Cancer cells that escape from senescence found to have an enhanced capacity to drive tumor growth

December 22, 2017 by Bob Yirka, Medical Xpress report
Credit: CC0 Public Domain

An international team of researchers has found that cancer cells that escape from senescence due to use of chemotherapy have an enhanced capacity to drive tumor growth. In their paper published in the journal Nature, the group describes their study that involved mouse models and cancer cells that escaped cell-division arrest after exposure to chemo drugs. Jan Paul Medema with the Cancer Center Amsterdam offers a News and Views piece on the work done by the team in the same journal issue.

In order to prevent from dividing, resulting in the growth of abnormal tissue, cells have a built-in mechanism called senescence—cell division is arrested, preventing the cell from causing problems. Over the past several years, researchers have taken advantage of this mechanism to combat tumor cells—stopping cell division in keeps the tumor from growing. Drugs have been developed and used as part of a chemotherapy regimen to treat cancers in this way. But now, it appears that there may be a side effect to such treatments—the researchers report tumors that escape senescence grow faster.

To learn more about what happens to tumor cells that survive senescence, the researchers started with the observation that signaling pathways in cells that have been forced into senescence were similar to those that have been seen in stem cells. To find out if there might be a connection, they created lymphoma mouse models with an induced state of cell-cycle arrest via the drug tamoxifen—stopping administration of the drug allowed the cells to exit senescence on-demand, allowing the researchers to watch what happened to the tumors. The researchers report that in nearly all cases, they found faster-growing tumors.

Upon taking a closer look at what was occurring, the researchers found that senescence in the was connected to the activation of the Wnt signaling pathway—a group of proteins that pass signals through cell surface receptors. Interestingly, they also found that if they added Wnt inhibitors after tamoxifen cessation, tumors grew slower after exiting senescence, suggesting that adding such inhibitors to chemotherapy mixtures might be coming in the future.

Explore further: Aging cells unravel their DNA

More information: Maja Milanovic et al. Senescence-associated reprogramming promotes cancer stemness, Nature (2017). DOI: 10.1038/nature25167

Abstract
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells1,2. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness')3. In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.

Related Stories

Aging cells unravel their DNA

December 16, 2013
Senescent cells, which are metabolically active but no longer capable of dividing, contribute to aging, and senescence is a key mechanism for preventing the spread of cancer cells. A study in The Journal of Cell Biology identifies ...

How NORE1A acts as a barrier to tumor growth

March 16, 2015
Researchers reveal how cells protect themselves from a protein that is a key driver of cancer. The study appears in The Journal of Cell Biology.

Elimination of senescent cells improves lung function in mice

August 4, 2016
Most cells can divide only a limited number of times and eventually undergo permanent cell cycle arrest, a state known as cellular senescence. Cellular senescence is mediated by activation of specific cellular signaling pathways ...

Cell senescence does not stop tumor growth

January 19, 2012
Since cancer cells grow indefinitely, it is commonly believed that senescence could act as a barrier against tumor growth and potentially be used as a way to treat cancer. A collaboration between a cancer biologist from the ...

In the lab and in the clinic, alisertib with TAK-228 excels against solid tumors

November 1, 2017
Two University of Colorado Cancer Center studies were presented this weekend at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting in Philadelphia, PA showing that using the drug alisertib along with the ...

Tipping the balance between senescence and proliferation

November 15, 2013
An arrest in cell proliferation, also referred to as cellular senescence, occurs as a natural result of aging and in response to cellular stress. Senescent cells accumulate with age and are associated with many aging phenotypes, ...

Recommended for you

High fruit and vegetable consumption may reduce risk of breast cancer, especially aggressive tumors

July 19, 2018
Women who eat a high amount of fruits and vegetables each day may have a lower risk of breast cancer, especially of aggressive tumors, than those who eat fewer fruits and vegetables, according to a new study led by researchers ...

Complementary medicine for cancer can decrease survival

July 19, 2018
People who received complementary therapy for curable cancers were more likely to refuse at least one component of their conventional cancer treatment, and were more likely to die as a result, according to researchers from ...

Overcoming resistance to a standard chemotherapy drug

July 19, 2018
Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors ...

Study finds melanoma biomarkers predicting checkpoint blocker response

July 18, 2018
Scientists at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) have identified biomarkers in melanoma that could help tailor immunotherapy treatments to maximize the benefits for patients while reducing the likelihood ...

Link found between bitter-taste sensitivity and cancer risk

July 18, 2018
High bitter-taste sensitivity is associated with a significantly increased risk of cancer in older British women, according to researchers who conducted a unique study of 5,500 women whose diet, lifestyle and health has been ...

Scientists discover a mechanism of drug resistance in breast and ovarian cancer

July 18, 2018
There is a highly sophisticated way to treat some breast and ovarian cancers—a class of drugs called PARP inhibitors, designed to exploit the very defects that make tumors with certain mutations especially deadly. Yet this ...

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.