Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Growth Signal Can Influence Cancer Cells’ Vulnerability to Drugs, Study Suggests

03.03.2015

In a study published February 26, in Cell, researchers at Rockefeller University home in on one culprit that fuels this variable vulnerability within squamous cell cancers: exposure to a signal known as TGF-β, given off by immune cells that congregate next to a tumor’s blood vessels.

“There are several reasons why some cancer stem cells, the cells at the root of tumors and metastases, can withstand therapy meant to eradicate them. Our results point to the importance of the environment immediately surrounding the skin cancer stem cells, specifically, their exposure to the signal TGF-β,” says senior researcher Elaine Fuchs, Rebecca C. Lancefield Professor, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development and a Howard Hughes Medical Institute Investigator.


Zach Veilleux

A cue for cancer: To see how exposure to the growth signal TGF-β influences cancer cells, the researchers used a red tag (top) to mark mouse tumor stem cells that received the signal, and a green tag (bottom) to track the behavior the stem cells’ progeny.

“Ultimately, we hope this new insight could lead to better means for preventing the recurrence of these life-threatening cancers, which can occur in the skin, head, neck, esophagus, and lung, and often evade treatment.”

Her team, which included first author Naoki Oshimori, a postdoctoral research associate in the lab and lab technician Daniel Oristian, focused on squamous cell carcinomas in the skin of mice. Like many normal tissue stem cells, the stem cells that produce squamous cell tumors can be classified into two types: those that divide and proliferate rapidly, and those that do so more slowly. This has led scientists to wonder whether the more dormant stem cells in a tumor might evade cancer drugs.

To investigate this possibility, the team zeroed in on TGF-β (transforming growth factor beta) which is known to restrict growth in many healthy tissues. The lab’s previous research has shown that mice whose normal skin stem cells cannot respond to TGF-β become susceptible to develop tumors that grow rapidly. Paradoxically, however, TGF-β contributes to metastasis in many cancers. The researchers wanted to know: How can TGF-β act both to suppress cancers and promote them?

By visualizing TGF-β signaling within developing mouse tumors, the researchers found that the cancer stem cells located nearest to the blood vessels of the tumor receive a strong TGF-β signal, while others further away don’t receive any. To see this difference and its effects, they used a red tag to illuminate those cells exposed and responding to TGF-β, and a green genetic tag, which they could switch on, to track the stem cells’ progeny. Over time, they saw that TGF-β-responding stem cells proliferate more slowly but they simultaneously invade, scatter and move away from the tumor. The opposite was true of cancer stem cells too far away to receive TGF-β, which proliferated rapidly, but were less invasive, growing as a tumor mass.

“We tested the implications for drug resistance by injecting cisplatin, a commonly used chemotherapy drug for these types of cancers, into the mice with tumors. While the drug killed off most of the TGF-β nonresponding cancer cells, it left behind many of the responders,” Oshimori says. “When the drug was withdrawn, the lingering TGF-β responding cancer stem cells grew back the tumor.”

“We found that the TGF-β heterogeneity in the tumor microenvironment produces some cancers stem cells that divide rapidly and lead to accelerated tumor growth, and other cancer stem cells that invade surrounding healthy tissue and escape cancer therapies,” Fuchs explains. “Moreover, conventional wisdom might say that a leisurely pace of cell division, like that seen in the TGF-β responders, makes it possible for these cells to circumvent anticancer treatments that target rapidly dividing cells. While this may be true for some types of anticancer drugs, we found changes in antioxidant activity in these cells are more important for their resistance to cisplatin.”

Indeed, when the team compared the genes expressed by the TGF-β responders with those of the nonresponders, they found highly elevated expression in a battery of genes encoding enzymes involved in making and utilizing glutathione, an important antioxidant and detoxifying substance in cells. This unexpected finding led the team to test the impact of glutathione metabolism and conclude this metabolic pathway prevents TGF-β responders from critical damage by anti-cancer drugs as well as oxidative stresses.

“If TGF-β signaling and elevated antioxidant activity plays the same role predisposing cancer stem cells to thwart chemotherapy in humans as we have shown it does in mice, this work may serve as a foundation for designing new therapeutics and combinatorial regiments to overcome drug resistance by this devastating cancer,” Fuchs says.

Contact Information
Zach Veilleux
212-327-8982
newswire@rockefeller.edu

Zach Veilleux | newswise

More articles from Life Sciences:

nachricht Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>