Advances in the Development of New Drugs and Treatment Targets for Brain Cancers.

Brain tumors are a significant concern for the global medical community, with over 300,000 cases reported annually worldwide [...].

Targeting glioblastoma stem cells: The first step of photodynamic therapy.

Glioblastoma is one of the most malignant types of brain cancer. Evidence suggests that within gliomas there is a small subpopulation of cells with the capacity for self-renewal, called glioma stem cells. These cells could be responsible for tumorigenesis, chemo and radioresistance, and finally for the recurrence of the tumor. Fluorescence-guided resection have improved the results of treatment against this disease, prolonging the survival of patients by a few months. Also, clinical trials have reported potential improvements in the therapeutic response after photodynamic therapy. Thus far, there are few published works that show the response of glioblastoma stem-like cells to photodynamic therapy. Here, we present a brief review exclusively commenting on the therapeutic approaches to eliminate glioblastoma stem cells and on the research publications about this topic of glioblastoma stem cells in relation to photodynamic therapy. It is our hope that this review will be useful to provide an overview about what is known to date on the topic and to promote the generation of new ideas for the eradication of glioblastoma stem cells by photodynamic treatment.

Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events.

Photodynamic therapy (PDT) has recently gained attention as an alternative treatment of malignant gliomas. Glioblastoma (GBM) is the most prevalent within tumors of the central nervous system (CNS). Conventional treatments for this CNS tumor include surgery, radiation, and chemotherapy. Surgery is still being considered as the treatment of choice. Even so, the poor prognosis and/or recurrence of the disease after applying any of these treatments highlight the urgency of exploring new therapies and/or improving existing ones to achieve the definitive eradication of tumor masses and remaining cells. PDT is a therapeutic modality that involves the destruction of tumor cells by reactive oxygen species induced by light, which were previously treated with a photosensitizing agent. However, in recent years, its experimental application has expanded to other effects that could improve overall performance against GBM. In the current review, we revisit the main advances of PDT for GBM management and also, the recent mechanistic insights about cellular and molecular aspects related to tumoral resistance to PDT of GBM.

Isolation and initial characterization of human glioblastoma cells resistant to photodynamic therapy.

Glioblastoma is the most severe form of brain cancer. Despite multimodal therapy combining surgery, radiotherapy and chemotherapy, prognosis of patients is dismal. It has been observed that the surgical resection guided by photosensitizer fluorescence followed by photodynamic therapy (PDT) prolongs the average survival in patients with glioblastoma. The main problem with all oncological treatments, including PDT, is the presence of resistant cells. The objective of this study was to isolate and perform an initial characterization of human glioblastoma cells resistant to PDT employing methyl-5-aminolevulinic acid. We obtained resistant cells from the T98 G cell line. Resistant populations accumulated less photosensitizer, formed spheroids of higher number of cells, had higher tumorigenic capacity, and expressed higher mRNA levels of fibroblastic growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ß-platelet-derived growth factor receptor (ßPDGFR) than parental cells. The studies of glioblastoma resistance to PDT would help to better understand the causes of tumor recurrence after PDT and to develop new therapeutic proposals in this field of oncology.

Heat shock proteins in the context of photodynamic therapy: autophagy, apoptosis and immunogenic cell death.

Photodynamic therapy (PDT) is an anti-tumor treatment administered for the elimination of early-stage malignancies and the palliation of symptoms in patients with late-stage tumors, which involves the activation of a photosensitizer (PS) using light of a specific wavelength, which also generates singlet oxygen and other reactive oxygen species (ROS) that cause tumor cell death. Several mechanisms are involved in the protective responses to PDT including the expression of chaperone/heat shock proteins (HSPs). The HSPs are a family of proteins that are induced by cells in response to exposure to stressful conditions. In the last few decades, it has been discovered that HSPs can play an important role in cell survival, due to the fact that they are responsible for many cytoprotective mechanisms. These proteins have different functions depending on their intracellular or extracellular location. In general, intracellular HSPs have been related to an anti-apoptotic function and recently, HSP-induced autophagy has shown to have a protective role in these chaperones. In contrast, extracellular HSPs or membrane-bound HSPs mediate immunological functions. In the present article, we attempt to review the current knowledge concerning the role of HSPs in the outcome of PDT in relation to autophagy and apoptosis mediated-resistance to photodynamic treatment. We will also discuss how certain PDT protocols optimally stimulate the immune system through HSPs.

Ecological photodynamic therapy: new trend to disrupt the intricate networks within tumor ecosystem.

As with natural ecosystems, species within the tumor microenvironment are connected by pairwise interactions (e.g. mutualism, predation) leading to a strong interdependence of different populations on each other. In this review we have identified the ecological roles played by each non-neoplastic population (macrophages, endothelial cells, fibroblasts) and other abiotic components (oxygen, extracellular matrix) directly involved with neoplastic development. A way to alter an ecosystem is to affect other species within the environment that are supporting the growth and survival of the species of interest, here the tumor cells; thus, some features of ecological systems could be exploited for cancer therapy. We propose a well-known antitumor therapy called photodynamic therapy (PDT) as a novel modulator of ecological interactions. We refer to this as "ecological photodynamic therapy." The main goal of this new strategy is the improvement of therapeutic efficiency through the disruption of ecological networks with the aim of destroying the tumor ecosystem. It is therefore necessary to identify those interactions from which tumor cells get benefit and those by which it is impaired, and then design multitargeted combined photodynamic regimes in order to orchestrate non-neoplastic populations against their neoplastic counterpart. Thus, conceiving the tumor as an ecological system opens avenues for novel approaches on treatment strategies.

Direct and indirect photodynamic therapy effects on the cellular and molecular components of the tumor microenvironment.

Photodynamic therapy (PDT) is a novel cancer treatment. It involves the activation of a photosensitizer (PS) with light of specific wavelength, which interacts with molecular oxygen to generate singlet oxygen and other reactive oxygen species (ROS) that lead to tumor cell death. When a tumor is treated with PDT, in addition to affect cancer cells, the extracellular matrix and the other cellular components of the microenvironment are altered and finally this had effects on the tumor cells survival. Furthermore, the heterogeneity in the availability of nutrients and oxygen in the different regions of a tridimensional tumor has a strong impact on the sensitivity of cells to PDT. In this review, we summarize how PDT affects indirectly to the tumor cells, by the alterations on the extracellular matrix, the cell adhesion and the effects over the immune response. Also, we describe direct PDT effects on cancer cells, considering the intratumoral role that autophagy mediated by hypoxia-inducible factor 1 (HIF-1) has on the efficiency of the treatment.