Cxcl10 protein can indicate both positive and negative directions of cancer trajectory
PHOENIX, Ariz. — Dec. 22, 2021 — What if the presence of a protein that indicates a robust immune response in some cancers, also could indicate the progression of malignancy in other types of cancers? What might cause such opposite outcomes?
The findings of a study by the University of Arizona School of Medicine-Phoenix and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, point to some likely explanations, and clues toward possible new treatment options for breast cancer patients.
“There are many different types of breast cancer, some of which have good treatments, but others are as difficult-to-treat and as deadly as ever. We need to find better treatments for those patients,” said Suwon Kim, Ph.D., the senior author of the study, Associate Professor in TGen’s Cancer and Cell Biology Division, and head of the institute’s Breast Cancer Genetics Lab.
As reported in the journal Molecular and Cellular Biology, Cxcl10 is a chemokine protein that attracts immune-system white blood cells to infection sites. Various immune cells secrete Cxcl10, with excessive amounts of Cxcl10 implicated in a variety of autoimmune diseases, including arthritis, colitis and diabetes. Cxcl10 also is expressed in cancer cells, where it is an indicator of both positive and negative outcomes.
Tumor expression of Cxcl10 was initially characterized as a good prognostic indicator of therapy response in several cancers, including ovarian, colon and esophageal cancer. Paradoxically, high expression of Cxcl10 also correlated with aggressive disease and poor patient survival in several cancers, including breast cancer, pancreatic cancer and melanoma, suggesting that Cxc10 may promote cancer progression in some settings.
A gene called ING4 is key
The study results suggest that the difference could be the presence, or absence, of a tumor-suppressor gene known as ING4.
To understand the relationship between Cxcl10 and ING4, researchers examined the METABRIC dataset containing the genomic data of breast tumors from more than 1,900 patients, representing all of the molecular subtypes of breast cancer. Their analysis suggests that patients with low ING4 had poor disease-free survival, building on previous findings that revealed low levels of ING4 in 34% of all breast cancers.
In addition, they found that high expression of the CXCL10 gene was associated with poor patient outcomes in breast cancer.
Study leads to potential new therapy
Strikingly, ING4-low/Cxcl10-high tumor patients had significantly reduced disease-free survival, suggesting a potential direct functional relationship.
“If ING4 is present in the tumor, Cxcl10 does its normal job, which is killing tumor cells,” Dr. Kim explained. “If ING4 is not present, then Cxcl10 turns around and makes the tumor more aggressive.”
Targeting this novel mechanism — a cascading cellular pathway that links ING4 to Cxcl10 and the proteins Egfr and Cxcr3 — may have a potential therapeutic benefit in ING4-deficient breast cancer, and Dr. Kim adds, those patients with an ING4 deficiency should be selected to participate in future clinical trials.
Emily Tsutsumi, a graduate-student researcher in Clinical Translational Sciences at the UArizona medical school, and the study’s lead author, said: “This study highlights a unique relationship between ING4 and Cxcl10 in aggressive breast cancer.”
Funding for this study — Cxcl10 chemokine induces migration of ING4-deficient breast cancer cells via a novel crosstalk mechanism between the Cxcr3 and Egfr receptors — was provided by a partnership between TGen and the Baylor Scott & White Research Institute. Additional support came from: the UArizona College of Medicine-Phoenix, UArizona RDI Metastatic Breast Cancer, the Fidelity Charitable Donor-Advised Yoo Family Fund, the Partnership for Native American Cancer Prevention, the National Cancer Institute’s Partnership to Advance Health Equity, and Helios Education Foundation.
About TGen, an affiliate of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
TGen Senior Science Writer