Switching sides: The betrayal of an anti-cancer gene

July 25, 2018, Weizmann Institute of Science
The effects of p53 in cancer-associated fibroblasts on cancer cell migration: Cancer cells (magenta) migrate in the direction of cancer-associated fibroblasts (yellow) that express a non-mutated p53 gene (left); this migration slows down (center) when the p53 in the fibroblasts is silenced; when substances released by the cancer-associated fibroblasts are added to the laboratory dish, the migration is restored (right). Credit: Weizmann Institute of Science

It doesn't often happen that army generals switch sides in the middle of a war, but when cancer's attack is underway, it may even cause a gene that acts as the body's master defender to change allegiance. As reported recently in the Proceedings of the National Academy of Sciences (PNAS), researchers at the Weizmann Institute of Science have discovered that the betrayal of this gene can occur in more ways than previously appreciated.

All cells carry this gene, known as p53. This gene normally plays a central role in protecting the body against malignancy, orchestrating the cell's defenses against cancer and often killing a potentially cancerous cell if these fail. In about half of cancer patients, the p53 gene within the cancerous cells contains alterations—mutations—that can result in the production of a that not only fails to suppress cancer, but can even launch cancer-promoting activities.

But besides the cancerous cells, a malignant contains a variety of non- and connective tissue elements, commonly referred to as the tumor microenvironment. In the initial stages of cancer development, the microenvironment is hostile to the tumor. Prof. Moshe Oren of the Molecular Cell Biology Department and other scientists found in earlier studies that the p53 of the microenvironment cells contributes to this hostility, blocking the spread of the cancer. "This protective campaign probably often succeeds, otherwise people would get cancer much more frequently than they actually do," says Oren.

As the cancer progresses and becomes more malignant, the tumor microenvironment gradually changes. Scientists refer to this process as "education": The microenvironment is being co-opted by the progressing tumor into promoting, rather than restricting, the cancer.

PNAS p53 aids cancer cell migration. Credit: Weizmann Institute of Science

Among the co-opted cells are the fibroblasts, which supply the tissue with structural "cement." Initially these help recruit immune cells against the cancer, but they now start releasing substances that encourage tumor growth, invasion and survival. At this stage, these cells are referred to as cancer-associated fibroblasts.

The new study, conducted in Oren's lab in collaboration with Weizmann Institute colleagues, shows that the microenvironment's "education—a more appropriate term would probably be "brainwashing—is directed in part at the fibroblasts' p53. As the cancer grows, the p53 in the fibroblasts switches sides. Although the p53 in the cancer-associated fibroblasts doesn't acquire mutations as it does in the , it nevertheless becomes altered in a manner that causes it to switch from restricting to supporting the cancer.

In the study, led by postdoctoral fellow Dr. Sharath Chandra Arandkar, in collaboration with departmental colleague Prof. Benjamin Geiger, and with Prof. Yosef Yarden and Dr. Igor Ulitsky of the Biological Regulation Department, the researchers showed that eliminating the p53 protein from cancer-associated fibroblasts by silencing their caused these cells to lose many of their tumor-supporting features and behave more like normal fibroblasts. In particular, the silencing of fibroblast p53 reduced the migration of adjacent cancer cells in a laboratory dish—a crucial change, considering that invasive migration facilitates the metastatic spread of cancer. Moreover, the silencing of p53 in cancer-associated fibroblasts greatly reduced the ability of these cells to promote tumor growth in mice.

Study authors included Weizmann's Drs. Noa Furth, Yair Elisha and Nishanth Belugali Nataraj, and, from Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, Germany: Prof. Walter Aulitzky and the late Dr. Heiko van der Kuip, to whose memory this publication was dedicated.

Finding ways to "re-educate" the renegade p53 in the tumor microenvironment—to reverse its behavior back to suppressing tumors—may pave the way to the development of novel therapies that will target the microenvironment rather than the cancer cells themselves. Indeed, strategies targeting the microenvironment are being increasingly explored in recent years. The hope is that they might provide a new window of opportunity for launching effective therapy, because the microenvironment tends to evolve more slowly than the mutation-ridden tumor cells. Cancer and it's : Time lapse movie of GFP-expressing immortalized NFshLacZ cells from patient 4731 (Yellow) and mCherry-expressing Calu1 cells (magenta). Cells were seeded in 12-well plates containing ibidi culture inserts. The next day, inserts were removed and were allowed to migrate. Images were captured every 15 min, for a total of 6 h

Explore further: Cancer cells thrive in stiff tissue, according to new study

More information: Sharathchandra Arandkar et al. Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1719076115

Related Stories

Cancer cells thrive in stiff tissue, according to new study

May 4, 2018
Stiffer breast tissue creates an environment more prone to cancer by enabling the disease to interfere with the surrounding healthy cells, according to a recent study published in Biomaterials.

When healthy cells stimulate the migration of tumor cells

June 15, 2017
Estrogens act as a driving force of both healthy and cancerous mammary cell growth by binding to receptors that include a type named GPER, which is generally located in cell membranes. Recent studies have, however, revealed ...

Researchers describe how tumors recruit and use stem cells to support tumor growth and progression

October 20, 2016
A new study has identified a mechanism used by tumors to recruit stem cells from bone and convert them into cancer-associated fibroblasts (CAFs) that facilitate tumor progression. This work, which pinpoints the specific biochemical ...

Immune cells help reverse chemotherapy resistance in ovarian cancer

May 20, 2016
Inside each ovarian tumor, there are good cells and bad cells. A new paper explains their roles:

Mechanism for esophageal cancer uncovered

April 11, 2011
A gene thought to be associated with cancer development can be a tumor suppressor gene in mice, researchers have discovered. Understanding which genes are involved in spreading cancer could lead to future therapies.

Telomere length prognostic in hepatocellular carcinoma

August 24, 2017
(HealthDay)—Telomere attrition occurs in tumor cells from patients with hepatocellular carcinoma (HCC), and shortened telomeres are independent prognosticators for HCC patients, according to a study published online Aug. ...

Recommended for you

Pushing closer to a new cancer-fighting strategy

December 11, 2018
A molecular pathway that's frequently mutated in many different forms of cancer becomes active when cells push parts of their membranes outward into bulging protrusions, Johns Hopkins researchers report in a new study. The ...

Receiving genetic information can change risk

December 11, 2018
Millions of people in the United States alone have submitted their DNA for analysis and received information that not only predicts their risk for disease but, it turns out, in some cases might also have influenced that risk, ...

Scientists have identified and modelled a distinct biology for paediatric AML

December 11, 2018
Scientists have identified and modelled a distinct biology for paediatric acute myeloid leukaemia, one of the major causes of death in children.

HER2 mutations can cause treatment resistance in metastatic ER-positive breast cancer

December 11, 2018
Metastatic breast cancers treated with hormone therapy can become treatment-resistant when they acquire mutations in the human epidermal growth factor receptor 2 (HER2) that were not present in the original tumor, reports ...

How glial cells develop in the brain from neural precursor cells

December 11, 2018
Two types of cells are active in the brain: nerve cells and glial cells. Glial cells have long been regarded primarily as supportive cells, but researchers increasingly recognize that they play an active role in the communication ...

Loss of two genes drives a deadly form of colorectal cancer, reveals a potential treatment

December 11, 2018
Colorectal cancers arise from earlier growths, called polyps, found on the inner surface of the colon. Scientists are now learning that polyps use two distinct molecular pathways as they progress to cancer, called the "conventional" ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.