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Prostate Tumorigenesis Induced by PTEN Deletion Involves Estrogen Receptor beta Repression

eScholarship@UMMS - Mon, 05/18/2015 - 3:05pm

The role of ERbeta in prostate cancer is unclear, although loss of ERbeta is associated with aggressive disease. Given that mice deficient in ERbeta do not develop prostate cancer, we hypothesized that ERbeta loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERbeta is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERbeta is important for tumor formation. ERbeta transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERbeta expression is regulated in prostate cancer. Repression of ERbeta contributes to tumorigenesis because it enables HIF-1/VEGF signaling that sustains BMI-1 expression. These data reveal a positive feedback loop that is activated in response to PTEN loss and sustains BMI-1.

Autophagy in malignant transformation and cancer progression

eScholarship@UMMS - Mon, 05/18/2015 - 3:05pm

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

Aldehyde Dehydrogenase Is Regulated by beta-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells

eScholarship@UMMS - Mon, 05/18/2015 - 3:05pm

Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial-mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH(+) and ALDH(-) cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/beta-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of beta-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH(+) tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH(+) cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy. Cancer Res; 75(7); 1482-94. (c)2015 AACR.

Eaten alive: novel insights into autophagy from multicellular model systems

eScholarship@UMMS - Mon, 05/18/2015 - 3:05pm

Autophagy delivers cytoplasmic material to lysosomes for degradation. First identified in yeast, the core genes that control this process are conserved in higher organisms. Studies of mammalian cell cultures have expanded our understanding of the core autophagy pathway, but cannot reveal the unique animal-specific mechanisms for the regulation and function of autophagy. Multicellular organisms have different types of cells that possess distinct composition, morphology, and organization of intracellular organelles. In addition, the autophagic machinery integrates signals from other cells and environmental conditions to maintain cell, tissue and organism homeostasis. Here, we highlight how studies of autophagy in flies and worms have identified novel core autophagy genes and mechanisms, and provided insight into the context-specific regulation and function of autophagy.

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

eScholarship@UMMS - Mon, 05/18/2015 - 3:05pm

Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

Micro Pacer Leads Novel Technologies at HRS (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 3:00pm
(MedPage Today) -- Presenters discuss a self-contained miniaturized leadless pacemaker, a visually-guided laser balloon, and more.

Early Results Promising for Novel Schizophrenia Drug (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 2:30pm
(MedPage Today) -- Investigational medication safe, well tolerated, and showed efficacy in phase II trial.

UMCCTS Newsletter, May 2015

eScholarship@UMMS - Mon, 05/18/2015 - 2:21pm

This is the May 2015 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

European Commission unveils long-awaited science advice plans

news@nature - Mon, 05/18/2015 - 2:21pm

Team of expert researchers will bridge between politicians and wider science community.

Nature News doi: 10.1038/nature.2015.17557

Botulinum Toxin A Injections Tame Overactive Bladder (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 2:00pm
(MedPage Today) -- Injections controlled symptoms for up to 4 years

CardioBreak: Mitra Clip, Ambulatory BP Apathy

Headlines from MedPage Today® - Mon, 05/18/2015 - 1:30pm
(MedPage Today) -- Recent developments of interest in cardiovascular medicine.

Lau on Liraglutide: Is It Safe? AACE Video

Headlines from MedPage Today® - Mon, 05/18/2015 - 1:18pm
NASHVILLE (MedPage Today) -- Exclusive AACE Video Conference Reporter coverage, with Hallway Takes from David C.W. Lau, PhD, on Liraglutide Safety; Shashank R. Joshi, MD, on the Saragliptin Trial; and Carolina Solis-Herrera, MD, on the Dapagliflozin Trial.

Robotic Prostatectomy: Volume, Complications, Disincentives (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 1:00pm
(MedPage Today) -- Study links complications to falling volume, payment system

Follicular Priming May Boost Oocyte Retrieval (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 12:30pm
(MedPage Today) -- Low ovarian response is major cause of poor outcomes during assisted reproduction techniques.

Bloodletting Improves Vascular Health in Genetic Disorder

Headlines from MedPage Today® - Mon, 05/18/2015 - 12:00pm
(MedPage Today) -- Endothelial function better after standard treatment in hereditary hemochromatosis, small study says.

Rogue antimatter found in thunderclouds

news@nature - Mon, 05/18/2015 - 11:21am

Aeroplane detects signature spike in photons that does not fit any known source of antiparticles.

Nature 521 135 doi: 10.1038/521135a

Regulate gene editing in wild animals

news@nature - Mon, 05/18/2015 - 11:21am

The use of genome-modification tools in wild species must be properly governed to avoid irreversible damage to ecosystems, says Jeantine Lunshof.

Nature 521 127 doi: 10.1038/521127a

PBC Patients Face High Wait-List Mortality (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 11:00am
(MedPage Today) -- Consider allocation of exception MELD points to primary biliary cirrhosis patients on transplant list.

Paramedics Steer Non-Emergency Patients Away From ERs

Headlines from MedPage Today® - Mon, 05/18/2015 - 10:30am
(MedPage Today) -- One study showed a $5.5 million savings over 2 years for three projects in Nevada.

Morning Break: CDC Says Death Like Politics Is Local; Is the ACP the Conscience of Medicine?

Headlines from MedPage Today® - Mon, 05/18/2015 - 9:45am
(MedPage Today) -- Health news and commentary from around the Web, gathered by the MedPage Today staff.
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