RRS GRID, Lattice, FLAS and Microbeam working Group published a FOCUS issue in Radiation Research, the official journal of the Radiation Research Society (RRS).
Dr. Robert Griffin, Chairperson of Biology for the working group was a guest editor and has a special introduction in the latest issue of the Radiation Research Journal.
This journal is open access and you can read the journal and Dr. Griffin’s introduction HERE.
Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models.
Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non-peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO2) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1—e.g., by OTX008—may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care.
Galectins are a family of small, highly conserved, molecular effectors that mediate various
biological processes, including chemotaxis and angiogenesis, and that function by interacting with
various cell surface glycoconjugates, usually targeting -galactoside epitopes. Because of their
significant involvement in various biological functions and pathologies, galectins have become a
focus of therapeutic discovery for clinical intervention against cancer, among other pathological
disorders. In this review, we focus on understanding galectin structure-function relationships,
their mechanisms of action on the molecular level, and targeting them for therapeutic intervention
DNA Methylation in Radiation-Induced Carcinogenesis: Experimental Evidence and Clinical Perspectives
Ionizing radiation is a valuable tool in many spheres of human life. At the same time, it is a genotoxic agent with a well-established carcinogenic potential. Progress achieved in the last two decades has demonstrated convincingly that ionizing radiation can also target the cellular epigenome. Epigenetics is defined as heritable changes in the expression of genes that are not due to alterations of DNA sequence but consist of specific covalent modifications of chromatin components, such as methylation of DNA, histone modifications, and control performed by non-coding RNAs. Accumulating evidence suggests that DNA methylation, a key epigenetic mechanism involved in the control of expression of genetic information, may serve as one of the driving mechanisms of radiation-induced carcinogenesis. Here, we review the literature on the effects of ionizing radiation on DNA methylation in various biological systems, discuss the role of DNA methylation in radiation carcinogenesis, and provide our opinion on the potential utilization of this knowledge in radiation oncology.
Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells
Hypoxia, a hallmark characteristic of glioblastoma (GBM) induces changes in the transcriptome and the proteome of tumor cells. We discovered that hypoxic stress produces significant qualitative and quantitative changes in the protein content of secreted exosomes from GBM cells. Among the proteins found to be selectively elevated in hypoxic exosomes were protein-lysine 6-oxidase (LOX), thrombospondin-1 (TSP1), vascular derived endothelial factor (VEGF) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), well studied contributors to tumor progression, metastasis and angiogenesis. Our findings demonstrate that hypoxic exosomes induce differential gene expression in recipient glioma cells. Glioma cells stimulated with hypoxic exosomes showed a marked upregulation of small nucleolar RNA, C/D box 116–21 (SNORD116-21) transcript among others while significantly downregulated the potassium voltage-gated channel subfamily J member 3 (KCNJ3) message. This differential expression of certain genes is governed by the protein cargo being transferred via exosomes. Additionally, compared to normoxic exosomes, hypoxic exosomes increased various angiogenic related parameters vis-à-vis, overall tube length, branching intervals and length of isolated branches studied in tube formation assay with endothelial progenitor cells (EPCs). Thus, the intercellular communication facilitated via exosomes secreted from hypoxic GBM cells induce marked changes in the expression of genes in neighboring normoxic tumor cells and possibly in surrounding stromal cells, many of which are involved in cancer progression and treatment resistance mechanisms.