Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Researchers Block Pathway to Cancer Cell Replication

NOTCH1 Signaling Promotes T-Cell Acute Lymphoblastic Leukemia-Initiating Cell Regeneration

Research suggests that patients with leukemia sometimes relapse because standard chemotherapy fails to kill the self-renewing leukemia initiating cells, often referred to as cancer stem cells. In such cancers, the cells lie dormant for a time, only to later begin cloning, resulting in a return and metastasis of the disease.

One such type of cancer is called pediatric T cell acute lymphoblastic leukemia, or T-ALL, often found in children, who have few treatment options beyond chemotherapy.

A team of researchers – led by Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine and Director of Stem Cell Research at UC San Diego Moores Cancer Center – studied these cells in mouse models that had been transplanted with human leukemia cells. They discovered that the leukemia initiating cells which clone, or replicate, themselves most robustly activate the NOTCH1 pathway, usually in the context of a mutation.

Earlier studies showed that as many as half of patients with T-ALL have mutations in the NOTCH1 pathway – an evolutionarily conserved developmental pathway used during differentiation of many cell and tissue types. The new study shows that when NOTCH1 activation was inhibited in animal models using a monoclonal antibody, the leukemia initiating cells did not survive. In addition, the antibody treatment significantly reduced a subset of these cancer stem cells (identified by the presence of specific markers, CD2 and CD7, on the cell surface.)

“We were able to substantially reduce the potential of these cancer stem cells to self-renew,” said Jamieson. “So we’re not just getting rid of cancerous cells: we’re getting to the root of their resistance to treatment – leukemic stem cells that lie dormant.”

The study results suggest that such therapy would also be effective in other types of cancer stem cells, such as those that cause breast cancer, that also rely on NOTCH1 for self-renewal.

“Therapies based on monoclonal antibodies that inhibit NOTCH 1 are much more selective than using gamma-secretase inhibitors, which also block other essential cellular functions in addition to the NOTCH1 signaling pathway,” said contributor A. Thomas Look, MD of Dana-Farber/Children Hospital Cancer Center in Boston. “We are excited about the promise of NOTCH1-specific antibodies to counter resistance to therapy in T-ALL and possibly additional types of cancer.”

In investigating the role of NOTCH1 activation in cancer cell cloning, the researchers showed that leukemia initiating cells possess enhanced survival and self-renewal potential in specific blood-cell, or hematopoietic, niches: the microenvironment of the body in which the cells live and self-renew.

The scientists studied the molecular characterization of CD34+ cells – a protein that shows expression in early hematopoietic cells and that facilitates cell migration – from a dozen T-ALL patient samples.

They found that mutations in NOTCH1 and other genes capable of promoting the survival of cancer stem cells co-existed in the CD34+ niche. Mice transplanted with CD34-enriched NOTCH1 mutated T-ALL cells demonstrated significantly greater leukemic cloning potential than did mice without the NOTCH1 mutation. The mutated cells were uniquely susceptible to targeted inhibition with a human monoclonal antibody, according to the scientists.

Additional contributors to the study include Wenxue Ma, Daniel J. Goff, Ifat Geron, Anil Sadarangani, Christina A. M. Jamieson, Angela C. Court, Alice Y. Shih, Qingfei Jiang, Christina C. Wu, Kristen M. Smith, Leslie A. Crews, Ida Deichaite, Sheldon R. Morris and Dennis A. Carson, UC San Diego Department of Medicine and Stem Cell Program, UC San Diego Moores Cancer Center; Alejandro Gutierrez, Dana-Farber/Children Hospital Cancer Center in Boston; and Kang Li, Ping Wei and Neil W. Gibson, Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego.

This work was supported by the Ratner Family Foundation, the Leichtag Family Foundation, and Moores Cancer Center Donor Funds; grants from the National Institute of Health (1K08CA133103 and 5P01CA68484); the William Lawrence Foundation, and the American Society of Hematology-Amos Medical Faculty Development program. Jamieson’s work was supported by the California Institute for Regenerative Medicine (CIRM).

Debra Kain | Newswise Science News
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>