Nav: Home

Cell death or cancer growth: A question of cohesion

November 19, 2019

Activation of CD95, a receptor found on all cancer cells, triggers programmed cell death - or does the opposite, namely stimulates cancer cell growth. Scientists from the German Cancer Research Center (DKFZ) have now shown that the impact of CD95 activation depends on whether there are isolated cancer cells or three-dimensional structures. Individual cells are programmed to die following CD95 activation. In contrast, CD95 activation stimulates growth in clusters of cancer cells, for example in solid tumors. This finding points to new ways of specifically transforming growth-stimulating signals into cell death signals for the cancer cells.

The receptor protein CD95 is exposed on the surface of all cancer cells like small antennae. Activation of the receptor by the CD95 ligand (CD95L) triggers apoptosis in the cancer cell - or the exact opposite: "We studied various types of cancer tissue and found that CD95 activation usually stimulates tumor growth under natural conditions," remarked Ana Martin-Villalba, who has been conducting research at DKFZ on the role of CD95 for many years now. She was the first to describe the cancer-promoting effect of CD95 in glioblastomas (malignant brain tumors).

Researchers are investing considerable effort into examining how medicine could harness the other side of CD95 and cause cancer cells to die in a targeted way. To do so, Martin-Villalba and her team attempted to understand which factors decide whether CD95 activation leads to cell death or cell growth.

The team from DKFZ collaborated with Motomu Tanaka from the University of Heidelberg, jointly developing artificial cell membranes into which they could insert any amount of the CD95 ligand. Using this method, they discovered that a particular distance between the individual ligand molecules was necessary to achieve ideal activation of CD95 - and to actually induce cell death in cells isolated from biopsies of pancreatic cancer or glioblastomas grown in a petri dish.

The researchers then assumed that they had found the perfect way to cause tumor cells in the body to die and extended their experiments to brain tumors in mice. They gave the animals latex beads with the ideal surface density of CD95 ligands. However, instead of observing a reduction in the tumor mass, as expected, the opposite occurred: tumor growth was accelerated.

In order to clarify the apparent discrepancy between cell culture and animal experiments, the researchers experimented with tumorspheres, tiny tumors grown in culture. CD95 activation via the artificial cell membrane stimulated growth in these cell spheroids, which behaved like natural tumor tissue.

"The impact of CD95 activation - cell death or growth - appears to depend primarily on whether there are isolated cancer cells, as grown in culture, or cells in three-dimensional structures," Gülce Gülculer from Martin-Villalba's team explained. Individual cells are programmed to die following CD95 activation. In natural conditions, however, namely in a tissue structure, CD95 activation stimulates growth. In Gülculer's experiments, even contact to a single neighboring cell was enough to protect tumor cells from CD95-induced cell death.

"The result will enable us to develop new strategies to transform the growth-stimulating signals of CD95 into cell death signals for the cancer cells. This could help us stop tumor cells becoming resistant to treatment," study director Martin-Villalba added.

A clinical phase II study conducted several years ago already showed that, when combined with radiotherapy, blocking the CD95 signal could lead to better survival rates in patients with advanced glioblastomas. The study used a substance that Ana Martin-Villalba played a key role in developing. "Our current findings provide an explanation for the first time of why blocking CD95 does actually slow down cell death," Martin-Villalba explained.

Gülce Gülcüler Balta, Cornelia Monzel, Susanne Kleber, Joel Beaudouin, Emre Balta, Thomas Kaindl, Si Chen, Liang Gao, Meinolf Thiemann, Christian R. Wirtz, Yvonne Samstag, Motomu Tanaka and Ana Martin-Villalba: 3D cellular architecture modulates tyrosine kinase activity thereby switching CD95 mediated apoptosis to survival. Cell Reports 2019; DOI: 10.1016/j.celrep.2019.10.054

Why animal experiments are vital in cancer research

Death signals or growth stimulators - up to now, scientists did not know why CD95 activation in cancer cells can have such different outcomes. As a result, they were unable to conduct further targeted research into this signaling system - so promising for cancer treatment - to benefit patients.

The different outcomes of the experiments on cancer cells grown in culture and on brain tumors in mice allowed the researchers to find the explanation for the first time. Using tumorspheres, the researchers were subsequently able to confirm the effect of cell contact in an experimental setting and rule out other influencing factors such as the immune system.

This finding will enable the therapeutic potential of blocking CD95 to be harnessed in a much more targeted way.
-end-


German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Our Relationship With Water
We need water to live. But with rising seas and so many lacking clean water – water is in crisis and so are we. This hour, TED speakers explore ideas around restoring our relationship with water. Guests on the show include legal scholar Kelsey Leonard, artist LaToya Ruby Frazier, and community organizer Colette Pichon Battle.
Now Playing: Science for the People

#568 Poker Face Psychology
Anyone who's seen pop culture depictions of poker might think statistics and math is the only way to get ahead. But no, there's psychology too. Author Maria Konnikova took her Ph.D. in psychology to the poker table, and turned out to be good. So good, she went pro in poker, and learned all about her own biases on the way. We're talking about her new book "The Biggest Bluff: How I Learned to Pay Attention, Master Myself, and Win".
Now Playing: Radiolab

Uncounted
First things first: our very own Latif Nasser has an exciting new show on Netflix. He talks to Jad about the hidden forces of the world that connect us all. Then, with an eye on the upcoming election, we take a look back: at two pieces from More Perfect Season 3 about Constitutional amendments that determine who gets to vote. Former Radiolab producer Julia Longoria takes us to Washington, D.C. The capital is at the heart of our democracy, but it's not a state, and it wasn't until the 23rd Amendment that its people got the right to vote for president. But that still left DC without full representation in Congress; D.C. sends a "non-voting delegate" to the House. Julia profiles that delegate, Congresswoman Eleanor Holmes Norton, and her unique approach to fighting for power in a virtually powerless role. Second, Radiolab producer Sarah Qari looks at a current fight to lower the US voting age to 16 that harkens back to the fight for the 26th Amendment in the 1960s. Eighteen-year-olds at the time argued that if they were old enough to be drafted to fight in the War, they were old enough to have a voice in our democracy. But what about today, when even younger Americans are finding themselves at the center of national political debates? Does it mean we should lower the voting age even further? This episode was reported and produced by Julia Longoria and Sarah Qari. Check out Latif Nasser's new Netflix show Connected here. Support Radiolab today at Radiolab.org/donate.