Kinins in Glioblastoma Microenvironment

Abstract

Tumour progression involves interactions among various cancer cell clones, including the cancer stem cell subpopulation and exogenous cellular components, termed cancer stromal cells. The latter include a plethora of tumour infiltrating immunocompetent cells, among which are also immuno-modulatory mesenchymal stem cells, which by vigorous migration to growing tumours and susequent transdifferentiation into various types of tumour-residing stromal cells, may either inhibit or support tumour progression. In the light of the scarce therapeutic options existing for the most malignant brain tumour glioblastoma, mesenchymal stem cells may represent a promising novel tool for cell therapy, e.g. drug delivery vectors. Here, we review the increasing number of reports on mutual interactions between mesenchymal stem cells and glioblastoma cells in their microenvironment. We particularly point out two novel aspects: the different responses of cancer cells to their microenvironmental cues, and to the signalling by kinin receptors that complement the immuno-modulating cytokine-signalling networks. Inflammatory glioblastoma microenvironment is characterised by increasing expression of kinin receptors during progressive glioma malignancy, thus making kinin signalling and kinins themselves rather important in this context. In general, their role in tumour microenvironment has not been explored so far. In addition, kinins also regulate blood brain barrier-related drug transfer as well as brain tumour angiogenesis. These studies support the ongoing research on kinin antagonists as candidates in the development of anti-invasive agents for adjuvant glioblastoma therapy. Keywords Co-culture. Glioma. Kinin receptors. Mesenchymal stem cells. Microenvironment. Tumour heterogeneity Brain Tumours-Glioblastoma Brain tumours originate from various types of cells, of which astroglial tumours being the most frequent. The World Health Organisation (WHO) distinguishes four grades of glioma, of which glioblastoma (GBM) is the most aggressive, invasive, and lethal among all types of brain tumours. Unfortunately, it is also the most common among glial tumours with 5-7 cases per 100.000 individuals yearly, and represents 50% of all gliomas [1, 2]. It is characterised by histological features such as necrosis, vascular proliferation and pleomorphism. Contrary to most tumour types, irradiation and chemotherapy has proven to be ineffective to impair long term GBM progression, demonstrating its remarkable therapeutic resistance [3-5]. Radiotherapy is combined with chemotherapy, for which the alkylating agent temozolomide has been used in most cases. There is a constant search for novel adjuvant therapeutics, including kinase inhibitors, anti-angiogenic agents and recently also immunotherapy to increase average survival of GBM patients. Several reasons for GBM resistance to therapy has been recognised, such as diffuse infiltration of cancer cells into neighbouring brain parenchyma that are hard to target by surgery [6-8]. Furthermore, the presence of het...

CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

“…A high rate of relapse is mostly due to the resistance of glioblastoma stem cells (GSCs) and their heterogeneity and plasticity that are contributing to the resistance of recurrent tumors [ 3 , 5 , 6 ]. Tumor heterogeneity is due to both the variety of glioblastoma subtypes [ 7 , 8 ] and the presence of different types of stromal cells of the tumor microenvironment (TME), both contributing to the inter- and intra-tumor heterogeneity, respectively [ 9 , 10 ]. GSCs have an important role in the development, growth, and aggressiveness of glioblastoma, due to their efficient DNA repair mechanisms, heterogeneity, cell plasticity [ 5 ], and cooperation with differentiated glioblastoma cells [ 11 ].…”

“…In tumor tissues, GSCs are maintained in hypoxic and peri-arteriolar GSC niches [ 12 , 13 ] where the TME contributes to paracrine interactions with endothelial cells [ 12 ]. The brain TME is comprised not only of resident astrocytes, neurons, and microglial cells but also infiltrating mesenchymal stem cells (MSCs), hematopoietic stem cells (HSC), and differentiated immune cells, such as macrophages [ 9 ], altogether comprising so-called tumor stroma. Understanding these selective interactions between non-cancerous so-called stromal and glioblastoma cells is crucial for the effectiveness of treatment strategies.…”

Mesenchymal stem cell‐glioblastoma interactions mediated via kinin receptors unveiled by cytometry

“…Not only MSCs per se are applicable as cytotherapeutic agents, but also their secretomes, comprised of exosomes, microvesicles, cytokines, and other exocytic factors, are being increasingly investigated for acellular and regenerative therapies [66–68]. Several immuno‐modulatory factors/chemokines that regulate inflammation, cell death, angiogenesis, fibrosis, and tissue regeneration are produced and secreted by MSCs [69]. Extracellular vesicles from bone‐marrow‐derived MSCs (BM‐MSCs) and umbilical cord‐derived MSCs (UC‐MSCs) were shown to be internalized by GBM cells, inhibiting their proliferation and subsequently inducing apoptosis.…”

Problems of Effective Therapy of Brain Neoplasms: Fatality or Positive Outlook

“…MicroRNA molecules released from Extracellular Vesicles of umbilical cord MSCs are considered to be the proposed mechanism of such therapeutic effect [3]. Therefore, data are accumulating on the functional role of exosomes in oncological topics and the reality of MSCs use as one of the components in the treatment of GB [3][4][5].…”

“…It is advisable to pay attention to the problem of tumor tissue heterogeneity. Any tumor tissue includes both different populations of cancer cells and a variety of stromal cells [4]. Intercellular matrix contains many immunocompetent cells and MSCs that exhibit an immunosuppressive effect and are capable of either inhibiting or supporting tumor progression [4].…”