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A fusion gene is a new gene made by joining parts of two different genes. The current thought is that fusion genes can happen in cells with unstable genome when part of the DNA from one chromosome moves to another chromosome. When the fusion gene is transcribed into RNA, the product is a fusion RNA that then is translated into a fusion protein. Fusion proteins may lead to cancer development. For instance, they are found in some types of cancer such as leukemia, prostate, breast, lung and others, and are being studied for the diagnosis and treatment of these diseases.

Model of prostate cancer. Courtesy of NCI/NIH Dr. Laising Yen

“According to this accepted notion, fusion genes precede fusion RNA, but some studies have raised doubts that this is always the case. In particular, cancer studies have reported the presence of fusion RNA in individuals in which the corresponding fusion gene cannot be detected,” said corresponding author Dr. Laising Yen, associate professor of pathology & immunology and of molecular and cellular biology at Baylor College of Medicine.

To explain these findings, about 10 years ago scientists proposed the ‘cart-before-the-horse-hypothesis,’ which puts forward the idea that fusion RNA can form first and then guide the rearrangement of genes to form the corresponding fusion gene. Although this process has been found in simpler organisms such as the paramecium, studies have yet to come forward showing that this proposed RNA-mediate gene rearrangements also happen in mammalian cells. Until now.

“The Yen lab works on RNA, and one of our interests is to study it in relation to cancer, ovarian and prostate cancer specifically,” said first author Dr. Sachin Kumar Gupta, postdoctoral associate in pathology at Baylor College of Medicine. “In this study, we investigated whether the cart could actually be before the horse. Can a fusion RNA induce the corresponding fusion gene?”

Dr. Gupta Sachin Kumar

The researchers worked with prostate cancer cell line LNCaP, which lacks the fusion gene TMPRSS2–ERG found in 50 percent of prostate cancers. To test ‘the cart before the horse’ hypothesis, Gupta and his colleagues expressed in LNCaP cells a short fusion RNA consisting of part gene TMPRSS2 and part gene ERG. If the short fusion RNA led to the formation of the fusion gene TMPRSS2–ERG, they expected to find evidence of the newly created fused gene both in the DNA genome and in the form of the full-length fusion RNA produced from that fusion gene.

Making ‘sense’ of the ‘cart before the horse’

“When we expressed the sense or coding short fusion RNA, we did not detect evidence that the fusion gene had been formed,” Gupta said. “We then thought, why not try the antisense fusion RNA instead?”

Antisense RNA is an RNA strand with a sequence that is complementary to the one of a sense or coding RNA. Coding RNA is the one that is involved in the translation of genetic instructions into protein. In theory, the authors explain, antisense RNAs should bind to the same genome segment sense RNA binds, just to a different DNA strand, and could mediate gene rearrangements leading to the formation of fusion genes.

“We found that if we overexpress the short fusion RNA in the antisense orientation, but not in the sense orientation, we can induce gene fusion in a tissue culture setting in three days,” Yen said. “We showed this for two different fusion genes.”

“We were very surprised. This is a non-coding RNA for which we have shown a new function: it can induce the formation of fusion genes. The antisense RNA, not the sense RNA, is the cart before the horse,” Gupta said.

Antisense fusion RNA interacts with two respective genes and leads to the formation of fusion gene in mammalian cells. The fused gene is visualized by fluorescence in situ hybridization. Courtesy of the Yen lab.

The researchers also showed that this RNA-induced gene fusion can occur in non-cancerous, normal cells. Expressing antisense fusion RNA in normal prostate epithelial cell lines resulted in the formation of the corresponding fusion gene in these cells.

“Our study suggests an early stage mechanism for the formation of cancer fusion genes that provides a new perspective in cancer development,” Yen said.

We have uncovered a second way by which gene recombination can happen. We propose that this process is mediated by RNA with sequences that are similar to, and antisense to, those of the joined genes.”

Cancer fusion genes are important for therapy and biomarker development. Fusion genes also have a lot to say regarding how a normal cell begins to transform into a cancer cell. Therefore, the authors explain, understanding the mechanisms of fusion gene formation could lead to the development of treatments to prevent cancer.

The researchers would next like to investigate whether RNA-mediated gene fusion also can happen in other types of cancer and explore the molecular mechanism for diagnosis and therapy.

Interested in learning all the details of this work? Read it in the Proceedings of the National Academy of Sciences.

Dr. Liming Luo at Baylor College of Medicine also contributed to this work.

Financial support was provided by the National Institutes of Health (grants R01EB013584, DK56338 and CA125123), the Cancer Prevention Research Institute of Texas (grants HIHRRA RP160795, RP150578 and RP160283), the Pilot Grant from Dan L Duncan Comprehensive Cancer Center and the Dunn Gulf Coast Consortium for Chemical Genomics.

By Ana María Rodríguez, Ph.D.

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The post Making ‘sense’ of the ‘cart before the horse’ in mammalian cells appeared first on Baylor College of Medicine Blog Network.

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The five winners of this year’s Michael E. DeBakey M.D. Award for Research Excellence exemplify the breadth and depth of scientific research at Baylor College of Medicine – from the development of the field of molecular endocrinology and the study of endocrine cancers, to research into the brain’s sensory maps as well as the circuits of feeding behavior in mice, to the study of congenital defects of natural killer cell immunity and the care of patients affected by it, to clinical and basic science research aimed at improving outcomes in patients with aortic aneurysms and other diseases of the aorta, to the research into norovirus and rotavirus, the leading causes of gastrointestinal illness. Congratulations to all the awardees!

From left: Dr. Benjamin Arenkiel; Dr. Bert O’Malley; Dr. Mary Estes; Dr. George Noon, professor of surgery and Meyer-DeBakey Chair in Investigative Surgery; Dr. Paul Klotman, president and CEO of Baylor College of Medicine; Dr. Jordan Orange; and Dr. Joseph Coselli.

Award recipients:

Dr. Benjamin Arenkiel

Dr. Benjamin Arenkiel, an associate professor of molecular and human genetics and neuroscience, has focused his research on improving our understanding of how the mammalian brain forms and maintains neural circuits. He recently described novel roles for neuropeptide signaling in synaptic remodeling within the adult mouse nervous system. In the area of circuit development, he discovered a new piece to the puzzle of how the brain organizes and processes information. The study, published in Nature Neuroscience, reports that although both depend on experience, excitatory and inhibitory neural maps mature in opposite ways. Excitatory neurons mature by sculpting and refining neural maps, while inhibitory neurons form maps that become broader with maturation. In addition, his contributions to the workings of the circuits of the mouse olfactory system have added to our understanding of how newly born neurons integrate into an existing network in the adult brain. His research, reported in Developmental Cell, shows that local corticotropin hormone signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation, and integration of new neurons in the adult brain. Recently, a serendipitous finding triggered his interest in the neural mechanisms that govern feeding behavior. His lab discovered that cholinergic signaling in the basal forebrain exerts a strong influence on body weight control. Published in Nature, this is the first time that this neural circuit has been reported to influence feeding behavior, sensory processing, and stress, opening new research opportunities in these high-interest fields.

Dr. Joseph Coselli

Dr. Joseph Coselli is professor of surgery and chief of cardiothoracic surgery. He has dedicated his career to optimizing the care of patients with aortic life-threatening thoracoabdominal aortic aneurisms, or TAAAs, focusing on reducing the risk of neurological and renal complications following TAAA repair. Through his study published in the Annals of Thoracic Surgery, he was able to demonstrate the value of using left heart bypass to reduce the problem of inadequate organ blood supply. In another study reported in the Journal of Vascular Surgery (2002), he showed that cerebrospinal fluid drainage reduces the risk of spinal cord injury. In a report appearing in the Journal of Vascular Surgery (2009), he addressed the problem of renal complications on a subsequent study demonstrating that providing cold crystalloid perfusion to the kidneys reduces the risk of renal problems. Dr. Coselli’s studies have made TAAA surgery safer. Patient outcomes have significantly improved and the practice of aortic surgery has changed. His multimodal approach to organ protection is now used in many major aortic centers around the world. In 2016, he published in the Journal of Thoracic and Cardiovascular Surgery the results of his 30 years of experience performing open TAAA repairs, presenting the largest series of patients treated for TAAAs ever reported.

Dr. Mary Estes

Dr. Mary Estes, a Distinguished Service Professor of Virology and Microbiology, has concentrated her research on norovirus and rotavirus, the leading causes of food-borne gastroenteritis in children worldwide. In 2016, her paper in Science reported the development of the first replication system for noroviruses, solving a nearly 50 year old mystery and allowing researchers around the world to study the biology, pathogenesis and treatments against this major illness. The novel culture system consist of human intestinal epithelium preparations called enteroids or ‘mini-guts’ because under the microscope they look like a miniature intestine. In this system, researchers can now study human host-pathogen interactions, gaining insight into how noroviruses cause disease and answering questions such as why one strain of norovirus infects one person, but not another. On a previous work, she was the first to clone the norovirus genome and led the development of a new diagnostic test based on the viral proteins and genome. She also demonstrated that host susceptibility to norovirus infection depends on blood group antigens. Her lab also has developed virus-like particles, which are currently being tested as norovirus candidate vaccine in phase II clinical trials. In addition to the work with noroviruses, her lab has used the mini-guts to study rotavirus. In a 2017 publication in the Proceedings of the National Academy of Sciences, she revealed for the first time that rotavirus can fight back the immune response by antagonizing the interferon response at pre-and post-transcriptional levels. In 2015, a paper in the Journal of Virology was the first to establish a new model to study genetic susceptibility to rotavirus vaccines. Dr. Estes’ work with norovirus and rotavirus provides new opportunities for advancing basic and applied studies in viral gastrointestinal diseases.

Dr. Bert O’Malley

Dr. Bert O’Malley, professor of molecular and cell biology, has focused his research on the molecular mechanisms that guide gene regulation in endocrinology and endocrine cancers. His work has improved our understanding of the molecular mechanisms by which hormones, receptors and coactivators contribute to the disease process. His pioneering work in this field has shown that intracellular hormones and cofactors act at the level of DNA to regulate the production of proteins and affect the function of the cell. Recent research reported in Molecular Cell was the first to solve the structure of a functional receptor-coactivator complex on DNA capable of regulating gene transcription in vitro. In addition, in a paper published in the Journal of Clinical Investigation, he showed that steroid receptor coactivator-2 (SRC-2), which is highly elevated in a variety of tumors, is likely implicated in metabolic coordination of cancer metastasis, opening the possibility of therapeutically targeting the SRC-2 pathway. His work with steroid receptor coactivator-3 (SRC-3), a prognostic marker for aggressive human breast cancer, showed that small-molecule inhibitors that directly bind SRC-3 cause selective degradation of the complex, hereby killing cancer cells with no observable toxicity. Small-molecule inhibitors represent a new type of oncologic drugs that target coactivators. This was published in the Proceedings of the National Academy of Sciences.

Dr. Jordan Orange

Dr. Jordan Orange, professor of pediatrics and rheumatology, has concentrated his research on the study of primary immunodeficiency, and on the cell biology and deficiencies of natural killer (NK) cell defenses, a major player in the rejection of tumors and viral infections. His work has improved our understanding of the genetic bases and mechanisms of immunodeficiencies, underscoring the importance of NK cells defenses. Recent work, reported in Nature Genetics, applied cell biology, genomic and microscopy techniques, and revealed an unexpected molecular link between a vesicular transport protein and a hereditary autoimmune-mediated lung disease and arthritis. In 2016, a paper in the Journal of Clinical Investigation was the culmination of a 12 year study to determine the cause of an NK deficiency that makes patients susceptible to severe viral infections. Their investigation pinpointed two rare variants of the gene IRF8; one of them had not been reported before. The individuals carrying two defective IRF8 variants have fewer mature NK cells than those with the normal gene, and these fewer cells do not work properly. On another study, Dr. Orange has moved forward our understanding of how NK cells kill their targets. He had previously described that NK cells concentrate their lytic granules on the area of contact with the diseased cell, but why this concentration occurred was not clear. His paper published in the Journal of Cell Biology this year showed that by converging their lytic granules, NK cells improved the killing efficiency of their targets while preventing collateral damage to neighboring healthy cells.

Ana María Rodríguez, Ph.D.

The post 2017 Michael E. DeBakey M.D. Award for Research Excellence appeared first on Baylor College of Medicine Blog Network.

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Genetic factors can explain, at last in part, the higher incidence of prostate cancer among African American men compared with men of other ethnic groups. A team of scientists has identified MNX1 as a new oncogene – a gene than can cause cancer – that is more active in African American prostate cancer than in European American prostate cancer. The study appeared in Cancer Research.

Michael Ittmann, M.D., Ph.D.

“African Americans have about one-and-a-half times the incidence and twice the mortality associated with prostate cancer of European Americans, and the reasons for this are not clear,” said senior author Dr. Michael Ittmann, professor of pathology & immunology at Baylor College of Medicine and the Michael E. DeBakey Department of Veterans Affairs Medical Center,

Most scientists think that some of the health disparities among ethnic groups can be explained by differences in biology. Socio-economic factors, such as unequal access to healthcare services that make African American men less likely to receive regular physical examinations and screening for prostate cancer, may also be involved.

To study the genetic differences between African American prostate cancer and European American prostate cancer, the scientists took advantage of the tremendously diverse resources available at the Dan L Duncan Comprehensive Cancer Center at Baylor, which include one of the most extensive African American prostate tissue banks.

Chad Creighton, Ph.D.

“We determined the gene expression profiling of African American prostate cancers,” said Ittmann, “and compared it with that of normal prostate tissue. Then, in collaboration with Dr. Chad Creighton, associate professor of medicine at Baylor and member of the Dan L Duncan Comprehensive Cancer Center Division of Biostatistics, we compared the gene expression profiling of African American prostate cancers with that of European American prostate cancers, which is available in published datasets.”

“We found 24 genes that were different between the African American and the European American prostate cancer datasets,” said Ittmann. “Some of the genes were less active in African American prostate cancer, but we concentrated on those that were more active as they could potentially be oncogenes. MNX1 was at the top of the list.”

MNX1 had been previously described as an oncogene linked to infantile acute myeloid leukemia, a rare cancer of the bone marrow and lymph nodes.

“Our study so far suggested that MNX1 was likely an oncogene in prostate cancer. The protein the MNX1 gene produces is a transcription factor; it can turn on gene transcription in other genes, which results in those genes producing more of their proteins. So we went on and studied MNX1 more extensively,” said Ittmann.

The scientists discovered that, compared with normal prostate tissues, both African American and European American prostate cancer have MNX1 genes that are more active and produce more of the MNX1 protein. However, MNX1 is significantly more active in African American prostate cancer than in European American prostate cancer.

Further research shed light on what can increase MNX1 activity in prostate cancer and strengthened MNX1’s ties to the disease.

Increased lipogenesis (formation of fatty acids, in red) in prostate cancer cells. Lipids act as important energy storage during the spread of cancer. Therapies that disrupt lipogenesis or inhibit oncoproteins that enhance fatty acid biosynthesis could potentially block tumor metastasis. Nucleus of the cell is stained blue. National Cancer Institute / Duncan Comprehensive Cancer Center at Baylor College of Medicine / Subhamoy Dasgupta.

“Interestingly, we found that both androgens, such as testosterone, and AKT, a signaling pathway, increase MNX1 activity. It’s been known for quite some time that androgens and the AKT pathway play a central role in prostate cancer,” said Ittmann.

Arun Sreekumar, Ph.D.

The scientists then determined whether increased MNX1 activity affected a metabolic pathway prostate cancer uses to grow. Dr. Arun Sreekumar, professor of molecular and cellular biology, who also is with the Alkek Center for Molecular Discovery and the Verna and Marrs McLean department of biochemistry and molecular biology at Baylor, performed lipid analysis in African American prostate cancer tissues and showed that products of lipid metabolism increased when compared with those of normal prostate tissues.

“I am excited that these data highlight the existence of a biological basis in health disparity in prostate cancer,” said Sreekumar.

In summary, in African American prostate cancer androgen and the AKT signaling pathway can increase the activity of MNX1, which in turn increases lipid metabolism. Increased lipid metabolism is a hallmark of aggressive prostate cancer, which is more common on African American men.

These results can potentially lead to new approaches to treat and diagnose prostate cancer. For instance, currently, there are medications available to control lipid synthesis, which allows for exploring the effect of targeting lipid synthesis on prostate cancer growth. The scientists will also explore whether MNX1 can help predict cases of aggressive prostate cancer in the clinic.

“The better we can understand different subsets of prostate cancer, for instance, prostate cancer from African American men, the better we can treat them. A “one-size-fits-all” approach to treatment may not work for all patients,” said Creighton.

###

Other contributors to this work include Li Zhang, Jianghua Wang, Yongquan Wang, Yiqun Zhang, Patricia Castro, Longjiang Shao, Nagireddy Putluri, Nilanjan Guha, Saligrama Deepak and Arunkumar Padmanaban. The previous authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Third Military Medical University in China, the Michael E. DeBakey Department of Veterans Affairs Medical Center, the Dan L Duncan Comprehensive Cancer Center and Agilent Technologies India Pvt. Ltd.

This work was supported by grants from the Department of Defense W81XWH-12-1-0046  and W81XWH-12-546 1-0130; the National Cancer Institute U01 CA167234 and the Dan L Duncan Comprehensive Cancer Center (P30 CA125123) supporting Human Tissue Acquisition and Pathology and Genomic and RNA Profiling Shared Resources; CPRIT Core Facility Support Award RP120092; funds from the Alkek Center for Molecular Discovery, the Prostate Cancer Foundation and by the use of the facilities of the Michael E. DeBakey VAMC.

Learn more about prostate cancer.

Ana María Rodríguez, Ph.D.

The post New oncogene MNX1 contributes to higher incidence of prostate cancer among African American men appeared first on Baylor College of Medicine Blog Network.

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During the month of September, Baylor College of Medicine will be partnering with the Blue Cure Foundation for its annual prostate cancer awareness campaign, Light It Blue. The Blue Cure Foundation is a non-profit organization dedicated to providing information on integrative approaches to prostate cancer prevention and treatment. During the campaign, the foundation works with local organizations to light up their buildings in blue lights in support of prostate cancer.

Baylor joins the Blue Cure Foundation for its Light It Blue campaign.

To help spread awareness and education, Dr. Jennifer Taylor, assistant professor of urology at Baylor, shares prostate cancer risk factors, symptoms and prevention guidelines.

Q: How important is it for an institution like Baylor to help generate awareness for prostate cancer?
A: Prostate cancer touches lives every day, and it’s likely that everyone knows somebody who has survived or is suffering from it. It’s so highly prevalent, but there is a very wide spectrum of disease, so it’s important to spread accurate and informative facts about it.

Most cases of prostate cancer have very good survival rates, so many men have been treated for it and may endure long-term side effects of their treatment. Awareness can bring an understanding to those patients’ friends and family members.
Prostate cancer is very treatable when it’s in early stages, and can have significant symptoms in its late stages, so awareness about it and interest in being checked for it is critical.

Q: What are some risk factors associated with prostate cancer?
A: Family history is one of the strongest risk factors, so having a 1st degree relative, such as a brother or father with the disease, significantly increases a man’s chances of being diagnosed. Additionally, the African-American race is associated with diagnosis at an earlier age, and with a more aggressive form of the disease.

Prostate cancer is more common in Western-style diets than in diets with less fat and red meat, and there is evidence that cigarette smoking can lead to a greater risk for the disease. Veterans who served in Vietnam and were exposed to Agent Orange may also have a higher risk of prostate cancer.

Q: Are there any symptoms or signs to look out for?
A: Prostate cancer does not typically cause symptoms until it’s more advanced or has spread. Many common symptoms that people attribute to a man’s prostate are due to a non-cancerous enlargement of the gland, and not from cancer growth.

An elevated PSA, or prostate specific antigen, which is checked with a blood test, may be an indicator of prostate cancer, but there are other things that can elevate the blood test when it’s in single or double digits.

Fortunately, most men with prostate cancer have no symptoms, and it can be very slow growing, so much so that a number of men will not have a definitive treatment when their prostate cancer is first found. Instead, these men, who have what is termed “low-risk cancer,” can have their cancer carefully monitored without treatment.

Q: Can you perform a self-exam for prostate cancer at home?
A: There is no self-exam for prostate cancer, but over 90 percent of prostate cancers grow in the part of the prostate that can be felt by a simple exam, so checking for prostate cancer is still a necessary part of routine checkups with a doctor.

Q: How can we help prevent prostate cancer?
A :There have been studies looking at supplements or vitamins to prevent prostate cancer, but none have been shown to be effective thus far. Regular exercise, stress management, and following a more lean and low-fat diet are all associated with lower risk of developing prostate cancer. Those principles also apply to better outcomes and survival if a man is diagnosed with prostate cancer. It’s never too late to adopt healthy lifestyle habits, even after cancer is diagnosed.

All men are encouraged to ask their primary care doctor about screening for prostate cancer. The American Urological Association and American Society of Clinical Oncology both recommend continued screening in men whose life expectancy is at least 10 years. Screening should occur generally between the ages of 55 – 70, and start earlier if a man is African-American or has a family history of prostate cancer. Further testing to diagnose prostate cancer and treatment of prostate cancer must occur after an informed discussion and shared decision-making between a man and his doctors.

Additional Resources

To support Blue Cure’s mission, sign up for the Night Run 5K, which raises funds and awareness for cancer prevention and youth programs.

Learn more about the Light It Blue campaign.

Visit the Blue Cure Foundation website.

-By Allison Huseman

The post Prostate cancer awareness: What you need to know appeared first on Baylor College of Medicine Blog Network.

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Advanced prostate cancer is usually treated by removing androgen, the male hormone that helps it grow. Although initially effective, this treatment often leads to the tumor becoming castration resistant — it is able to grow without androgen, a lethal condition.

Histological slide (H & E stain at x300) showing prostate cancer. On the right is moderately differentiated cancer. On the left is less normal tissue. (National Cancer Institute)

Researchers from Baylor College of Medicine and University of Michigan, along with collaborators in other institutions, have determined that castration-resistant prostate cancer (CRPC) has particular metabolic characteristics that may open new possibilities for treatment. The results appear in Nature Communications.

Arun Sreekumar, Ph.D.

“Using an innovative approach to integrate gene expression and metabolomics data, we identified key metabolic pathways that are altered in prostate cancer,” said corresponding author Dr. Arun Sreekumar, professor of Molecular and Cellular Biology, the Alkek Center for Molecular Discovery and the Verna and Marrs McLean department of Biochemistry and Molecular Biology at Baylor. “Of these metabolic pathways, the hexosamine biosynthetic pathway (HBP) showed significant alterations.”

The researchers discovered that HBP is much less active in castration-resistant than in androgen-dependent prostate cancers. Furthermore, having reduced HBP activity is likely to enhance tumor growth.

“When we experimentally knocked down genes involved in HBP in cells similar to CRPC tumor cells, the cells responded with a marked increase in proliferation, both in cell culture and animal experiments,” said Sreekumar. “When the cells with reduced HBP received UDP-N-acetylglucosamine, a product of this metabolic pathway they lacked, the cells slowed down their growth.”

When the researchers added UDP-N-acetylglucosamine and a clinically used anti-androgen (i.e., enzalutamide) to the CRPC cells growing in the laboratory, the cells reduced their proliferation further.

“This result is particularly noteworthy because our cells were essentially resistant to enzalutamide alone,” said Sreekumar.

The results indicate that studying the metabolic characteristics of tumors resistant to therapy offers the possibility of discovering new targets to treat cancer. In this case, the results identify HBP as a potential therapeutic target for castration-resistant prostate cancer, a disease that accounts for close to 30,000 deaths annually in the United States.

###

Other researchers who participated in this work include Akash K. Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas T. Vasu, Yiqing Zhang, Ayesha S. Khan, Stacy Lloyd, Adam T. Szafran, Subhamoy Dasgupta, David A. Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini Tsouko, Shixia Huang, Daniel E. Frigo, Lawrence Chan, Dean P Edwards, Benny A. Kaipparettu, Nicholas Mitsiades, Nancy L. Weigel, Michael Mancini, Sean E. McGuire, Rohit Mehra, Michael M. Ittmann, Arul M. Chinnaiyan, Nagireddy Putluri, Ganesh S. Palapattu and George Michailidis, from Baylor College of Medicine, University of Washington, University of Michigan, Maharaja Sayajirao University of Baroda, University Houston, Houston Methodist Research Institute, Howard Hughes Medical Institute, and the Dan L Duncan Comprehensive Cancer Center. Drs. Sreekumar, Palapattu and Michailidis are co-corresponding authors of this study.

This project was supported by the Diana Helis Henry Medical Research Foundation, the National Institutes of Health (grants 1RO1CA133458-01, U01 CA167234, RCA145444A, P30CA125123, R01 CA184208, R21CA173150 and R21CA179720), Department of Defense (W81XWH-12-1-0130), National Science Foundation (Q5 DMS-1161759, DMS-12-28164, DMS-11617838, RP150451), American Cancer Society (27430-RSG-15-105-01-CNE), CPRIT, as well as funds from the Alkek Center for Molecular Discovery. This project was also supported by the Agilent Technologies Center of Excellence in Mass Spectrometry at Baylor College of Medicine, Integrated Microscopy Core and shared Proteomics and Metabolomics core at Baylor College of Medicine with funding from the NIH (HD007495, DK56338 and CA125123), CPRIT (RP120092), the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

Ana María Rodríguez, Ph.D.

The post Altered metabolism in castration-resistant prostate cancer may point to new therapies appeared first on Baylor College of Medicine Blog Network.

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Nearly 200 thousand men are diagnosed with prostate cancer every year. Most of the deaths associated with prostate cancer occur in advanced stages of the disease, which are the result of metastasis – the spreading of the tumor away from its origin.

This image shows hematoxylin and eosin staining of metastatic lesions in liver and lung. (Courtesy of L. Xin and Oh-Joon Kwon.)

Notch signaling pathway is involved in prostate cancer and, in a paper published June 2016 in The Journal of Clinical Investigation, researchers at Baylor College of Medicine and other institutions showed that, in a mouse model of the disease, Notch alterations promote metastasis.

In normal tissues of many species, Notch signaling pathway is crucial for tissue development and homeostasis, helping to maintain a balance of the body’s normal functions. Scientists studying the Notch pathway have reached a consensus that Notch signaling is altered during prostate carcinogenesis, but its role in prostate cancer remains inadequately defined.

Li Xin, Ph.D.

“Most previous studies on the role that Notch plays in prostate cancer were performed in cultured cells in the laboratory. These studies produced contradictory results. Some studies concluded that Notch was an oncogene, that it promoted cancer development, and others that it was a tumor suppressor gene,” said Dr. Li Xin, associate professor of molecular and cellular biology at Baylor. “To gain a better understanding of Notch in prostate cancer we decided to study its role in an animal model in a defined genetic context.”

Xin and colleagues developed the mouse animal model according to previous analysis of human prostate cancer specimens that had revealed that Pten is a tumor suppressor gene whose loss-of-function correlates with prostate cancer progression. In addition, “we found an inverse correlation between the level of expression of Pten and the level of Notch activity,” said Xin. To reproduce the observations in human tissues, the researchers used a mouse model of prostate cancer with prostate specific loss-of-function of Pten to determine the role of Notch signaling in prostate cancer progression.

In this mouse model, the scientists discovered that activation of Notch signaling can drive tumor metastasis to major internal organs such as lung and liver. To determine how Notch drives metastasis, the scientists carried out further molecular studies.

“Our major conclusion is that Notch is able to increase the production of another molecule called FoxC2, which is very important for the metastatic potential of cells. If we suppress FoxC2, we can attenuate Notch-mediated metastatic activity,” said Xin.

This mouse study showed directly in vivo that increased Notch activity can drive prostate cancer metastasis,” said Xin. “Future studies will aim to address whether Notch inhibition can suppress tumor metastasis. These studies will serve as solid rationale for treating human prostate cancer with Notch inhibitors.”

Other contributors of this work include Oh-Joon Kwon, Li Zhang, Jianghua Wang, Qingtai Su, Qin Feng, Xiang H.F. Zhang, Sendurai A. Mani, Robia Paulter, Chad J. Creighton and Michael M. Ittmann of Baylor College of Medicine and The University of Texas MD Anderson Cancer Center, Houston.

This project was supported by the National Institutes of Health (grants P30-AI036211, P30-CA125123, S10-RR024574, NIH R01-CA190378, R21-CA196570, U01-CA141497 and P30-CA125123) and the Cancer Center Shared Resources Grant.

By Ana María Rodríguez, Ph.D.

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September officially kicks off National Prostate Cancer Awareness Month, and in a show of support for increased awareness, education, research and clinical advances, the Baylor College of Medicine main Cullen Building will “light up blue.”

Baylor is home to the Dan L. Duncan Cancer Center, an NCI-Designated Comprehensive Cancer Center.

The Duncan Cancer Center was one of the first organizations to commit to the #lightitblue campaign initiated by the Blue Cure Foundation, a local non-profit organization focused on providing information on integrative approaches to prostate cancer prevention and treatment. The Foundation is calling upon organizations across the country to light up blue in honor of the month.

Follow us on social media as we share information on prostate cancer screening and new procedures throughout the month.

-By Glenna Vickers

The post Baylor College of Medicine lights up blue in honor of Prostate Cancer Awareness Month appeared first on Baylor College of Medicine Blog Network.

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