scholarly journals Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

2021 ◽  
Vol 11 ◽  
Author(s):  
Marike W. van Gisbergen ◽  
Emma Zwilling ◽  
Ludwig J. Dubois
Keyword(s):  
Normal Tissue ◽  
Hypoxia Inducible Factor ◽  
Cellular Metabolism ◽  
Redox Balance ◽  
Metastatic Lesion ◽  
Proliferative Potential ◽  
Malignant Cells ◽  
Therapeutic Ratio ◽  
Current State ◽  
Lesion Treatment

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

Nuclear expression of hypoxia-inducible factor 1α protein is heterogeneous in human malignant cells under normoxic conditions

2002 ◽  
Vol 181 (2) ◽  
pp. 233-238 ◽  
Author(s):  
Hua Zhong ◽  
Nicola J. Mabjeesh ◽  
Margaret T. Willard ◽  
Jonathan W. Simons
Keyword(s):  
Hypoxia Inducible Factor ◽  
Malignant Cells ◽  
Hypoxia Inducible Factor 1Α ◽  
Nuclear Expression

scholarly journals HIF1A signaling selectively supports proliferation of breast cancer in the brain

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Richard Y. Ebright ◽  
Marcus A. Zachariah ◽  
Douglas S. Micalizzi ◽  
Ben S. Wittner ◽  
Kira L. Niederhoffer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Tumor Growth ◽  
Hypoxia Inducible Factor ◽  
Metastatic Breast ◽  
Major Complication ◽  
Proliferative Potential ◽  
Therapeutic Implications ◽  
Drug Inhibition ◽  
The Brain

AbstractBlood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.

Peroxisomal fatty acid α- and β-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases

2001 ◽  
Vol 29 (2) ◽  
pp. 250-267 ◽  
Author(s):  
R. J. A. Wanders ◽  
P. Vreken ◽  
S. Ferdinandusse ◽  
G. A. Jansen ◽  
H. R. Waterham ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Genetic Diseases ◽  
Cellular Metabolism ◽  
Peroxisomal Membrane ◽  
Subcellular Organelles ◽  
Current State ◽  
Peroxisomal Fatty Acid

Peroxisomes are subcellular organelles with an indispensable role in cellular metabolism. The importance of peroxisomes for humans is stressed by the existence of a group of genetic diseases in humans in which there is an impairment in one or more peroxisomal functions. Most of these functions have to do with lipid metabolism including the α and β-oxidation of fatty acids. Here we describe the current state of knowledge about peroxisomal fatty acid α- and β-oxidation with particular emphasis on the following: (1) the substrates β-oxidized in peroxisomes; (2) the enzymology of the α- and β-oxidation systems; (3) the permeability properties of the peroxisomal membrane and the role of the different transporters therein; (4) the interaction with other subcellular compartments, including the mitochondria, which are the ultimate site of NADH reoxidation and full degradation of acetyl-CoA to CO2 and water; and (5) the different disorders of peroxisomal α- and β-oxidation.

Significance of hypoxia inducible factor-1 expression in liver metastasis of colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 464-464
Author(s):  
Yuma Wada ◽  
Yuji Morine ◽  
Satoru Imura ◽  
Tetsuya Ikemoto ◽  
Shuichi Iwahashi ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Hypoxia Inducible Factor ◽  
Metastatic Lesion ◽  
Primary Lesion ◽  
Clinicopathological Factors ◽  
Negative Group ◽  
Mesenchymal Transition ◽  
Positive Group ◽  
Hypoxia Inducible Factor 1 ◽  
The Difference

464 Background: In colorectal liver metastasis (CRLM), the difference of tumor malignancy between primary and metastatic lesion has been elucidated. Hypoxia inducible factor-1 (HIF-1) represent tumor malignancy including angiogenesis, tumor growth and epithelial mesenchymal transition (EMT). The aim of this study was to investigate the difference of tumor malignancy between metastatic and primary lesion of CRLM and its impact for patient’s prognosis. Methods: In an initial curative hepatectomy of 75 cases in CRLM, HIF-1 expression in primary and metastatic lesion was evaluated by immunostaining method (Sigma-Aldrich, HPA 001275). Staining score was classified as follows, staining intensity (0: negative, 1: low, 2: medium, 3: high) and staining area (0: 0%, 1: -25%, 2: 26-50%, 3: ≥ 51%), and defined more than 4 points as positive expression. We evaluated the clinicopathological features according to HIF-1 expression. Results: Regarding HIF-1 expression of metastatic site, we divided into the positive group (n = 54) and the negative group (n = 21). There was no difference between metastatic HIF-1 expression and clinicopathological factors. Nevertheless, in overall survival, multivariate analysis revealed that HIF-1 positive in metastasis (HR: 2.850, p = 0.042) and poor differentiation type of primary lesion (HR: 20.873, p = 0.001) were independent prognostic factors. HIF-1 positive and negative patients were 3 year survival of 95.2% and 58.6%, respectively. Also, in disease free survival, HIF-1 positive in metastasis (HR: 2.608, p = 0.004), Synchronous (HR: 1.794, p = 0.049), Grade BC (HR: 2.145, p = 0.008), and lymph node metastasis in primary lesion (HR: 2.070, p = 0.016) was identified. Regarding HIF-1 expression of primary site, we divided into 51 cases of positive group and 24 cases of negative group. There was no relationship to clinicopathological factors as well as HIF-1 expression in metastasis, besides HIF-1 expression of prognosis was not associated. Conclusions: In CRLM, HIF-1 expression in the metastatic lesion is not associated with the primary lesion and may be useful as prognostic marker.

scholarly journals Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
David Kung-Chun Chiu ◽  
Aki Pui-Wah Tse ◽  
Cheuk-Ting Law ◽  
Iris Ming-Jing Xu ◽  
Derek Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Biogenesis ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Notch Pathway ◽  
Redox Balance ◽  
Therapeutic Interventions ◽  
Luciferase Reporter ◽  
Mitochondrial Activity ◽  
Chip Sequencing

AbstractHypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O2) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. Through hypoxia-inducible factor 1 (HIF-1) which elicits various molecular events, cells are able to overcome low O2. Knowledge about the new molecular mechanisms governed by HIF-1 is important for new therapeutic interventions targeting hypoxic tumors. Using hepatocellular carcinoma (HCC) as a model, we revealed that the HIF-1 and the Notch signaling pathways cross-talk to control mitochondrial biogenesis of cancer cells to maintain REDOX balance. From transcriptome sequencing, we found that HEY1, a transcriptional repressor, in the NOTCH pathway was consistently induced by hypoxia in HCC cell lines. We identified a strong hypoxia response element (HRE) in HEY1 by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Transcriptome and ChIP sequencing further identified PINK1, a gene essential for mitochondrial biogenesis, as a novel transcriptional target of HEY1. HCC cells with HEY1 knockdown re-expressed PINK1. HEY1 and PINK1 expressions inversely correlated in human HCC samples. Overexpression of HEY1 and under-expression of PINK1 were detected in human HCC and associated with poor clinical outcomes. Functionally, we found that overexpression of HEY1 or knockdown of PINK1 consistently reduced mitochondrial cristae, mitochondrial mass, oxidative stress level, and increased HCC growth.

Abstract LB-280: FLASH: A novel paradigm changing tumor irradiation platform that enhances therapeutic ratio by reducing normal tissue toxicity and activating immune pathways

2019 ◽  
Author(s):  
Swati Girdhani ◽  
Eric Abel ◽  
Alexander Katsis ◽  
Andrew Rodriquez ◽  
Shilpa Senapati ◽  
...  
Keyword(s):  
Normal Tissue ◽  
Therapeutic Ratio ◽  
Normal Tissue Toxicity ◽  
Tumor Irradiation ◽  
Immune Pathways

scholarly journals The therapeutic ratio is preserved for radiotherapy or cisplatin treatment in BRCA2-mutated prostate cancers

2013 ◽  
Vol 5 (2) ◽  
pp. 31
Author(s):  
Danny Vesprini ◽  
Steven A. Narod ◽  
John Trachtenberg ◽  
Juanita Crook ◽  
Farid Jalali ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Normal Tissue ◽  
Parp Inhibitors ◽  
Therapeutic Ratio ◽  
Normal Tissue Toxicity ◽  
Prostate Cancers ◽  
Precision Radiotherapy

Prostate cancers in patients with a mutation in BRCA2 have earlierdisease onset and an aggressive course, often necessitatingthe use of systemic therapy. However, these tumours are DNArepair-defective and could respond favourably to Parp inhibitors orDNA-damaging agents, depending on the therapeutic ratio (ratio oftumour response to normal tissue toxicity). We describe 3 patientstreated with precision radiotherapy or cisplatin who respondedfavourably to both agents, yet did not suffer undue toxicity. Wereview the concept of treating such patients with agents that areselectively toxic to repair-deficient tumours.

Are DNA polymerases from malignant cells different from those of normal tissue?

1993 ◽  
Vol 3 ◽  
pp. 35
Author(s):  
O. Popanda ◽  
G. Fox ◽  
H. W. Thielmann
Keyword(s):  
Normal Tissue ◽  
Dna Polymerases ◽  
Malignant Cells

scholarly journals The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Scott F. Leiser ◽  
Matt Kaeberlein
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Hypoxia Inducible Factor ◽  
Direct Connection ◽  
Hypoxic Response ◽  
The Past ◽  
Current State ◽  
Negative Modulator

Abstract In the past year and a half, five studies have independently established a direct connection between the hypoxic response transcription factor, HIF-1, and aging in Caenorhabditis elegans. These studies demonstrated that HIF-1 can both promote and limit longevity via pathways that are mechanistically distinct. Here, we review the current state of knowledge regarding modulation of aging by HIF-1 and speculate on potential aspects of HIF-1 function that could be relevant for mammalian longevity and healthspan.

scholarly journals Flow Cytometric Detection of the Classical Hodgkin Lymphoma: Clinical and Research Applications

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Mikhail Roshal ◽  
Brent L. Wood ◽  
Jonathan R. Fromm
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
B Cell Lymphoma ◽  
Clinical Samples ◽  
Malignant Cells ◽  
Classical Hodgkin Lymphoma ◽  
Flow Cytometric ◽  
Current State ◽  
Viable Tumor

Classical Hodgkin lymphoma (CHL) is a relatively uncommon B cell-derived neoplasm that presents with rare malignant cells in an abundant reactive background. The diagnosis of CHL currently relies on a combination of morphologic findings and immunohistochemical stains. With the exception of rare cases with dramatically increased malignant populations, isolation of pure viable tumor cells has not been historically possible. Recently, a reliable flow cytometric assay for direct detection and isolation of the malignant cells in this disease has been developed. This assay has proven useful diagnostically and has been clinically validated to have a very high sensitivity and nearly absolute specificity for the diagnosis of CHL in routine clinical samples. This paper describes the methodology for the flow cytometric detection of CHL in clinical samples as well as current state of evaluation of background lymphocytes as an adjunct diagnostic test. Also discussed are exciting research applications of the direct isolation of viable tumor cells in CHL. The current state of flow cytometric evaluation of nodular lymphocyte predominant Hodgkin lymphoma and T cell-rich large B cell lymphoma is also briefly discussed.

Sign in / Sign up

Export Citation Format

Share Document