New findings hope for cancer patients with kidney failure

intestinal tumours, molecular scissors, disease, genetic, immune cells, drug development, Diabetes, Antibiotic, hydrogen generation, chronic obstructive pulmonary disease, malaria, photosynthesis, kidney failure, Brain tumours, mental health, blood cancer, cancer, dementia, cancer treatment, antibiotic resistance, blood vessel leakage, quantum simulations, atrial fibrillation, batteries, goiter treatment, terahertz radiation, organic materials , Guild of European Research Intensive Universities, gene copies, social anxiety, blue light screens, ‘Our hope is that these findings will make it possible to discover a way to selectively inhibit the TGF-beta signals that stimulate tumour development without knocking out the signals that inhibit tumour development, and that this can eventually be used in the fight against cancer,’ says Eleftheria Vasilaki, postdoctoral researcher at Ludwig Institute for Cancer Research at Uppsala University and lead author of the study. TGF-beta regulates cell growth and specialisation, in particular during foetal development. In the context of tumour development, TGF-beta has a complicated role. Initially, it inhibits tumour formation because it inhibits cell division and stimulates cell death. At a late stage of tumour development, however, TGF-beta stimulates proliferation and metastasis of tumour cells and thereby accelerates tumour formation. TGF-beta’s signalling mechanisms and role in tumour development have been studied at the Ludwig Institute for Cancer Research at Uppsala University for the past 30 years. Recent discoveries at the Institute, now published in the current study in Science Signaling, explain part of the mechanism by which TGF-beta switches from suppressing to enhancing tumour development. Uppsala researchers, in collaboration with a Japanese research team, discovered that TGF-beta along with the oncoprotein Ras, which is often activated in tumours, affects members of the p53 family. The p53 protein plays a key role in regulating tumour development and is often altered – mutated – in tumours. TGF-beta and Ras suppress the effect of mutated p53, thereby enhancing the effect of another member of the p53 family, namely delta-Np63, which in turn stimulates tumour development and metastasis.

Kidney dysfunction affects more than 50 per cent of all cancer patients, and is directly linked to poor survival. Despite the high occurrence, it is still not clear how presence of a tumour contributes to kidney dysfunction and how this can be prevented. A new study from researchers at Uppsala University shows that kidney dysfunction can be caused by the patient’s own immune system, ‘tricked’ by the tumour to become activated.

The study is published in the scientific journal Oncoimmunology and describes how a cell type in the blood, the neutrophil, causes kidney dysfunction in mice with cancer. The data suggests that these neutrophils are promising targets for future therapies to treat kidney injury in cancer patients.

Tumours ‘trick’ the immune system

Neutrophils play an important role in our immune system to protect us against infections. However, a tumour can trick neutrophils to become activated even in the absence of an infection, and as a consequence they contribute to disease progression and tissue damage.

“We have previously demonstrated that neutrophils form so called neutrophil extracellular traps, NETs, in the vasculature of mice with cancer, which cause impaired blood flow and inflammation in organs such as kidneys. Our new findings show that this leads to decreased kidney function in mice with cancer,” says Anna-Karin Olsson, researcher at the Department of Medical Biochemistry and Microbiology at Uppsala University, who led the study.

The signs of kidney damage in mice resemble those observed in cancer patients, suggesting that NETs could be a cause of kidney dysfunction also in humans.

New treatment opportunity

The study also shows that kidney function can be restored in mice with cancer through treatment, using an inhibitor to target the enzyme peptidyl arginine deiminase 4 (PAD4) – an enzyme required for neutrophils to form NETs. This is promising since it shows that kidney function can be restored if NETs are removed. The inhibitor (GSK484) has previously proven to be effective in preventing formation of NETs both in mouse and human neutrophils in test tubes. This study is the first to demonstrate the potential of the inhibitor GSK484 to prevent kidney damage in mice with cancer.

“We believe that these findings can lead to novel treatment options to prevent kidney damage and improve survival rates in cancer patients,” says Jessica Cedervall, researcher at the Department of Medical Biochemistry and Microbiology at Uppsala University.

Full article: Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice, Oncoimmunology, DOI: 10.1080/2162402X.2017.1320009