Researchers based at the University of Arizona School of Medicine-Phoenix and the Translational Genomics Research Institute (TGen) have uncovered what they believe is the answer to why the chemokine protein known as CXCL10 seems to help fight some cancers, but promotes progression in others.
CXCL10 is involved in the body’s immune response. It attracts white blood cells to infection sites to fight foreign pathogens and is also over expressed in a number of autoimmune disorders such as arthritis and diabetes.
Expression of this protein by tumors was initially thought to be a good sign, as patients with CXCL10 expressing ovarian, colon and esophageal tumors had improved prognosis following therapy. However, later research showed that the chemokine was also linked to poor prognosis in other cancers including breast cancer, pancreatic cancer and melanoma.
Recent research by the authors of the current study suggested the apparent opposing actions of CXCL10 across different cancers was linked to the actions of another protein encoded by the tumor suppressor gene ING4.
“If ING4 is present in the tumor, CXCL10 does its normal job, which is killing tumor cells,” said lead researcher and senior study author Suwon Kim, Associate Professor at the University of Arizona College of Medicine-Phoenix and the Translational Genomics Research Institute, in a press statement. “If ING4 is not present, then CXCL10 turns around and makes the tumor more aggressive.”
To investigate this connection further, Kim and colleagues analyzed genomic data from more than 1900 patients in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. This cohort includes patients with all recorded molecular subtypes of breast cancer.
As described in the journal Molecular and Cellular Biology, the team found that breast cancer patients with high CXCL10, but low levels of the ING4 protein (34% of breast cancers) in their tumors had poor disease-free survival.
When the researchers investigated this further in the lab, they saw that the CXCL10 protein encouraged cancer cells to spread if the ING4 protein was absent, but not if it was active. This was dependent on interaction with other proteins in the signaling pathway including chemokine receptor CXCR3 and the EGFR protein.
“Our findings suggest that ING4 status could be a biomarker for CXCL10 targeting agents. In other words, an ING4 ‘low’ status can be an indicator for therapy using inhibitors targeting the CXCL10 signaling pathway,” Kim told Inside Precision Medicine.
The findings of this study fit with those of many others showing strong tumor-suppressing action for ING4. The protein is known to play a role in cell cycle arrest, apoptosis, autophagy, adaptation to low oxygen, contact inhibition, among others. Dysfunctional or low levels of ING4 are known to help promote tumor invasion and blood vessel formation, along with metastasis at a later stage.
Kim believes patients with low levels of ING4 could be a good sub-group to target in clinical trials for new cancer drugs. She and her colleagues also plan to investigate the dual role of CXCL10 and ING4 in other cancers in future research.
“We believe deciphering CXCL10 signaling components is a high priority with a goal in mind to identify tractable therapeutic targets. We are also working toward connecting the mechanistic dots from the extracellular CXCL10 to the nuclear ING4 – we have many hypotheses, which is exciting!”