Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

Abstract

Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours.

Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment

“…Effects of CAP have been observed on different parts of the TME, which is composed of malignant cells, immune cells, endothelial cells, fibroblasts, tumor vasculature and the extracellular matrix, which are in constant communication with each other. In addition to the various cell types, the TME consists of collagen, elastin, fibronectin, glycoproteins, and proteoglycan [92]. It has been observed that prolonged treatment with CAP inhibits cell viability and collagen production of murine fibroblasts [93].…”

“…It has also been shown that calcium ions can be transported from apoptotic to non-apoptotic neighbour cells via gap junctions, which also explains the widespread effect of plasma [107]. A comprehensive review on CAP effects regarding numerous other parts of the TME was provided by Privat-Maldonado et al [92].…”

Impact of the Tumor Microenvironment on the Gene Expression Profile in Papillary Thyroid Cancer

“…It is well known that the tumor microenvironment (TME) contributes to cancer development and promotes angiogenesis, invasion, metastasis, and chronic inflammation [19]. The possible role of TME in response to chemotherapy [20] or antiangiogenic therapy [21] has been addressed recently.…”

“…The possible role of TME in response to chemotherapy [20] or antiangiogenic therapy [21] has been addressed recently. In healthy tissues the wound healing process is promoted by the activation, migration, and proliferation of fibroblasts, whereas cancer-associated fibroblasts play a role in tumor growth and therefore are crucial for disease progression [19,22].…”

Plasma in Cancer Treatment

“…This Special Issue on “Plasma in Cancer Treatment” brings together 16 original research papers [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] and two insightful reviews [ 24 , 25 ]. The papers published in the Special Issue provide valuable information regarding the efficacy of CAP against osteosarcoma, glioblastoma, cholangiocarcinoma, melanoma, pancreatic, ovarian, breast, cervical and colorectal cancer.…”