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Search Results: 1 - 10 of 155110 matches for " Kevin B. Jones "
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Osteosarcomagenesis: Modeling Cancer Initiation in the Mouse
Kevin B. Jones
Sarcoma , 2011, DOI: 10.1155/2011/694136
Abstract: Osteosarcoma remains a deadly malignancy afflicting adolescents and young adults. The lack of a precursor and the panoply of genetic aberrations present in identified osteosarcomas makes study of its initiation difficult. A number of candidate hypotheses have been tested in the mouse, a species with a higher background incidence of osteosarcoma. Chemical carcinogens, external beam radiation, and bone-seeking heavy metal radioisotopes have all proven to be osteosarcomagenic in wild-type mice. A number of oncogenes, introduced via integrating viruses or aberrantly activated from heritable genetic loci, participate in and can individually drive osteosarcomagenesis. Germline and conditional gene ablations in the form of some but not all aneuploidy-inducing genes, conventional tumor suppressors, and factors that function normally in mesenchymal differentiation have also proven osteosarcomagenic, especially in combinations that silence the Rb1 and p53 pathways. This paper reviews the rich history of mouse models of osteosarcomagenesis, what they have taught us about the human disease, and what future mouse experiments yet promise to teach.
Osteosarcomagenesis: Modeling Cancer Initiation in the Mouse
Kevin B. Jones
Sarcoma , 2011, DOI: 10.1155/2011/694136
Abstract: Osteosarcoma remains a deadly malignancy afflicting adolescents and young adults. The lack of a precursor and the panoply of genetic aberrations present in identified osteosarcomas makes study of its initiation difficult. A number of candidate hypotheses have been tested in the mouse, a species with a higher background incidence of osteosarcoma. Chemical carcinogens, external beam radiation, and bone-seeking heavy metal radioisotopes have all proven to be osteosarcomagenic in wild-type mice. A number of oncogenes, introduced via integrating viruses or aberrantly activated from heritable genetic loci, participate in and can individually drive osteosarcomagenesis. Germline and conditional gene ablations in the form of some but not all aneuploidy-inducing genes, conventional tumor suppressors, and factors that function normally in mesenchymal differentiation have also proven osteosarcomagenic, especially in combinations that silence the Rb1 and p53 pathways. This paper reviews the rich history of mouse models of osteosarcomagenesis, what they have taught us about the human disease, and what future mouse experiments yet promise to teach. 1. Introduction Osteosarcoma is the most common primary bone malignancy and a leading cause of cancer death in adolescents and young adults [1]. Phenotypically, osteosarcoma adheres to a narrowly defined pattern of disease. Most osteosarcomas arise in the 2nd and 3rd decades of life in the metaphyses of long bones, especially near the major growth centers of the distal femur, proximal tibia, and proximal humerus [1, 2]. When osteosarcoma rarely develops in a patient over 40, it is usually secondary to prior radiation exposure or Paget's metabolic disease of bone. The vast majority of osteosarcomas (~95 percent) present as high-grade neoplasms, with microscopic metastatic disease at presentation the expectation in every case [3]. Intermediate and low-grade variants of osteosarcoma are extremely scarce [4]; benign bone-forming neoplasms are also much more rare than conventional osteosarcoma itself. There is no identifiable precursor to osteosarcoma. Despite this narrow clinical phenotype, the genotype of osteosarcoma aligns best with high-grade carcinomas, by its many cytogenetic aberrations and multiple mutations. It is difficult to discern which of these many derangements are causative of, as opposed to resultant from oncogenic transformation. Naturally, when the final state of these cells fails to readily highlight the pathway of transformation that engendered them, and no precursor lesion is known, scientists turn to
Copy Number Alterations and Methylation in Ewing's Sarcoma
Mona S. Jahromi,Kevin B. Jones,Joshua D. Schiffman
Sarcoma , 2011, DOI: 10.1155/2011/362173
Abstract: Ewing's sarcoma is the second most common bone malignancy affecting children and young adults. The prognosis is especially poor in metastatic or relapsed disease. The cell of origin remains elusive, but the EWS-FLI1 fusion oncoprotein is present in the majority of cases. The understanding of the molecular basis of Ewing's sarcoma continues to progress slowly. EWS-FLI1 affects gene expression, but other factors must also be at work such as mutations, gene copy number alterations, and promoter methylation. This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation. While CNAs consistently have been reported in Ewing's sarcoma, their clinical significance has been variable, most likely due to small sample size and tumor heterogeneity. Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies. Future CNA and methylation studies will help to understand the molecular basis of this disease.
Copy Number Alterations and Methylation in Ewing's Sarcoma
Mona S. Jahromi,Kevin B. Jones,Joshua D. Schiffman
Sarcoma , 2011, DOI: 10.1155/2011/362173
Abstract: Ewing's sarcoma is the second most common bone malignancy affecting children and young adults. The prognosis is especially poor in metastatic or relapsed disease. The cell of origin remains elusive, but the EWS-FLI1 fusion oncoprotein is present in the majority of cases. The understanding of the molecular basis of Ewing's sarcoma continues to progress slowly. EWS-FLI1 affects gene expression, but other factors must also be at work such as mutations, gene copy number alterations, and promoter methylation. This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation. While CNAs consistently have been reported in Ewing's sarcoma, their clinical significance has been variable, most likely due to small sample size and tumor heterogeneity. Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies. Future CNA and methylation studies will help to understand the molecular basis of this disease. 1. Introduction Ewing’s sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing’s sarcoma development are beginning to be understood, but the genetic risk factors leading to disease susceptibility remain largely unknown. Ewing’s sarcoma is the second most common pediatric bone cancer after osteosarcoma, with 30–60% survival depending on tumor site and metastases at diagnosis [1, 2]. When patients with Ewing's sarcoma relapse, it is usually fatal: less than 20% survive [3–5]. Beyond incremental improvements in cytotoxic chemotherapy regimens, there have been no major treatment advances in the last 20 years [6, 7]. Clinical features are the only markers that have been found to correlate reliably with the outcome in Ewing’s sarcoma, but no risk-adapted therapy has proven successful; worse prognosis in Ewing’s is predicted by metastatic disease measured by imaging and bone marrow examination, larger tumor volume, and primary tumors in the pelvis [8]. While osteosarcoma is thought to originate from bone cell progenitors [9], the cell of origin of Ewing’s sarcoma is less clear with some evidence suggesting that tumors arise from a mesenchymal stem or progenitor cells [10–12]. Other researchers in the field believe instead that Ewing's sarcoma develops from a neuroectodermal origin [13–17]. The lack of a known cell of origin contributes to the difficulty in understanding exactly how Ewing's sarcoma develops or even how to design laboratory experiments to study
Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis
George T. Calvert,Michael J. Monument,Randall W. Burt,Kevin B. Jones,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/726537
Abstract: Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome.
Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas
David E. Joyner,Kevin B. Jones,Stephen L. Lessnick,Joshua D. Schiffman,R. Lor Randall
Sarcoma , 2011, DOI: 10.1155/2011/847409
Abstract: One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor and in vitro data suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas.
Sarcoma Immunotherapy
Launce G. Gouw,Kevin B. Jones,Sunil Sharma,R. Lor Randall
Cancers , 2011, DOI: 10.3390/cancers3044139
Abstract: Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.
Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas
David E. Joyner,Kevin B. Jones,Stephen L. Lessnick,Joshua D. Schiffman,R. Lor Randall
Sarcoma , 2011, DOI: 10.1155/2011/847409
Abstract: One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor and in vitro data suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas. 1. Introduction Sarcomas, as cancers of mesenchyme, are rare and often quite deadly. Neoplastic processes arising in tissues of mesenchymal origin occur less frequently than those of ectodermal or endodermal origin, but behave in a very aggressive manner. In the United States, sarcomas have an annual incidence of over 10,000 cases per annum. Although relatively uncommon, these tumors as a group can behave in a nefarious fashion with currently reported mortality rates for certain subtypes greater than 50% [1]. As sarcomas arise in all parts of the body, especially the musculoskeletal system, the associated morbidity is substantially higher. Sarcomas inflict a tremendous emotional, physical, and financial toll on individuals and society alike. Furthermore, sarcomas affect patients of all ages, with 15% arising in patients younger than 15 years and 40% in patients older than 55 years. Accordingly, as the population ages, the incidence of these cancers will likely increase [2]. Aphoristically, the norm for a patient afflicted with metastatic sarcoma is death after an almost invective conflagration of mutilating surgery, radiation, and cytotoxic chemotherapy. Survival rates for stage IV sarcoma are 25% at best with this current triumvirate of clinical care [3]. Biotargeting has fueled limited optimism in the form of inhibitors of tyrosine kinases, mammalian target of rapamycin (mTOR), insulin growth factor receptor (IGFR), and histone
Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis
George T. Calvert,Michael J. Monument,Randall W. Burt,Kevin B. Jones,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/726537
Abstract: Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome. 1. Introduction Desmoid tumors (DTs), also known as aggressive fibromatosis, are fibroblastic neoplasms which are often locally aggressive but lack metastatic potential. They may occur sporadically or in association with familial adenomatous polyposis (FAP) syndrome. Among individuals with FAP, desmoids most frequently occur in intra-abdominal and abdominal wall locations with most arising from the peritoneum. These abdominal desmoids range in severity from indolent, asymptomatic lesions to highly invasive, sometimes fatal tumors. Although less common than abdominal desmoids and very rarely fatal, extra-abdominal desmoids are also a significant cause of morbidity in this population. This paper will review recent developments in the diagnosis, screening, treatment, and prognosis of FAP-associated extra-abdominal DTs. 2. Epidemiology of FAP-Associated Desmoid Tumors The overall incidence of DTs has frequently been quoted at 2–4 per million people per year [1, 2]. This estimate is derived from a 1986 Finnish study which used the pathologic records of several regional hospitals and their known catchment area populations to calculate an incidence figure [3]. Recently, the Dutch national pathology database was analyzed, and 519 total desmoid cases in patients over the age of ten were identified from 1999 to 2009. There were 480 sporadic DTs and 39 FAP-DTs. The annual incidence was 3.7 per million overall [4] consistent with the earlier Finnish study. The same nationwide study from The Netherlands identified 1400 patients over the age of ten with FAP during the 1999 to 2009 period. FAP-associated DTs (FAP-DTs) made up 7.5% of all DTs, and the relative risk of an FAP patient developing a DT was over 800-fold higher than the general population [4]. The Dutch study was limited by the use of pathologic specimens as many DTs may be identified based upon history, physical exam, and imaging but not biopsied or surgically excised especially in the FAP cohort. Additionally, some individuals with sporadic DTs may have had as yet
Lost in Translation: Ambiguity in Nerve Sheath Tumor Nomenclature and Its Resultant Treatment Effect
Nicholas M. Bernthal,Kevin B. Jones,Michael J. Monument,Ting Liu,David Viskochil,R. Lor Randall
Cancers , 2013, DOI: 10.3390/cancers5020519
Abstract: There is much ambiguity surrounding the diagnosis of nerve sheath tumors, including atypical neurofibroma and low-grade MPNST, and yet, the distinction between these entities designates either benign or malignant behavior and thus carries presumed profound prognostic importance that often guides treatment. This study reviews the diagnostic criteria used to designate atypical neurofibroma from low-grade MPNSTs and reviews existing literature the natural history of each of these tumors to see if the distinction is, in fact, of importance.
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