Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer.

Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to β-catenin-driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.

A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.

Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours.

Oxygen Monitoring in Model Solutions and In Vivo in Mice During Proton Irradiation at Conventional and FLASH Dose Rates.

FLASH is a high-dose-rate form of radiation therapy that has the reported ability, compared with conventional dose rates, to spare normal tissues while being equipotent in tumor control, thereby increasing the therapeutic ratio. The mechanism underlying this normal tissue sparing effect is currently unknown, however one possibility is radiochemical oxygen depletion (ROD) during dose delivery in tissue at FLASH dose rates. In order to investigate this possibility, we used the phosphorescence quenching method to measure oxygen partial pressure before, during and after proton radiation delivery in model solutions and in normal muscle and sarcoma tumors in mice, at both conventional (Conv) (∼0.

FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response.

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose.

Estrogen Receptor β-Mediated Inhibition of Actin-Based Cell Migration Suppresses Metastasis of Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ERα) negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein-coupled receptors and downstream effectors that activate Rho GTPases.

Radiobiological effectiveness difference of proton arc beams versus conventional proton and photon beams.

This paper aims to demonstrate the difference in biological effectiveness of proton monoenergetic arc therapy (PMAT) compared to intensity modulated proton therapy (IMPT) and conventional 6 MV photon therapy, and to quantify this difference when exposing cells of different radiosensitivity to the same experimental conditions for each modality. V79, H1299 and H460 cells were cultured in petri dishes placed in the central axis of a cylindrical and homogeneous solid water phantom of 20 cm in diameter. For the PMAT plan, cells were exposed to 13 mono-energetic proton beams separated every 15° over a 180° arc, designed to deliver a uniform dose of higher LET to the petri dishes.

Combination of CHEK1/2 inhibition and ionizing radiation results in abscopal tumor response through increased micronuclei formation.

We explore a novel strategy of activating immune signaling through increased micronuclei formation utilizing a cell cycle checkpoint inhibitor to drive cell cycle progression following ionizing radiation. The Chk1/2 inhibitor AZD7762 is used to abrogate radiation therapy (RT)-induced G2/M cell cycle arrest in multiple cell lines and, we find that this therapeutic combination promotes increased micronuclei formation in vitro and subsequently drives increased type I interferon signaling and cytotoxic T-cell activation. In vivo studies using B16-F10 melanoma cancer cells implanted in C57/BL6 mice demonstrate improved rates of tumor control at the abscopal (unirradiated) site, located outside of the radiation field, only in the AZD7762 + RT group, with a corresponding reduction in mean tumor volume, increase in the CD8 T-cell population, and immune activated gene signaling.

Is there a role for arcing techniques in proton therapy?

Proton arc therapy (PAT) has been proposed as a possible evolution for proton therapy. This commentary uses dosimetric and cancer risk evaluations from earlier studies to compare PAT with intensity modulated proton therapy. It is concluded that, although PAT may not produce better physical dose distributions than intensity modulated proton therapy, the radiobiological considerations associated with particular PAT techniques could offer the possibility of an increased therapeutic index.

Amifostine Protects Mouse Liver Against Radiation-induced Autophagy Blockage.

Background/aim: Amifostine is the only selective normal tissue cytoprotector, approved for the protection against platinum toxicities and radiotherapy-induced xerostomia. Free radical scavenger and DNA repair activities have been attributed to the drug.

Materials And Methods: We investigated the effect of amifostine on autophagy, lysosomal biogenesis and lipophagy of normal mouse liver exposed to clinically relevant doses of radiation.

Assessment of Radiobiological α/β Ratio in Lung Cancer and Fibroblast Cell Lines Using Viability Assays.

Background/aim: Altered fractionation is an area of intense clinical research in radiation oncology. Estimation of the α/β ratio of individual carcinomas after establishment of primary cell cultures from tumor biopsies may prove of importance in the individualization of radiotherapy schemes.

Materials And Methods: Here we proposed a simple method to estimate the α/β ratio in cultured cell lines (two lung carcinomas: A549 and H1299; one lung fibroblast cell line: MRC5), using viability assays.

Normal tissue radioprotection by amifostine via Warburg-type effects.

The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine.

Repression of the autophagic response sensitises lung cancer cells to radiation and chemotherapy.

Background: The cellular autophagic response to radiation is complex. Various cells and tissues respond differentially to radiation, depending on both the dose of exposure and the time post irradiation. In the current study, we determined the autophagosomal and lysosomal response to radiation in lung cancer cell lines by evaluating the expression of the associated proteins, as well as the effect of relevant gene silencing in radio and chemosensitisation.

Technical Note: Partial body irradiation of mice using a customized PMMA apparatus and a clinical 3D planning/LINAC radiotherapy system.

Purpose: In vivo radiobiology experiments involving partial body irradiation (PBI) of mice are of major importance because they allow for the evaluation of individual organ tolerance; overcoming current limitations of experiments using lower dose, whole body irradiation. In the current study, the authors characterize and validate an effective and efficient apparatus for multiple animal PBI, directed to the head, thorax, or abdomen of mice.

Methods: The apparatus is made of polymethylmethacrylate and consists of a rectangular parallelepiped prism (40 cm × 16 cm × 8 cm), in which five holes were drilled to accomodate standard 60 ml syringes, each housing an unanesthetized, fully immobilized mouse.

Increased expression of transcription factor EB (TFEB) is associated with autophagy, migratory phenotype and poor prognosis in non-small cell lung cancer.

Objectives: We investigated the role of lysosomal biogenesis and hydrolase activity in the clinical behavior and postoperative outcome of lung cancer.

Materials And Methods: Using immunohistochemistry we investigated the expression of the transcription factor EB (TFEB) which orchestrates lysosomal biogenesis, the lysosome membrane protein LAMP2a and of the lysosomal hydrolase cathepsin D in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery alone. In vitro experiments with the A549 and H1299 lung cancer cell lines were also performed.

Fever-range hyperthermia vs. hypothermia effect on cancer cell viability, proliferation and HSP90 expression.

Purpose: The current study examines the effect of fever-range hyperthermia and mild hypothermia on human cancer cells focusing on cell viability, proliferation and HSP90 expression.

Materials And Methods: A549 and H1299 lung carcinoma, MCF7 breast adenocarcinoma, U87MG and T98G glioblastoma, DU145 and PC3 prostate carcinoma and MRC5 normal fetal lung fibroblasts cell lines were studied. After 3-day exposure to 34°C, 37°C and 40°C, cell viability was determined.

Important role of autophagy in endothelial cell response to ionizing radiation.

Objectives: Vasculature damage is an important contributor to the side-effects of radiotherapy. The aim of this study is to provide insights into the radiobiology of the autophagic response of endothelial cells.

Methods And Materials: Human umbilical vascular endothelial cells (HUVEC) were exposed to 2 Gy of ionizing radiation (IR) and studied using confocal microscopy and western blot analysis, at 4 and 8 days post-irradiation.

Effects of catechin and epicatechin on superoxide dismutase and glutathione peroxidase activity, in vivo.

Objectives: The objective of this study was to investigate the effects of catechin and epicatechin on the activity of the endogenous antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) (as well as the total antioxidant capacity (TAC)) of rats after intra-peritoneal (i.p.) administration.