Fig 2 - uploaded by Carolina Bernauer
Content may be subject to copyright.
Hypoxia-targeted treatment strategies. Key interactions between tumour hypoxia and the tumour vasculature are depicted by the blood vessels and cancer cells of a solid tumour. The levels of oxygen (O 2 ) in cancer cells decrease with increasing distance from the blood vessel. In hypoxic cancer cells, hypoxia-inducible factor (HIF), a transcription factor, enters the nucleus and upregulates the expression of target genes, such as vascular endothelial growth factor (VEGF), which promotes angiogenesis, thus improving the blood supply to promote tumour progression, and carbonic anhydrase IX (CAIX), which regulates the acidification of the extracellular tumour microenvironment (TME). Counteracting the effects of hypoxia in a solid tumour for therapeutic benefit can be achieved by targeting distinctive areas of the tumour with therapies that have different mechanisms of action, as depicted: (i) increasing the supply of O 2 to cancer cells through surrounding blood vessels, (ii) decreasing the O 2 demand in well-oxygenated perihypoxic cells, thereby increasing O 2 availability for hypoxic cells, (iii) using inactive prodrugs that are activated by enzymes present specifically in hypoxic cells, (iv) directly inhibiting HIF and its downstream effects that enable hypoxic cells to adapt to hypoxia and inhibiting HIF downstream targets, such as (v) VEGF or (vi) CAIX. These treatment strategies can be used in combination with other therapies, such as radiotherapy and/or chemotherapy, or immunotherapy, or as single agents, for optimal therapeutic benefit.
Source publication
In tumours, hypoxia—a condition in which the demand for oxygen is higher than its availability—is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can allevia...
Context in source publication
Context 1
... strategies have been developed. The first involves increasing the level of oxygen in the tumour microenvironment (TME). Alternatively, hypoxia can be exploited so that hypoxic cancer cells are selectively targeted. Finally, the adaptive mechanisms that enable tumour cells to survive in hypoxia can be targeted. 8 These strategies are summarised in Fig. 2. The average level of oxygenation in peripheral tissues is 6.1%, 64 whereas in solid tumours, median oxygen levels can vary between 0.3 65,66 and 4.2%. 67 As areas of pathological hypoxia are heterogeneously distributed throughout tumours 13 between areas of physiological oxygenation, it might be necessary to combine hypoxia-targeting ...
Citations
... Consequently, deeper insight into the RMS microenvironment could not only more accurately reveal treatment limitations but also potentially provide opportunities to molecularly stratify patients for specific combination treatments. The RMS microenvironment features a hypoxic signature [115,116] that must be considered carefully when pursuing new knowledge to better understand RMS biology and/or treatment sensitivity/resistance mechanisms [117,118]. For example, emerging evidence indicates that CSCs might reside in the hypoxic niche, where they are believed to be more chemo-and radioprotected [119,120]. ...
Simple Summary
Rhabdomyosarcoma is a rare type of childhood cancer. Current treatment options include surgery, radiotherapy, and chemotherapy. Survival chances for RMS patients have increased over the last few decades as a result of improved risk-based patient allocation procedures in therapeutic protocols. However, RMS patients bearing an advanced disease at diagnosis still fare badly, and mortality rates remain very high. The novel chemotherapeutic combinations tested in clinical trials for RMS have failed to improve outcomes in this subset of patients. The impact of drug-metabolising enzymes (DMEs) on drug efficacy and their potential as targets for targeted therapy are sometimes overlooked. Here, we critically review the literature and what has been achieved in the treatment of RMS, with a focus on how DMEs modify patients’ responses to therapy, and discuss new ideas towards the development of targeted therapies.
Abstract
Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.
... Insufficient oxygen supply leads to a state of hypoxia, which is prevalent in various diseases, including anemia, cardiovascular disease, chronic obstructive pulmonary disease, neural degenerative disease, chronic kidney disease, [1][2][3][4] and even cancer. 5 When individuals travel to high-altitude areas rapidly, they will experience hypoxia and hypoxic adaptation processes, which may lead to acute mountain sickness (AMS) if they are maladapted. The clinical symptoms include headache, gastrointestinal symptoms, fatigue, dizziness, and sleep difficulties. ...
... Cell lines were seeded at the same density and incubated in Hx (1% O 2 ) for 7 days in the absence (Ctl) or presence of iGP-1 (100 µM) + AOAA (1 mM) + GNE-140 (5 µM). [27] clearly explains the importance of hypoxia in cancer cell resistance, our article addresses the issue of metabolism in a hypoxic environment and its therapeutic possibilities. We bring considerable expertise and experience from many years of work using this approach in colon [28,29] and kidney [30] cancers and focus on the critical role of mitochondria [31,32]. ...
Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.
... In particular, HIF-1α controls glucose uptake by the expression of glucose transporter GLUT1 and GLUT3, induces the expression of glycolytic enzymes and promotes pyruvate conversion to lactate by inducing LDHA and pyruvate dehydrogenase kinase PDK1 expression [68]. Hypoxia and HIF-1α over-activation have been correlated with tumor aggressiveness and progression in several cancers [69], including MB [70,71], where they are crucial for stem cell survival and stem cell maintenance [72]. ...
Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, and response to therapy in various types of cancer. Cancer cells exhibit remarkable adaptability by modulating glucose, lipids, amino acids, and nucleotide metabolism to survive in nutrient- and oxygen-deprived environments. Although medulloblastoma has been extensively studied from a genomic perspective, leading to the identification of four subgroups and their respective subcategories, the investigation of its metabolic phenotype has remained relatively understudied. This review focus on the available literature, aiming to summarize the current knowledge about the main metabolic pathways that are deregulated in medulloblastoma tumors, while emphasizing the controversial aspects and the progress that is yet to be made. Furthermore, we underscored the insights gained so far regarding the impact of metabolism on the development of drug resistance in medulloblastoma and the therapeutic strategies employed to target specific metabolic pathways.
... While the relevance of hypoxia in tumorigenesis and progression has been extensively studied and reviewed in many different cancer types [20][21][22][23], the current knowledge and particularities of hypoxia and HIF signaling in Ewing sarcoma (EwS) have not been systematically reviewed to date. EwS is the second most frequent bone-associated tumor predominantly occurring in children, adolescents, and young adults [24]. ...
... Therapeutic options to target hypoxia in childhood cancers have been recently reviewed and the urgent need for prognostic markers to evaluate hypoxia in the pediatric setting has been highlighted [21]. Therefore, expression of HIF-1-a, HIF-2-a, and their downstream targets such as VEGF, GLUT1, carbonic anhydrase 9 (CA9), phosphoglycerate kinase 1 (PGK1), and lysyl oxidase (LOX) was evaluated and their association with prognosis and chemotherapy-response seemed to vary between pediatric cancer entities [21]. ...
... Therapeutic options to target hypoxia in childhood cancers have been recently reviewed and the urgent need for prognostic markers to evaluate hypoxia in the pediatric setting has been highlighted [21]. Therefore, expression of HIF-1-a, HIF-2-a, and their downstream targets such as VEGF, GLUT1, carbonic anhydrase 9 (CA9), phosphoglycerate kinase 1 (PGK1), and lysyl oxidase (LOX) was evaluated and their association with prognosis and chemotherapy-response seemed to vary between pediatric cancer entities [21]. In this review, we evaluated the correlation of gene expression levels and survival in our cohort of 156 EwS patients and identified high HIF-1-a and GLUT1 expression to be significantly associated with worse prognosis (Fig. 2), which was not observed for PGK1, LOX, HIF-2-a, VEGF, and CA9 (not shown). ...
Hypoxia develops during the growth of solid tumors and influences tumoral activity in multiple ways. Low oxygen tension is also present in the bone microenvironment where Ewing sarcoma (EwS) – a highly aggressive pediatric cancer – mainly arises. Hypoxia inducible factor 1 subunit alpha (HIF-1-a) is the principal molecular mediator of the hypoxic response in cancer whereas EWSR1::FLI1 constitutes the oncogenic driver of EwS. Interaction of the two proteins has been shown in EwS. Although a growing body of studies investigated hypoxia and HIFs in EwS, their precise role for EwS pathophysiology is not clarified to date. This review summarizes and structures recent findings demonstrating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.
... e difference in oxygen levels between cancer cells and normal cells gives oxygen an important role in the development and treatment of cancer, as hypoxia in the environment causes cancer cells not to respond to treatment [17]. New treatment strategies aimed at counteracting hypoxia in the tumor environment by designing drugs that selectively target cancer cells and activate them in hypoxia [18]. erefore, the fluorescence signal contains more information than color and intensity. ...
Photodynamic therapy (PDT) is a selective and minimally invasive technique for the treatment of tumors. It includes three components such as photosensitizer, light, and molecular oxygen. The purpose of this work is to investigate the effect of the solvents such as methanol, ethanol, acetone, and water on fluorescent spectroscopy produced by one of the BODIPY derivatives in turbid media. A 520 nm laser diode is used for exciting one of the BODIPY derivatives as a photosensitizer in tissue-like optical phantoms. Results show that the photosensitizer studied without absorption and scattering components in the methanol and ethanol solvent has a prominent fluorescence peak at 600 nm, whereas acetone solvent has a prominent fluorescence peak at 546 nm. Experimental results reveal that when absorption and scattering components are present in addition to the studied solvents, the characteristic fluorescence intensity peak is red-shifted to 678 nm.
... Generally, the permissive cell and tissue survival factors, and the metabolic alteration induced by hypoxia in cancer cells leads to increased malignancy and thus lead to lower survival rates through enhanced treatment resistance and increased proliferation capacity. Clarifying the processes by which hypoxia leads to metabolic change at the cellular level will facilitate strategic focus on specific pathways, ultimately ensuring the death of cancer cells [2][3][4][5][6]. Additionally, nanoparticles having oxytactic microorganisms become essential in medical applications, mostly when the innovative cancer therapies, flow, heat, and mass transfers in drug delivery systems are considered. ...
The peristaltic flow of Carreau–Yasuda fluid through a micro-vessel involving oxytactic microorganisms and nanoparticles in a vertical asymmetric channel is examined. In early times, scientific research shows that the cancer cells exposed to low oxygen conditions had the advantage of staying in the bloodstream more and can invade healthy cells as well, whereas the oxytactic microorganisms exhibit negative chemotaxis to gradients of oxygen (oxygen repellents). So, it had to be studied the behavior of oxytactic microorganisms and nanoparticle and their roles in the drug-carriers system. All non-dimensional physical parameters are supposed to be variable as the viscosity of blood variable with fluid temperature and nanoparticle concentration. This system of partial differential equations was formulated and transformed mathematically using new theories of differential transform method combined by Pade' approximation (DTM-Pade′). The solution of the mentioned system is displayed digitally in tables and graphically in sketches. The existing study assured that the microorganism density in the direction near to the hypoxic tumor tissues regions grows with a rising in oxygen concentrations and the blood viscosity diminutions. Results show that the number of pores increases the flow and the particles of fluid moving more freely with increment in distribution of temperature.
... 2 As a result of vascular abnormalities that lead to low intratumoral blood flow, up to 50%-60% of locally advanced solid tumors develop areas of low O 2 (<10 mmHg) partial pressure compared with their surrounding tissues. [3][4][5] This hypoxic state has been associated with increased tumor aggressiveness and resistance to current therapies. 6 Of all the proteins induced by hypoxic conditions, hypoxia-inducible factors (HIFs) and their downstream targets are the most well studied. ...
Hypoxia is a characteristic feature of solid tumors that contributes to tumor aggressiveness and is associated with resistance to cancer therapy. The hypoxia inducible factor-1 (HIF-1) transcription factor complex mediates hypoxia-specific gene expression by binding to hypoxia responsive element (HRE) sequences within the promoter of target genes. HRE driven expression of therapeutic cargo has been widely explored as a strategy to achieve cancer-specific gene expression. By utilizing this system, we achieve hypoxia-specific expression of two therapeutically relevant cargo elements: the Herpes Simplex Virus thymidine kinase (HSV-tk) suicide gene and the CRISPR/Cas9 nuclease. Using an expression vector containing five copies of the HRE derived from the vascular endothelial growth factor gene, we are able to show high transgene expression in cells in a hypoxic environment, similar to levels achieved using the CMV and CBh promoters. Furthermore, we are able to deliver our therapeutic cargo to tumor cells with high efficiency using plasmid packaged lipid nanoparticles (LNPs) to achieve specific killing of tumor cells in hypoxic conditions, while maintaining tight regulation with no significant changes to cell viability in normoxia.
... Hypoxia is the central challenge to healthy individuals when they ascend to high altitude (B€ artsch and Gibbs, 2007;Hackett and Roach, 2001;Luks et al., 2008;West, 2004) and plays a pivotal role in hypoxic tissue damage and progression of almost all human diseases, including chronic kidney disease (CKD), cardiovascular disease, neurodegenerative disease, chronic pulmonary obstructive disease, hemolytic disorders, trauma, hemorrhage (DʼAlessandro et al., 2017), and even cancer (Arce, 2017;Basnyat, 2013;Bernauer et al., 2021;Fu et al., 2016;Semenza, 2014;Voit and Sankaran, 2020). Currently, substantial effort and research have largely focused on hypoxic damage and dysfunction of end organs. ...
Due to lack of nuclei and de novo protein synthesis, post-translational modification (PTM) is imperative for erythrocytes to regulate oxygen (O2) delivery and combat tissue hypoxia. Here, we report that erythrocyte transglutminase-2 (eTG2)-mediated PTM is essential to trigger O2 delivery by promoting bisphosphoglycerate mutase proteostasis and the Rapoport-Luebering glycolytic shunt for adaptation to hypoxia, in healthy humans ascending to high altitude and in two distinct murine models of hypoxia. In a pathological hypoxia model with chronic kidney disease (CKD), eTG2 is critical to combat renal hypoxia-induced reduction of Slc22a5 transcription and OCNT2 protein levels via HIF-1α-PPARα signaling to maintain carnitine homeostasis. Carnitine supplementation is an effective and safe therapeutic approach to counteract hypertension and progression of CKD by enhancing erythrocyte O2 delivery. Altogether, we reveal eTG2 as an erythrocyte protein stabilizer orchestrating O2 delivery and tissue adaptive metabolic reprogramming and identify carnitine-based therapy to mitigate hypoxia and CKD progression.
... Except for the malignant phenotypes of HCC cells, tumor microenvironment (TME) also plays critical roles in promoting HCC development [8,9]. Hypoxia is one of the critical characteristics of most solid cancers, including HCC [10][11][12][13]. Hypoxia inducible factor-1α (HIF-1α) is stabilized by hypoxia [14]. ...
Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.
