Biological pathways found that drive genomic changes and bone metastasis
in ewing sarcoma, a rare childhood cancer
Date:
April 28, 2022
Source:
Georgetown University Medical Center
Summary:
In studies using mice grafted with human Ewing sarcoma tissue,
researchers have identified a biological pathway that is activated
when tissue is starved of oxygen due to rapid growth of a tumor,
thereby allowing cancer cells to make genetic changes so they
can metastasize to the bone and thrive even when exposed to
chemotherapy.
FULL STORY ==========================================================================
In studies using mice grafted with human Ewing sarcoma tissue, researchers
from Georgetown University Medical Center and colleagues have identified
a biological pathway that is activated when tissue is starved of oxygen
due to rapid growth of a tumor, thereby allowing cancer cells to make
genetic changes so they can metastasize to the bone and thrive even when exposed to chemotherapy.
==========================================================================
The pathway the scientists identified involves a receptor on the
surface of a cancer cell, called Y5R, which plays a role in mediating oxygen-deprivation effects -- if it was blocked or turned off, genetic
changes would be limited, thereby inhibiting metastasis of a tumor.
The finding appeared April 28, 2022, in Nature Communications.
Each year, about 200 children and young adults in the United States are diagnosed with a Ewing tumor. About half of all Ewing sarcoma diagnoses
are in people between the ages of 10 and 20; almost all cases of Ewing
sarcoma occur in white and Hispanic people. If the tumor has spread to
distant areas at the time of diagnosis, the 5-year survival rate is 38
percent but if it spreads to the bone, survival drops to between 8 to
14 percent.
"While the role of rapid genetic changes in spurring the growth of
cancer is well known, the mechanisms initiating these changes are not
well understood and strategies to prevent them are lacking," says
Joanna Kitlinska, PhD, an associate professor in the Department of
Biochemistry and Molecular & Cellular Biology at Georgetown University
and corresponding author of the study. "That's why our identification of
Y5R's involvement in initiating such genetic alterations is important
as it gives us a target to aim at or block that could avert cancer
genome evolution and resulting progression to metastatic tumors that
are resistant to chemotherapy." The current standard-of-care for Ewing
sarcoma involves systemic cell-killing chemotherapy which can affect
all cells in the body leading to side effects.
There are no treatments targeted at genetic alterations that are used
in routine treatment of Ewing sarcoma, which might make treatments less
toxic. In particular, adequate treatments for patients with metastatic
disease are lacking.
There are currently a number of drugs available that target Y5R
because it's also implicated in regulating food intake and psychiatric disorders. Several Y5R-targeted drugs have been successfully used in
animal studies; one of them was used in human clinical trials for
obesity. However, most of them are designed to block functions in
the brain that inhibit food intake. According to Kitlinska, the main
challenge will be to design Y5R-targeted drugs that do not cross the blood-brain barrier as these effects are undesirable in cancer patients.
"We will keep performing experiments in mice in order to try to
identify the mechanisms triggering spread of Ewing to the bone," says Kitlinska. "Findings in Ewing sarcoma may also be relevant to other
cancer types known to have high expression levels of Y5R, including
another pediatric cancer, neuroblastoma, as well as common adulthood malignancies, such as breast, prostate and liver cancers."
========================================================================== Story Source: Materials provided by
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style and length.
========================================================================== Journal Reference:
1. Congyi Lu, Akanksha Mahajan, Sung-Hyeok Hong, Susana Galli,
Shiya Zhu,
Jason U. Tilan, Nouran Abualsaud, Mina Adnani, Stacey Chung, Nada
Elmansy, Jasmine Rodgers, Olga Rodriguez, Christopher Albanese,
Hongkun Wang, Maureen Regan, Valerie Zgonc, Jan Blancato, Ewa
Krawczyk, G. Ian Gallicano, Michael Girgis, Amrita Cheema, Ewa
Iżycka- Świeszewska, Luciane R. Cavalli, Svetlana D. Pack,
Joanna Kitlinska.
Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers
chromosomal instability and bone metastasis in Ewing sarcoma. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29898-x ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220428085649.htm
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