Neutrophils promote tumour growth and metastasis. What can be done?

Abstract

In 2004, a new type of cell death was described, known as NETosis. Three types of NETosis are described: suicidal, vital, and mitochondrial. The key factor that distinguishes NETosis from other forms of cell death is the decondensation of chromatin. The nucleus loses heterochromatin regions and contains only euchromatin. This process is carried out by means of citrullination. Decondensed chromatin mixes with proteins that come from cytoplasmic neutrophil granules (neutrophil elastase, myeloperoxidase, cathepsin G, lactoferrin, and gelatinase). In suicidal NETosis, the cell dies and its contents are released into the intercellular environment.

Decondensed chromatin threads together with granular proteins form a neutrophil trap similar to a necklace. Vital NETosis demonstrates the presence of a pore in the cell membrane through which part of the decondensed DNA of the nucleus leaves the cell. However, such neutrophils die after a while. The third variant of NETosis is mitochondrial. At the same time, DNA is not of nuclear origin but mitochondrial origin. Mitochondrial DNA, together with cytoplasmic granule proteins, is expelled through a pore in the cell membrane.

Neutrophils play a key role in tumour growth. Net traps mimic the tissue factor necessary for thrombus formation. A thrombus slows down the movement of blood cells, thereby facilitating the passage of tumour cells through the tissue-haematological barrier in postcapillary venules. In addition, in a “quiet environment” circulating tumour cells can more easily cover themselves with a “cloak” of platelets and neutrophil traps to avoid contact with cytotoxic lymphocytes. Neutrophils contribute to tumour formation by maintaining chronic inflammation. Later, as the initial tumour grows, tumour neutrophils release inflammatory and neoangiogenic mediators, enzymes (proteases) that “clear the way” for the tumour by destroying normal cells. Substances are also released that cause the immune system to develop immunological tolerance to the tumour. It has been proven that tumour cells overcome the blood-tissue barrier together with neutrophils, like a horseman on a horse. Inflammation produces angiogenic factors, which are normally essential for wound healing. However, in metastasis, these factors promote endothelial proliferation and the formation of new blood vessels (neoangiogenesis). Once it receives nutrients, the micrometastasis awakens and grows.

NETs negatively affect chemotherapy and long-term treatment outcomes, so it is essential to provide supportive therapy aimed at maximising the removal of NET traps. Preclinical studies are currently being conducted on targeted drugs that prevent the formation of traps and destroy them.