Curbing Cancer: Don't Cleave that OPN

by Adrienne Mueller, PhD
March 25, 2022

What causes cancer? There seem to be as many answers to that question as there are cancer patients, but a person’s genetics are often a determining factor. Scientists have looked at which genes have the strongest contribution to cancer and osteopontin (OPN) is one of the top 5% most highly expressed genes in cancer genetic data sets. OPN promotes tumor growth and metastasis in breast, lung, prostate and ovarian cancers, as well as some brain cancers. When it’s not contributing to cancer progression, osteopontin (OPN) is a protein found in the extracellular matrix and in the blood that can regulate behavior of immune and other cells. The question is: how is OPN contributing to cancer and how can we get it back under control.

We know a lot about OPN, including that it can be cleaved into fragments – each of which can have its own influence on cellular activities. Thrombin, an important enzyme for blood coagulation, is also the protein that cleaves OPN and generates fragments with new activities. Previously it has not been possible to tell what form, or which fragments, of OPN were contributing to cancer, but recently-developed technology allows researchers to differentiate between cleaved and uncleaved OPN.

A recent study published in the Journal of Thrombosis and Haemostasis, led by first author Sameera Peraramelli, PhD and senior authors John Morser, PhD and Lawrence L.K. Leung, MD, showed that OPN cleavage fragments suppress host-anti-tumor immunity - promoting tumor growth. Their study further went on to show that blocking thrombin cleavage of OPN enhances host-anti-tumor activity and suppresses tumor growth. Peraramelli et al generated mice expressing OPN protein that was resistant to cleavage by thrombin; and those mice had reduced tumor growth and less metastasis than control animals.

Tissue of animals with normal, thrombin-cleavable, osteopontin (OPN) shows numerous tumor nodules (left). Tissue from mice that have either thrombin cleavage-resistant OPN (middle), or no OPN at all (right) have fare fewer tumor nodules.

Peraramelli et al have shown that thrombin-cleaved OPN fragments initiate OPN’s tumor-promoting activity. This is the first report of a role for the thrombin-cleavage of OPN, identifying a new link in the crosstalk between thrombosis, inflammation and immunity and uncovering an important mechanism that contributes to cancer progression.

Additional Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Qi Zhou, Qin Zhou, Bettina Wanko, Lei Zhao, Toshihiko Nishimura, and Timothy Myles.

Dr. Sameera Peraramelli

Dr. John Morser

Dr. Lawrence L.K. Leung