Hamon Center for Therapeutic Oncology Research

Dallas, TX, United States

Hamon Center for Therapeutic Oncology Research

Dallas, TX, United States

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News Article | May 24, 2017
Site: www.biosciencetechnology.com

Patients with non-small cell lung cancer (NSCLC) often respond to standard chemotherapy, only to develop drug resistance later, and with fatal consequences. But what if doctors could identify those at greatest risk of relapse and provide a therapy to overcome or avoid it? Researchers at UT Southwestern Medical Center believe they have an answer: a 35-gene signature that identifies tumor cells most likely to develop resistance to treatment. The study, published today in Cell Reports, points to a new pharmacologic approach to target chemo-resistant lung cancer and even prevent development of such resistance in the first place. "Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure," said study co-author Dr. John Minna, a Professor and Director of in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. "These findings provide new insights into why resistance develops and how to overcome it." Dr. Minna, with additional appointments in Pharmacology and Internal Medicine, also holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. Investigators studied mouse and cellular models of NSCLC, a type of lung cancer that the American Cancer Society estimates accounts for 85 percent of all lung cancer cases in the United States. "Previous studies have shown that up to 70 percent of those cancers develop resistance to standard therapy, such as the platinum-taxane two-drug combo that is often given," said study senior author Dr. Elisabeth D. Martinez, Assistant Professor of Pharmacology and in the Hamon Center. Both she and Dr. Minna are also members of UTSW's Harold C. Simmons Comprehensive Cancer Center. Using long-term on/off drug cycles, lead author and former postdoctoral researcher Dr. Maithili Dalvi developed a series of cellular models of progressive tumor resistance to standard chemotherapy that ranged from very sensitive to highly insensitive. Next, the researchers identified genes commonly altered during the development of resistance across multiple cell line and mouse models and identified a 35-gene signature that indicated a higher genetic likelihood of chemotherapy resistance. "It's like a fingerprint for resistance," Dr. Martinez said, adding that it was predictive in both cells and mouse models. Next they compared this resistance biomarker using genetic profiles from human tumors in their National Cancer Institute (NCI) lung cancer Specialized Programs of Research Excellence (SPORE) database at UT MD Anderson Cancer Center in Houston. The database contained information on patient outcomes and those who had been treated with the two-drug chemotherapy. The genetic fingerprint for resistance correlated with cancer relapse in NSCLC patients in the database, she said. Researchers discovered that as cancer cells developed greater resistance to chemotherapy, they progressively made higher amounts of enzymes called JumonjiC lysine demethylases. Dr. Martinez said these enzymes facilitate resistance by changing the expression of - or turning on and off - genes. "Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy. By changing the expression of genes, the tumor cells can adapt and survive the toxins," she said. Investigators then tested two potential drugs, both JumonjiC inhibitors. One of them, JIB-04, was found by UT Southwestern researchers in the Martinez lab during a small-molecule screen conducted at the National Center for Advancing Translational Sciences' Chemical Genomics Center in Bethesda, Maryland. "I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress. In addition, and this is the most fascinating part: Dr. Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitors," she said. "The cancer cells develop a new Achilles' heel that we can hit." Because the chemo-resistant cancer cells are dependent on JumonjiC enzymes for survival, inhibiting those enzymes returns cancer cells to mortality and vulnerability to cell death, she explained. "We think these JumonjiC inhibitors have the potential to be used either to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether," she said. "In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells." Later, researchers tested whether the Jumonji inhibitors JIB-04 or GSK-J4 prevented chemotherapy resistance. This strategy succeeded in cell cultures and partially prevented resistance in animal models, Dr. Martinez said.


News Article | May 25, 2017
Site: www.sciencedaily.com

Patients with non-small cell lung cancer (NSCLC) often respond to standard chemotherapy, only to develop drug resistance later, and with fatal consequences. But what if doctors could identify those at greatest risk of relapse and provide a therapy to overcome or avoid it? Researchers at UT Southwestern Medical Center believe they have an answer: a 35-gene signature that identifies tumor cells most likely to develop resistance to treatment. The study, published in Cell Reports, points to a new pharmacologic approach to target chemo-resistant lung cancer and even prevent development of such resistance in the first place. "Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure," said study co-author Dr. John Minna, a Professor and Director of in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. "These findings provide new insights into why resistance develops and how to overcome it." Dr. Minna, with additional appointments in Pharmacology and Internal Medicine, also holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. Investigators studied mouse and cellular models of NSCLC, a type of lung cancer that the American Cancer Society estimates accounts for 85 percent of all lung cancer cases in the United States. "Previous studies have shown that up to 70 percent of those cancers develop resistance to standard therapy, such as the platinum-taxane two-drug combo that is often given," said study senior author Dr. Elisabeth D. Martinez, Assistant Professor of Pharmacology and in the Hamon Center. Both she and Dr. Minna are also members of UTSW's Harold C. Simmons Comprehensive Cancer Center. Using long-term on/off drug cycles, lead author and former postdoctoral researcher Dr. Maithili Dalvi developed a series of cellular models of progressive tumor resistance to standard chemotherapy that ranged from very sensitive to highly insensitive. Next, the researchers identified genes commonly altered during the development of resistance across multiple cell line and mouse models and identified a 35-gene signature that indicated a higher genetic likelihood of chemotherapy resistance. "It's like a fingerprint for resistance," Dr. Martinez said, adding that it was predictive in both cells and mouse models. Next they compared this resistance biomarker using genetic profiles from human tumors in their National Cancer Institute (NCI) lung cancer Specialized Programs of Research Excellence (SPORE) database at UT MD Anderson Cancer Center in Houston. The database contained information on patient outcomes and those who had been treated with the two-drug chemotherapy. The genetic fingerprint for resistance correlated with cancer relapse in NSCLC patients in the database, she said. Researchers discovered that as cancer cells developed greater resistance to chemotherapy, they progressively made higher amounts of enzymes called JumonjiC lysine demethylases. Dr. Martinez said these enzymes facilitate resistance by changing the expression of -- or turning on and off -- genes. "Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy. By changing the expression of genes, the tumor cells can adapt and survive the toxins," she said. Investigators then tested two potential drugs, both JumonjiC inhibitors. One of them, JIB-04, was found by UT Southwestern researchers in the Martinez lab during a small-molecule screen conducted at the National Center for Advancing Translational Sciences' Chemical Genomics Center in Bethesda, Maryland. "I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress. In addition, and this is the most fascinating part: Dr. Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitors," she said. "The cancer cells develop a new Achilles' heel that we can hit." Because the chemo-resistant cancer cells are dependent on JumonjiC enzymes for survival, inhibiting those enzymes returns cancer cells to mortality and vulnerability to cell death, she explained. "We think these JumonjiC inhibitors have the potential to be used either to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether," she said. "In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells." Later, researchers tested whether the Jumonji inhibitors JIB-04 or GSK-J4 prevented chemotherapy resistance. This strategy succeeded in cell cultures and partially prevented resistance in animal models, Dr. Martinez said.


News Article | May 23, 2017
Site: www.eurekalert.org

DALLAS - May 23, 2017 - Patients with non-small cell lung cancer (NSCLC) often respond to standard chemotherapy, only to develop drug resistance later, and with fatal consequences. But what if doctors could identify those at greatest risk of relapse and provide a therapy to overcome or avoid it? Researchers at UT Southwestern Medical Center believe they have an answer: a 35-gene signature that identifies tumor cells most likely to develop resistance to treatment. The study, published today in Cell Reports, points to a new pharmacologic approach to target chemo-resistant lung cancer and even prevent development of such resistance in the first place. "Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure," said study co-author Dr. John Minna, a Professor and Director of in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. "These findings provide new insights into why resistance develops and how to overcome it." Dr. Minna, with additional appointments in Pharmacology and Internal Medicine, also holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. Investigators studied mouse and cellular models of NSCLC, a type of lung cancer that the American Cancer Society estimates accounts for 85 percent of all lung cancer cases in the United States. "Previous studies have shown that up to 70 percent of those cancers develop resistance to standard therapy, such as the platinum-taxane two-drug combo that is often given," said study senior author Dr. Elisabeth D. Martinez, Assistant Professor of Pharmacology and in the Hamon Center. Both she and Dr. Minna are also members of UTSW's Harold C. Simmons Comprehensive Cancer Center. Using long-term on/off drug cycles, lead author and former postdoctoral researcher Dr. Maithili Dalvi developed a series of cellular models of progressive tumor resistance to standard chemotherapy that ranged from very sensitive to highly insensitive. Next, the researchers identified genes commonly altered during the development of resistance across multiple cell line and mouse models and identified a 35-gene signature that indicated a higher genetic likelihood of chemotherapy resistance. "It's like a fingerprint for resistance," Dr. Martinez said, adding that it was predictive in both cells and mouse models. Next they compared this resistance biomarker using genetic profiles from human tumors in their National Cancer Institute (NCI) lung cancer Specialized Programs of Research Excellence (SPORE) database at UT MD Anderson Cancer Center in Houston. The database contained information on patient outcomes and those who had been treated with the two-drug chemotherapy. The genetic fingerprint for resistance correlated with cancer relapse in NSCLC patients in the database, she said. Researchers discovered that as cancer cells developed greater resistance to chemotherapy, they progressively made higher amounts of enzymes called JumonjiC lysine demethylases. Dr. Martinez said these enzymes facilitate resistance by changing the expression of - or turning on and off - genes. "Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy. By changing the expression of genes, the tumor cells can adapt and survive the toxins," she said. Investigators then tested two potential drugs, both JumonjiC inhibitors. One of them, JIB-04, was found by UT Southwestern researchers in the Martinez lab during a small-molecule screen conducted at the National Center for Advancing Translational Sciences' Chemical Genomics Center in Bethesda, Maryland. "I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress. In addition, and this is the most fascinating part: Dr. Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitors," she said. "The cancer cells develop a new Achilles' heel that we can hit." Because the chemo-resistant cancer cells are dependent on JumonjiC enzymes for survival, inhibiting those enzymes returns cancer cells to mortality and vulnerability to cell death, she explained. "We think these JumonjiC inhibitors have the potential to be used either to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether," she said. "In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells." Later, researchers tested whether the Jumonji inhibitors JIB-04 or GSK-J4 prevented chemotherapy resistance. This strategy succeeded in cell cultures and partially prevented resistance in animal models, Dr. Martinez said. Other UT Southwestern researchers involved in this work were Dr. Luc Girard, Assistant Professor, Dr. Lei Wang, senior research associate, and Dr. Juan Bayo, postdoctoral researcher, all with the Hamon Center and of Pharmacology; Dr. Rahul Kollipara, a computational biologist in the Eugene McDermott Center for Human Growth and Development; Hyunsil Park, a research associate, and Dr. Brenda Timmons, a research scientist, both of the Hamon Center; Paul Yenerall, graduate student; Dr. Yang Xie, Associate Professor of Clinical Sciences and of Bioinformatics; Dr. Adi F. Gazdar, Professor in the Hamon Center, the Simmons Comprehensive Cancer Center, and Pathology and holder of the W. Ray Wallace Distinguished Chair in Molecular Oncology Research; and Dr. Ralf Kittler, Assistant Professor in the McDermott Center, Pharmacology, and the Simmons Comprehensive Cancer Center as well as a CPRIT Scholar and a John L. Roach Scholar in Biomedical Research. Researchers at MD Anderson Cancer Center, the Perelman School of Medicine at the University of Pennsylvania, and The Ohio State University College of Medicine also contributed. The study received support from the NCI, the Department of Defense, the Cancer Prevention and Research Institute of Texas (CPRIT), the Friends of the Cancer Center, The Welch Foundation, and an LLS Robert Arceci Scholar Award. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. . To automatically receive news releases from UT Southwestern via email, subscribe at http://www.


News Article | September 15, 2016
Site: www.cemag.us

Researchers with the Harold C. Simmons Comprehensive Cancer Center successfully developed a synthetic polymer that can transport a drug into lung cancer cells without going inside of normal lung cells. Since conventional chemo drugs indiscriminately kill all rapidly dividing cells to halt the growth of cancer, these selective nanoparticles could decrease side effects by reducing drug accumulation in normal cells. “The discovery that nanoparticles can be selective to certain cells based only on their physical and chemical properties has profound implications for nanoparticle-based therapies because cell type specificity of drug carriers could alter patient outcomes in the clinic,” says corresponding author Dr. Daniel Siegwart, Assistant Professor of Biochemistry at UT Southwestern Medical Center and with Simmons Cancer Center. “At the same time, a deeper understanding of nanoparticle interactions in the body opens the door to predict patient responses to existing liposome and nanoparticle therapies, and offers the potential to create future drug carriers customized according to individual genetic profiles.” The findings appear in the Proceedings of the National Academy of Sciences. The scientists tested hundreds of polymers to make the surprising discovery that cells could respond differently to the same drug carrier, even when those cancerous and normal cells came from the lungs of the same patient. “These functional polyester nanoparticles provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies,” says co-author Dr. John Minna, Professor and Director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, and Director of the W.A. “Tex” and Deborah Moncrief Jr. Center for Cancer Genetics at UT Southwestern. The researchers developed new chemical reactions to create a diverse library of polymers that could deliver nucleic acid drugs while possessing enough structural diversity to discover cancer cell-specific nanoparticles. This is an important step to improving tailored cancer therapies to an individual’s specific genetic makeup. “The ability to specifically target cancer cells using nanoparticles could alter how we administer drugs to patients,” says Minna, Professor of Pharmacology and Internal Medicine, and with Simmons Cancer Center, who holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research, and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. “It is already possible to use genetic sequencing to customize drug regimens for each patient. We may also be able to customize the drug carrier to predictably improve patient responses.” Nanoparticles are tiny spheres (1,000 times smaller than the width of a human hair) that can improve the solubility and delivery of drugs to cells. In this study, Cancer Center researchers delivered short interfering RNA (siRNA)-based drugs to disrupt the functioning and growth of tumor cells by eliminating the proteins the cells need to survive. Amazingly, the cancer selective nanoparticles stayed inside of tumors in mice for more than one week, while nonselective control nanoparticles were cleared within a few hours. This translated to improved siRNA-mediated cancer cell death and significant suppression of tumor growth. Support for this latest research came from the Cancer Prevention and Research Institute of Texas (CPRIT), Welch Foundation, American Cancer Society, UTSW’s Friends of the Comprehensive Cancer Center, the UTSW Translational Pilot Program, and the NIH National Cancer Institute SPORE grant in Lung Cancer. The Special Program of Research Excellence (SPORE) in Lung Cancer program, now in its 18th year, is the largest thoracic oncology effort in the U.S. Other UT Southwestern researchers involved in the study are Research Scientists Dr. Yunfeng Yan and Dr. Kenneth Huffman; Postdoctoral Researchers Dr. Hu Xiong and Dr. Petra Kos; Graduate Student Researchers Jason Miller and Sussana Elkassih with the UT Graduate School of Biomedical Sciences; Dr. James Kim, Assistant Professor of Internal Medicine and with the Hamon Center for Therapeutic Oncology Research; Dr. Li Liu, Assistant Professor of Radiology; Dr. Kejin Zhou, Assistant Instructor with Simmons Cancer Center; and researchers Dr. Ryan Carstens and John Norman. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.


News Article | December 6, 2016
Site: www.eurekalert.org

DALLAS - Dec. 6, 2016 - Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate grade gliomas. "As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations," said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center. According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent. Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis. "Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined," said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research. The findings are published in EBiomedicine. This work in brain cancer research is supported by the National Institutes of Health. Long-term goals of Dr. Gazdar's lab are to the determine molecular and genetic basis of human cancers, and to develop molecular insights to provide prognostic and diagnostic therapies in the treatment of human cancers. A former researcher at the National Cancer Institute, Dr. Gazdar's efforts there and at UT Southwestern have resulted in the collection and analysis of more than 2,500 human tumor specimens as well as the establishment of more than 400 lung, breast, ovary, and other types of tumor cell lines. Additional UT Southwestern researchers who contributed to the current study include Dr. Yu-An Zhang, Instructor in the Hamon Center for Therapeutic Oncology Research; Dr. Yunyun Zhou, Computational Biologist in the Department of Clinical Sciences; Dr. Xin Luo, Data Scientist in the Department of Bioinformatics; Dr. Luc Girard, Assistant Professor in the Hamon Center for Therapeutic Oncology Research; and Dr. Guanghua Xiao, Associate Professor in the Department of Clinical Sciences and a member of the Simmons Cancer Center. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. Generally speaking, gliomas arise due to aberrations in normal brain cells. Depending on the nature of the aberration, the glioma can be fast- , intermediate- or slow-growing. Gliomas do not metastasize or travel to other parts of the body. Patients with gliomas commonly present with headaches, seizures, weakness, or vision changes. Decades ago, patients were treated with aggressive regimens that resulted in significant side effects without an improvement in the quantity or quality of life. Today, treatments for gliomas are much more sophisticated. Because scientists have a better understanding of the underlying biology and genetics of gliomas, physicians are able to tailor treatments to maximize effectiveness while minimizing unwanted side effects. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. . To automatically receive news releases from UT Southwestern via email, subscribe at http://www. .


Yang L.,Mayo Medical School | Kwon J.,Mayo Medical School | Popov Y.,Beth Israel Deaconess Medical Center | Gajdos G.B.,Mayo Medical School | And 7 more authors.
Gastroenterology | Year: 2014

Background & Aims Vascular endothelial growth factor (VEGF)-induced angiogenesis is implicated in fibrogenesis and portal hypertension. However, the function of VEGF in fibrosis resolution has not been explored. Methods We developed a cholecystojejunostomy procedure to reconstruct biliary flow after bile duct ligation in C57BL/6 mice to generate a model of fibrosis resolution. These mice were then given injections of VEGF-neutralizing (mcr84) or control antibodies, and other mice received an adenovirus that expressed mouse VEGF or a control vector. The procedure was also performed on macrophage fas-induced apoptosis mice, in which macrophages can be selectively depleted. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, vascular permeability, real-time polymerase chain reaction, and flow cytometry assays. Results VEGF-neutralizing antibodies prevented development of fibrosis but also disrupted hepatic tissue repair and fibrosis resolution. During fibrosis resolution, VEGF inhibition impaired liver sinusoidal permeability, which was associated with reduced monocyte migration, adhesion, and infiltration of fibrotic liver. Scar-associated macrophages contributed to this process by producing the chemokine (C-X-C motif) ligand 9 (CXCL9) and matrix metalloproteinase 13. Resolution of fibrosis was impaired in macrophage fas-induced apoptosis mice but increased after overexpression of CXCL9. Conclusions In a mouse model of liver fibrosis resolution, VEGF promoted fibrogenesis, but was also required for hepatic tissue repair and fibrosis resolution. We observed that VEGF regulates vascular permeability, monocyte infiltration, and scar-associated macrophages function.


Sullivan J.P.,Hamon Center for Therapeutic Oncology Research | Sullivan J.P.,Simmons Comprehensive Cancer Center | Minna J.D.,Hamon Center for Therapeutic Oncology Research | Minna J.D.,Simmons Comprehensive Cancer Center | And 3 more authors.
Cancer and Metastasis Reviews | Year: 2010

The discovery of rare tumor cells with stem cell features first in leukemia and later in solid tumors has emerged as an important area in cancer research. It has been determined that these stem-like tumor cells, termed cancer stem cells, are the primary cellular component within a tumor that drives disease progression and metastasis. In addition to their stem-like ability to self-renew and differentiate, cancer stem cells are also enriched in cells resistant to conventional radiation therapy and to chemotherapy. The immediate implications of this new tumor growth paradigm not only require a re-evaluation of how tumors are initiated, but also on how tumors should be monitored and treated. However, despite the relatively rapid pace of cancer stem cell research in solid tumors such as breast, brain, and colon cancers, similar progress in lung cancer remains hampered in part due to an incomplete understanding of lung epithelial stem cell hierarchy and the complex heterogeneity of the disease. In this review, we provide a critical summary of what is known about the role of normal and malignant lung stem cells in tumor development, the progress in characterizing lung cancer stem cells and the potential for therapeutically targeting pathways of lung cancer stem cell self-renewal. © 2010 Springer Science+Business Media, LLC.


Rivera L.B.,Hamon Center for Therapeutic Oncology Research | Bradshaw A.D.,Medical University of South Carolina | Brekken R.A.,Hamon Center for Therapeutic Oncology Research
Cellular and Molecular Life Sciences | Year: 2011

SPARC is a matricellular protein, able to modulate cell/ECM interactions and influence cell responses to growth factors, and therefore is particularly attuned to contribute to physiological processes involving changes in ECM and cell mobilization. Indeed, the list of biological processes affected by SPARC includes wound healing, tumor progression, bone formation, fibrosis, and angiogenesis. The process of angiogenesis is complex and involves a number of cellular processes such as endothelial cell proliferation, migration, ECM degradation, and synthesis, as well as pericyte recruitment to stabilize nascent vessels. In this review, we will summarize current results that explore the function of SPARC in the regulation of angiogenic events with a particular emphasis on the modulation of growth factor activity by SPARC in the context of blood vessel formation. The primary function of SPARC in angiogenesis remains unclear, as SPARC activity in some circumstances promotes angiogenesis and in others is more consistent with an anti-angiogenic activity. Undoubtedly, the mercurial nature of SPARC belies a redundancy of functional proteins in angiogenesis as well as cell-type-specific activities that alter signal transduction events in response to unique cellular milieus. Nonetheless, the investigation of cellular mechanisms that define functional activities of SPARC continue to contribute novel and exciting paradigms to vascular biology. © 2011 Springer Basel AG.

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