ever-expanding understanding of cellular and molecular biology has provided substantial insights into the molecular underpinnings of the spectrum of diseases we call cancer. Yet, while researchers view this as tremendous progress, many patients have seen only limited improvement. In fact, the relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.

Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemythe cancer stem cell. Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease.

The idea that cancers are driven by cells with embryonic features is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ.

A number of groups, including our own, have identified cancer stem cell markers enabling the isolation and characterization of these cells. In addition, the development of in vitro and mouse functional assays has led to a veritable explosion of research on cancer stem cells from both blood-derived malignancies and solid tumors., However, the limitations of these markers and assays have generated heated debate regarding which tumors follow a stem cell model, and which do not. New data from our lab and from others is helping to clarify some of these areas of debate with the goal of better understanding how these cells can be identified and characterized.

A cancer stem cell (CSC) is defined as a cell that has the ability to self-renew, dividing to give rise to another malignant stem cell, as well as to produce the phenotypically diverse, differentiated tumor cells that form the bulk of the tumor. Evidence for CSCs was first documented in leukemia, where it was clear that only a small subset of cancer cells was capable of perpetuating the cancer upon serial transplantation from one mouse to another. Extensive knowledge of normal blood stem cells facilitated our recognition and understanding of leukemia stem cells. Evidence for CSCs in solid tumors has been more controversial, because it is more technically challenging to divide a solid mass into individual cells without damage or alteration, and knowledge of the properties of normal-tissue stem cells in these organs is more limited. However, some of the areas of contention may be resolved by continuing research into the biology of these CSCs.

Relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.

One of the points of confusion in CSC biology is the question of where these cells come from. Do they arise from normal stem cells that have become cancerous through mutation, or do they arise from partially differentiated tissue-progenitor cells that have acquired the ability to self-renew? Recent evidence suggests CSCs may arise from either source.

A second misconception is that the definition of CSCs precludes the possibility that cancers arise from sequential mutations that accumulate over many cell generations and are selected for through a Darwinian processthe so-called clonal evolution model. Some have proposed that the CSC model is a competing theory of carcinogenesis. In fact, both models may be correct. There is evidence that CSCs may also be genetically unstable, resulting in clonal evolution that generates several distinct CSC clones in a tumor.

While the identification of CSC markers and the development of in vitro and mouse models have led to important advances in the field, each of these markers and models has limitations that have fueled debate. Markers used to isolate cancer stem cells, such as CD44, CD24, CD133, aldehyde dehydrogenase (ALDH), and Hoechst dye exclusion, have proven useful for identifying these cell populations in tumor samples. However, expression of these markers is highly dependent on experimental conditions such as culture medium and oxygen concentration. Similarly, in vitro assays that rely on the ability to form spherical colonies in suspension can be useful, but are notoriously inaccurate. Since the definition of CSCs is ultimately an operational one, the most reliable assay for these cells has been their ability to initiate tumors when transplanted into mouse models. Because the immune system will reject any implanted foreign tissue, researchers have had to use immunosuppressed mice to test for human CSCs. In some tumor types, such as melanoma, the proportion of cells capable of initiating tumors is dependent on the degree of immunosuppression in the mouse models utilized. However, the more immunosuppressed mouse models may actually overestimate the true frequency of CSCs.

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Are Cancer Stem Cells Ready for Prime Time?

A leukemia patient who was twice turned down by a Shanghai stem cell donor recovered from the disease after receiving her mother's half-match stem cells and a unit of umbilical cord blood from Shanghai.

Jiang Jing, a 23-year-old Jiangsu Province native, left the transplant cabin at No. 1 Hospital affiliated with Suzhou University yesterday, fully recovered.

Jiang's saga was dramatic. She was diagnosed with acute leukemia on April 1 last year and was informed by the hospital that a full match donor was found in September. The transplant was scheduled for March 6 this year.

Jiang started to undergo therapy for stem cell transplant on February 24 to suppress her immune system, paving the way for the healthy stem cells from the donor, a Shanghai university student.

However the donor backed out on March 1. She agreed a second time to give a donation on March 5 but again backed away, this time leaving the hospital secretly at midnight after receiving an injection as preparation for the donation. There were reports that the would-be donor, who was not named, faced pressure from her family to forego the procedure.

Since medication had stopped Jiang's blood-forming function on March 6, she could survive for only seven days if not undergoing transplant. Doctors decided to transplant her mother's half-match stem cells and a unit of umbilical cord blood from the Shanghai Cord Blood Bank.

The umbilical cord blood, which had an 80 percent match to Jiang, was used to reduce rejection and streamline the transplant.

Though the incident had a happy ending, it has stirred wide discussion online as some web users accused the student of putting the patient's life in danger through her actions.

But health insiders said people must have the right to change their minds.

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Eastday-Rejected by donor, leukemia patient saved by mother

Dublin - Research and Markets (http://www.researchandmarkets.com/research/bac5f5c5/strategic_developm) has announced the addition of the "Strategic Development of Neural Stem & Progenitor Cell Products" report to their offering.

Overview: Neurogenesis is the process by which neurons are created. This process is most active during pre-natal development when neurogenesis is responsible for populating the growing brain. Neural stem cells (NSCs) are the self-renewing, multipotent cells that differentiate into the main phenotypes of the nervous system. These cell types include neurons, astrocytes, and oligodendrocytes. Neural progenitor cells (NPCs) are the progeny of stem cell division that normally undergo a limited number of replication cycles in vivo.

The terms neuronal and neural also need to be defined. Technically speaking, neuronal means pertaining to neurons, and neural means pertaining to nerves, which are the cordlike bundles of fibers made up of neurons. Since both terms ultimately are descriptive of neurons, the scientific community uses the terms "neuronal" and "neural" interchangeably. The complexity of this issue is explored from a marketing perspective within this report.

In 1992, Reynolds and Weiss were the first to isolate neural stem cells from the striatal tissue of adult mice brain tissue, including the subventricular zone, which is a neurogenic area. Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain, including non-neurogenic areas like the spinal cord, and from other species, including humans. During the development of the nervous system, neural progenitor cells can either stay in the pool of proliferating undifferentiated cells or exit the cell cycle and differentiate.

This market report focuses on recent advances in NSC research applications, explores research priorities by market segment, highlights individual labs and end-users of neuronal stem cell research products, explores the competitive environment for NSC research products, and provides 5-year growth and trend analysis. It provides detailed guidance for companies that wish to offer strategically positioned NSC research products, including cells, kits, assays, and related media and reagents.

This Market Report Includes:

- Recent advances in NSC research applications

- Research priorities by market segment

- Competitive analysis of NSC research supply companies

- Segmentation of existing NSC products

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Research and Markets: Strategic Development of Neural Stem & Progenitor Cell Products

Public release date: 29-Mar-2012 [ | E-mail | Share ]

Contact: Melissa Marino melissa.marino@vanderbilt.edu 615-322-4747 Vanderbilt University Medical Center

Vanderbilt-Ingram Cancer Center researchers have identified a new population of intestinal stem cells that may hold clues to the origin of colorectal cancer.

This new stem cell population, reported March 30 in the journal Cell, appears to be relatively quiescent (inactive) in contrast to the recent discovery of intestinal stem cells that multiply rapidly and is marked by a protein, Lrig1, that may act as a "brake" on cell growth and proliferation.

The researchers have also developed a new and clinically relevant mouse model of colorectal cancer that investigators can now use to better understand where and how the disease arises, as well as for probing new therapeutic targets.

Colorectal cancer is the second leading cause of cancer deaths in the United States. These tumors are thought to arise from a series of mutations in intestinal stem cells, which are long-lived, self-renewing cells that gives rise to all cell types in the intestinal tract.

For more than 30 years, scientists believed that intestinal stem cells were primarily quiescent, proliferating only rarely in order to protect the tissue against cancer. Then, in 2007, researchers reported finding a population of intestinal stem cells (marked by the molecule Lgr5) that were highly proliferative.

Those findings "really changed the way we think about intestinal stem cells," said Robert Coffey, Jr., M.D., Ingram Professor of Cancer Research, co-chair of Vanderbilt's Epithelial Biology Center and senior author on the study.

"It came to so dominate the field that it raised the question about whether quiescent stem cells even existand that's where we enter into the picture."

Coffey's lab studies the epidermal growth factor (EGF) signaling pathway which includes a family of receptors known as ErbBs and its role in cancers of epithelial tissues, like the intestinal tract.

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Newly identified stem cells may hold clues to colon cancer

ROCKVILLE, Md., March 28, 2012 /PRNewswire/ --Neuralstem, Inc. (NYSE Amex: CUR) announced that safety results from the first 12 patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) to receive its stem cells were reported online in the peer-reviewed publication, STEM CELLS, on March 13th. "Lumbar Intraspinal Injection of Neural Stem Cells in Patients with ALS: Results of a Phase I Trial in 12 Patients" (http://www.ncbi.nlm.nih.gov/pubmed/22415942.1) reports that one patient has shown improvement in his clinical status, even though researchers caution that the study was not designed to show efficacy. Additionally, there was no evidence of accelerated disease progression due to the intervention in any of the 12 patients, who were followed from 6-18 months after they were transplanted with the cells. All of the patients, who received transplants in the lumbar (lower back) region, tolerated the treatment without any long-term complications related to either the surgery or the cells.

(Logo: http://photos.prnewswire.com/prnh/20061221/DCTH007LOGO )

The 12 patients, part of the ongoing Phase I trial to evaluate the safety of Neuralstem's stem cells and transplantation procedure in patients with ALS, were the first in the world to receive intraspinal stem cell injections. Results from these patients were also were reported at the American Academy of Neurology Annual Meeting last September.

Based on a positive safety assessment, the trial has now been approved by the FDA to progress to transplanting ALS patients in the cervical (upper back) region of the spine, where the goal is to protect the motor neurons which affect respiratory function, and possibly prolong life. The fourteenth patient was transplanted earlier this month. All patients were treated at Emory University Hospital in Atlanta, Georgia.

"For these first 12 patients, we have met the objective of the Phase I trial, demonstrating safety for both the procedure of intraspinal injection and the presence of the neural stem cells in the spinal cords of ALS patients," said Jonathan Glass, MD, lead author of the publication. "We are encouraged by these results and have now advanced our trial to injections into the cervical spinal cord, targeting the motor neurons that control respiratory function." Dr. Glass is Professor of Neurology and Pathology at Emory University School of Medicine, as well as the Director of the Emory ALS Center.

"This important peer-reviewed publication reinforces our belief that we have demonstrated a safe, reproducible and robust route of administration into the spine for these spinal cord neural stem cells," said Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. "The publication covers data up to 18 months out from the original surgery. However, we must be cautious in interpreting this data, as this trial was neither designed nor statistically powered to study efficacy." Dr. Feldman is senior author on the study, principal investigator (PI) of the ALS trial and serves as a consultant to Neuralstem as part of her University of Michigan activities.

"As this article points out, our experience in the lumbar spinal cord has been overwhelmingly positive," commented Karl Johe, PhD, study author and Neuralstem Chairman and Chief Scientific Officer. "We have already transplanted two patients in the cervical spinal cord, where we believe we can affect patients' lives the most by improving their breathing. We are in active discussions with the FDA to increase the number of cells and the number of injections as well."

"We wish to thank the teams at Michigan and Emory for the tireless efforts required to refine this breakthrough method of administration of our neural stem cells. We'd also like to thank the patients and families involved in the trial," said Richard Garr, Neuralstem CEO and President. "The progress we have made to date is both substantial, and a true team effort."

About the Study

Safety results were reported on the first 12 patients in an ongoing Phase I study to evaluate the safety of Neuralstem's spinal cord stem cells (HSSC's), as well as the transplantation technique, in the treatment of ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

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Neuralstem ALS Stem Cell Trial Interim Results Reported in the Journal, STEM CELLS

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Verastem, Inc., (NASDAQ: VSTM - News) a biopharmaceutical company focused on discovering and developing drugs to treat breast and other cancers by targeting cancer stem cells (CSCs), congratulates Robert Weinberg, Ph.D., Verastem co-founder and co-chair of the Scientific Advisory Board, and announces the presentation of preclinical data at the American Association for Cancer Research annual meeting being held March 31 to April 4, 2012, in Chicago, IL.

Dr. Weinberg has been awarded the 2012 Pezcoller Foundation-AACR International Award for Cancer Research for his outstanding work in the fields of cancer genetics and cell biology. Dr. Weinberg will deliver an award lecture entitled Epithelial-Mesenchymal Transition, Cancer Stem Cells and Metastasis at the annual meeting on Monday, April 2, 2012.

Verastem will present data on its programs targeting the focal adhesion kinase (FAK; VS-4718 and VS-5095) and Wnt/Beta-catenin (VS-507) signaling pathways. Research on the FAK and Wnt/Beta-catenin signaling pathways has revealed critical roles for each in the survival and metastatic capability of CSCs. Verastem will present data on FAK and Wnt inhibition in preclinical cancer models as well as data on the development of biomarkers for companion diagnostic tests to identify CSCs.

The schedule for Dr. Weinbergs award address and Verastems poster presentations is as follows:

Dr. Weinbergs award lecture: Date & Time: Monday, April 2, 2012, at 5:30 p.m. (CT) Title: Epithelial-Mesenchymal Transition, Cancer Stem Cells and Metastasis Location: Skyline Ballroom of McCormick Place

Verastems poster presentations: Date & Time: Monday, April 2, 2012, from 1:00 to 5:00 p.m. (CT) Poster Title: The FAK Inhibitors VS-4718 and VS-5095 Attenuate Breast Cancer Stem Cell Function In Vitro and Tumor Growth In Vivo Abstract Number: LB-192 Location: McCormick Place West (Hall F), Poster Section 38

Date & Time: Monday, April 2, 2012, from 1:00 to 5:00 p.m. (CT) Poster Title: The Wnt Inhibitor VS-507 Reduces Cancer Stem Cell Function In Vitro and Tumorigenicity in Mice Abstract Number: LB-194 Location: McCormick Place West (Hall F), Poster Section 38

Date & Time: Monday, April 2, 2012, from 1:00 to 5:00 p.m. (CT) Poster Title: An Alternative Splicing Signature that Identifies Breast Cancer Stem Cells Abstract Number: LB-197 Location: McCormick Place West (Hall F), Poster Section 38

About Verastem, Inc.

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Verastem Congratulates Co-founder Robert Weinberg and Announces the Presentation of Data at the 2012 AACR Annual Meeting