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from The American Association for Cancer Research aacr.org:

 

AACR Congratulates Dr. William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza on 2019 Nobel Prize in Physiology or Medicine

10/7/2019

PHILADELPHIA — The American Association for Cancer Research (AACR) congratulates Fellow of the AACR Academy William G. Kaelin Jr., MDSir Peter J. Ratcliffe, MD, FRS, and AACR member Gregg L. Semenza, MD, PhD, on receiving the 2019 Nobel Prize in Physiology or Medicine for their discoveries of how cells sense and adapt to oxygen availability.

Kaelin, professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School in Boston; Ratcliffe, director of Clinical Research at the Francis Crick Institute in London; and Semenza, director of the Vascular Program at the Institute for Cell Engineering at Johns Hopkins University School of Medicine in Baltimore, are being recognized by the Nobel Assembly at the Karolinska Institute for identifying the molecular machinery that regulates the activity of genes in response to varying levels of oxygen, which is one of life’s most essential adaptive processes. Their work has provided basic understanding of several diseases, including many types of cancer, and has laid the foundation for the development of promising new approaches to treating cancer and other diseases.

Kaelin, Ratcliffe, and Semenza were previously recognized for this work with the 2016 Lasker-DeBakey Clinical Medical Research Award.

Kaelin’s research focuses on understanding how mutations affecting tumor-suppressor genes cause cancer. As part of this work, he discovered that a tumor-suppressor gene called von Hippel–Lindau (VHL) is involved in controlling the cellular response to low levels of oxygen. Kaelin’s studies showed that the VHL protein binds to hypoxia-inducible factor (HIF) when oxygen is present and targets it for destruction. When the VHL protein is mutated, it is unable to bind to HIF, resulting in inappropriate HIF accumulation and the transcription of genes that promote blood vessel formation, such as vascular endothelial growth factor (VEGF). VEGF is directly linked to the development of renal cell carcinoma and therapeutics that target VEGF are used in the clinic to treat this and several other types of cancer.

Kaelin has been previously recognized with numerous other awards and honors, including the 2006 AACR-Richard and Hinda Rosenthal Award.

Ratcliffe independently discovered that the VHL protein binds to HIF. Since then, his research has focused on the molecular interactions underpinning the binding of VHL to HIF and the molecular events that occur in low levels of oxygen, a condition known as hypoxia. Prior to his work on VHL, Ratcliffe’s research contributed to elucidating the mechanisms by which hypoxia increases levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells.

Semenza’s research, which was independent of Ratcliffe’s, identified in exquisite detail the molecular events by which the EPO gene is regulated by varying levels of oxygen. He discovered HIF and identified this protein complex as the oxygen-dependent regulator of the EPO gene. Semenza followed up this work by identifying additional genes activated by HIF, including showing that the protein complex activates the VEGF gene that is pivotal to the development of renal cell carcinoma.

The recognition of Kaelin and Semenza increases the number of AACR members to have been awarded a Nobel Prize to 70, 44 of whom are still living.

The Nobel Prize in Physiology or Medicine is awarded by the Nobel Assembly at the Karolinska Institute for discoveries of major importance in life science or medicine that have changed the scientific paradigm and are of great benefit for mankind. Each laureate receives a gold medal, a diploma, and a sum of money that is decided by the Nobel Foundation.

The Nobel Prize Award Ceremony will be Dec. 10, 2019, in Stockholm.

Please find following articles on the Nobel Prize and Hypoxia in Cancer on this Open Access Journal:

2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

The History, Uses, and Future of the Nobel Prize, 1:00pm – 6:00pm, Thursday, October 4, 2018, Harvard Medical School

2017 Nobel prize in chemistry given to Jacques Dubochet, Joachim Frank, and Richard Henderson  for developing cryo-electron microscopy

Tumor Ammonia Recycling: How Cancer Cells Use Glutamate Dehydrogenase to Recycle Tumor Microenvironment Waste Products for Biosynthesis

Hypoxia Inducible Factor 1 (HIF-1)[7.9]

 

 

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3 Dimensional Ex vivo Technique for In situ Tumor Growth

Reporter: Stephen J. Williams, Ph.D.

3D Brain Culture, Ex vivo Brain, Vascular Glioma Chemotherapy

Brain tumors are both difficult to treat and hard to study because of the organ they affect. The structure of the brain is extremely sensitive to alterations. Until recently the study of architectural alterations and their effects was mostly restricted to in vivo experiments. Typical culturing of brain tissue requires disaggregation and manipulation into a 2-dimensional format, losing any anatomically relevant structure. To study the in situbrain structure, a new technique has been described by researchers from the University of Erlangen-Nürnberg. By carefully sectioning the brains of 4 day-old mice and placing them on a 0.4 uM pore-size transwell membrane 6 well plate insert within required culture medium, they were able to study the endogenous structure under varying conditions. They injected astrocytes or glioma cells with a micropipette into the slices, and investigated the structural changes brain tumors effect in their environment. Termed the Vascular Organotypic Glioma Impact Model (VOGIM), it revealed all the characteristic pathological alterations normally associated with the disease in vivo such as tumor size and borders, vessel length, vessel junctions, and vessel branches, microglia, cell survival, and neuronal modifications. As this method allows for live cell fluorescent observation, they employed the technique to observe cultures treated with the chemotherapeutic Temozolamide (TMZ, Temodal/Temcad®). Indeed they found reduced tumor growth in treatment groups vs controls, but also revealed surprising reduction in microglial cells in the peritumoral region. Additionally, they were able to observe the lack of response TMZ elicited from microglial in healthy regions of the tissue, despite its overall reduction in vascularization towards normal levels. The VOGIM technique allows for ex vivo study of brain tissue requiring three dimensional measurements, but may also be extended to other tissues with unique morphology such as kidney, liver, and intestine.

antibody news book Ghoochani, et al. (December, 2015) A versatile ex vivo technique for assaying tumor angiogenesis and microglia in the brainONCOTARGET

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