Oxygen Levels Do Not Determine Radiation Survival of Breast Cancer Stem Cells

For more than a century oxygen has been known to be one of the most powerful radiosensitizers. However, despite decades of preclinical and clinical research aimed at overcoming tumor hypoxia, little clinical progress has been made so far. Ionizing radiation damages DNA through generation of free radicals. In the presence of oxygen these lesions are chemically modified, and thus harder to repair while hypoxia protects cells from radiation (Oxygen enhancement ratio (OER)). Breast cancer stem cells (BSCSs) are protected from radiation by high levels of free radical scavengers even in the presence of oxygen. This led us to hypothesize that BCSCs exhibit an OER of 1. Using four established breast cancer cell lines (MCF-7, T47D, MDA-MB-231, SUM159PT) and primary breast cancer samples, we determined the number of BCSCs using cancer stem cell markers (ALDH1, low proteasome activity), compared radiation clonogenic survival and mammosphere formation under normoxic and hypoxic conditions, and correlated these results to the expression levels of key members of the free radical scavenging systems. The number of BCSCs increased with increased aggressiveness of the cancer. This correlated with increased radioresistance (SF8Gy), and decreasing OERs. When cultured as mammospheres, breast cancer cell lines and primary samples were highly radioresistant and not further protected by hypoxia (OER∼1)

Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice

<p>Abstract</p> <p>Background</p> <p>Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression <it>in vivo.</it></p> <p>Methods</p> <p>Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated.</p> <p>Results</p> <p>We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression <it>in vitro</it>, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na⁺-K⁺ATPase α1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1α and HIF2α) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na⁺-K⁺ATPase α1, c) increased HIF1α expression (no HIF2α was detected) and d) increased microvessel density in the tumor tissues.</p> <p>Conclusions</p> <p>This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na⁺-K⁺ATPase was involved in hypoxic inhibition of tumor progression. The results from this study provide new insights into the role of hypoxia in tumor progression and therapeutic strategies for cancer treatment.</p

Controlled membrane translocation provides a mechanism for signal transduction and amplification.

Transmission and amplification of chemical signals across lipid bilayer membranes is of profound significance in many biological processes, from the development of multicellular organisms to information processing in the nervous system. In biology, membrane-spanning proteins are responsible for the transmission of chemical signals across membranes, and signal transduction is often associated with an amplified signalling cascade. The ability to reproduce such processes in artificial systems has potential applications in sensing, controlled drug delivery and communication between compartments in tissue-like constructs of synthetic vesicles. Here we describe a mechanism for transmitting a chemical signal across a membrane based on the controlled translocation of a synthetic molecular transducer from one side of a lipid bilayer membrane to the other. The controlled molecular motion has been coupled to the activation of a catalyst on the inside of a vesicle, which leads to a signal-amplification process analogous to the biological counterpart.We thank the University of Cambridge Oppenheimer Fund for an Early Career Research Fellowship (M.J.L); the Wiener-Anspach Foundation (FWA) for postdoctoral fellowship (FK) ; and Franziska Kundel and David Klenerman for TIRFM imaging experiments

Utilisation des simulations informatiques et de la réalité virtuelle pour comprendre, concevoir et optimiser les canaux d'eau artificiels

International audienceIn biology, metabolite transport across cell membranes occurs through natural channels and pores. Artificial ion-channel architectures represent potential mimics of natural ionic conduction. Many such systems were produced leading to a remarkable set of alternative artificial ion-channels. Far less advances were achieved in the area of synthetic biomimetic water channels, even though they could improve our understanding of the natural function of protein channels and may provide new strategies to generate highly selective, advanced water purification systems. Most realizations have used the selectivity components of natural protein channels embedded in artificial systems. Such biomolecules provide building blocks to constitute highly selective membrane-spanning water transport architec-tures. The simplification of such compounds, while preserving the high conduction activity of natural macromolecules, lead to fully synthetic artificial biomimet-ic channels. These simplified systems offer a particular chance to understand mechanistic and structural behaviors, providing rationales to engineer better artificial water-channels. Here we focus on computer simulations as a tool to complement experiment in understanding the properties of such systems with the aim to rationalize important concepts, design and optimize better compounds. Molecular dynamics simulations combined with advanced visual scrutiny thereof are central to such an approach. Novel technologies such as virtual reality headsets and stere-oscopic large-scale display walls offer immersive collaborative insight into the complex mechanisms underlying artificial water channel function.En biologie, le transport des métabolites à travers les membranes cellulaires se fait par les canaux naturels et les pores. Les architectures artificielles à canaux ioniques représentent des imitations potentielles de la conduction ionique naturelle. Beaucoup de ces systèmes ont été produits, ce qui a conduit à un ensemble remarquable de canaux ioniques artificiels alternatifs. Beaucoup moins d'avancées ont été réalisées dans le domaine des canaux d'eau biomimétiques synthétiques, même si elles pourraient améliorer notre compréhension de la fonction naturelle des canaux protéiques et peuvent fournir de nouvelles stratégies pour générer des systèmes de purification d'eau avancés et hautement sélectifs. La plupart des réalisations ont utilisé les composants de sélectivité des canaux protéiques naturels intégrés dans des systèmes artificiels. Ces biomolécules fournissent des éléments constitutifs pour constituer des architec-tures de transport d'eau à membrane hautement sélective. La simplification de ces composés, tout en préservant l'activité de conduction élevée des macromolécules naturelles, conduit à des canaux biomimétiques artificiels entièrement synthétiques. Ces systèmes simplifiés offrent une chance particulière de comprendre les comportements mécanistiques et structurels, offrant des justifications pour concevoir de meilleurs canaux d'eau artificiels. Ici, nous nous concentrons sur les simulations informatiques en tant qu'outil pour compléter l'expérience dans la compréhension des propriétés de ces systèmes dans le but de rationaliser les concepts importants, de concevoir et d'optimiser de meilleurs composés. Les simulations de dynamique moléculaire combinées à un examen visuel avancé de celles-ci sont au cœur d'une telle approche. De nouvelles technologies telles que des casques de réalité virtuelle et des murs d'affichage à grande échelle stéréoscopiques offrent un aperçu collaboratif immersif des mécanismes complexes qui sous-tendent la fonction de canal d'eau artificiel