Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Block Pathway to Cancer Cell Replication

04.07.2012
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:
http://www.ucsd.edu

More articles from Life Sciences:

nachricht Scientists enlist engineered protein to battle the MERS virus
22.05.2017 | University of Toronto

nachricht Insight into enzyme's 3-D structure could cut biofuel costs
19.05.2017 | DOE/Los Alamos National Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

Im Focus: Using graphene to create quantum bits

In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.

In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...

Im Focus: Bacteria harness the lotus effect to protect themselves

Biofilms: Researchers find the causes of water-repelling properties

Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...

Im Focus: Hydrogen Bonds Directly Detected for the First Time

For the first time, scientists have succeeded in studying the strength of hydrogen bonds in a single molecule using an atomic force microscope. Researchers from the University of Basel’s Swiss Nanoscience Institute network have reported the results in the journal Science Advances.

Hydrogen is the most common element in the universe and is an integral part of almost all organic compounds. Molecules and sections of macromolecules are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

Innovation 4.0: Shaping a humane fourth industrial revolution

17.05.2017 | Event News

Media accreditation opens for historic year at European Health Forum Gastein

16.05.2017 | Event News

 
Latest News

New approach to revolutionize the production of molecular hydrogen

22.05.2017 | Materials Sciences

Scientists enlist engineered protein to battle the MERS virus

22.05.2017 | Life Sciences

Experts explain origins of topographic relief on Earth, Mars and Titan

22.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>