Selective Plasma Adsorption of Extracellular DNA in Prevention of Intraoperative Metastasis in Pancreatic Cancer (Pilot Study)

Rationale for the study Tumor metastasis is the leading cause of cancer-associated mortality. In pancreatic cancer, metastases develop in more than 80% of patients (in 40-50% of cases in the first year after tumor removal surgery). All the details of the metastasis formation process are still unknown to science, but the key stages have been identified and are actively studied: tumor cell dissemination, intravasation, epithelial-mesenchymal and mesenchymal-epithelial transition, extravasation of circulating tumor cells, formation of remote pro-tumor niches, as well as evasion from immune surveillance. The tumor microenvironment plays a key role in the formation of metastases and in modulating the response to therapy in patients with cancer. It is represented by cancer-associated fibroblasts, as well as a number of infiltrating immune cells, including cancer-associated neutrophils (CAN). CAN make up a significant proportion of all cells surrounding the tumor. It has been shown that an increase in their number is associated with metastases and, in general, a worse prognosis in a number of cancer diseases. Moreover, the neutrophil-to-lymphocyte ratio has found wide clinical application as a predictor of overall and cancer progression-related mortality. The most studied mechanism of the positive effect of CAN on metastasis and evasion of the immune response is the production of neutrophil extracellular traps (NETs). NETs are web-like structures whose main purpose is to immobilize pathogens (bacteria, fungi, etc.). They consist of chromatin, histones, a number of signaling molecules and antimicrobial peptides. However, in cancer, the ability of NETs to entangle targets, on the contrary, promotes tumor metastasis. It has been shown that NETs surrounding a tumor cell can serve as an adhesive substrate, which mediates the anchoring of metastasis in a new niche. NETs promote the transition of naïve CD4 cells to immunosuppressive regulatory T cells, allowing metastases to further evade immune surveillance. Also, for example, NETs components such as myeloperoxidase promote tumor cell extravasation and metastasis by degrading the extracellular matrix. Co-culture of cancer cells with NETs has been shown to increase the expression of E-cadherin and vimentin, which enhances their migratory capacity. There is a wealth of data, both in animal models and in patient biomaterial, indicating that elevated NETs levels are associated not only with cancer in general, but also with the presence of metastases. A number of studies have shown that administration of DNase, which cleaves NETs, to animals stops the spread of metastases. Moreover, clinical trials are currently underway on the use of DNase in chemotherapy (NCT00536952, NCT02462265, etc.). It is worth noting that NETs are not the only DNA-containing structures that promote metastasis. There are also cancer extracellular chromatin networks (CECN); In animal models, it has been shown that the introduction of DNase, which affects NETs and CECN, significantly reduces the likelihood of metastasis, while no decrease in the level of circulating tumor cells is observed, indicating a significant modulating role of these DNA structures in the metastasis process. At the same time, it is known that long-term use of DNase leads to a decrease in the overall survival of laboratory animals, which raises the question of when metastasis prevention should be carried out, given the ambiguous safety of this approach. The dynamics of metastasis formation throughout a patient's life are not completely clear. There is evidence that metastasis can begin almost in parallel with the development of the primary tumor, and in such cases (the frequency of which, unfortunately, cannot be estimated) it is very difficult to influence the development of metastases. At the same time, many researchers note that the most significant (and potentially controllable) moment at which metastases can form is the invasive intervention (biopsy, perhaps to a greater extent - resection). According to the results of dozens of studies in various types of oncological diseases in patients and in animal models, it is noted that invasive intervention is significantly associated with both an increase in the level of circulating tumor cells and the development of metastases (dissemination of cells along the needle or when tumor tissue is damaged; the occurrence of a proinflammatory background that promotes the breakdown of the extracellular matrix and extravasation, etc.). Thus, there is a need to develop a technology for intraoperative prevention of metastasis formation based on the removal of DNA-containing structures (NETs and CECN) from the bloodstream of patients with pancreatic cancer, for which the use of selective plasma adsorption using the NucleoCor® sorption column might be of great value.