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Sample records for musculoaponeurotic fibrosarcoma oncogene

  1. V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells.

    PubMed

    Corritore, Elisa; Lee, Yong-Syu; Pasquale, Valentina; Liberati, Daniela; Hsu, Mei-Ju; Lombard, Catherine Anne; Van Der Smissen, Patrick; Vetere, Amedeo; Bonner-Weir, Susan; Piemonti, Lorenzo; Sokal, Etienne; Lysy, Philippe A

    2016-11-01

    : β-Cell replacement therapy represents the most promising approach to restore β-cell mass and glucose homeostasis in patients with type 1 diabetes. Safety and ethical issues associated with pluripotent stem cells stimulated the search for adult progenitor cells with endocrine differentiation capacities. We have already described a model for expansion and differentiation of human pancreatic duct-derived cells (HDDCs) into insulin-producing cells. Here we show an innovative and robust in vitro system for large-scale production of β-like cells from HDDCs using a nonintegrative RNA-based reprogramming technique. Synthetic modified RNAs for pancreatic transcription factors (pancreatic duodenal homeobox 1, neurogenin3, and V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A [MAFA]) were manufactured and daily transfected in HDDCs without strongly affecting immune response and cell viability. MAFA overexpression was efficient and sufficient to induce β-cell differentiation of HDDCs, which acquired a broad repertoire of mature β-cell markers while downregulating characteristic epithelial-mesenchymal transition markers. Within 7 days, MAFA-reprogrammed HDDC populations contained 37% insulin-positive cells and a proportion of endocrine cells expressing somatostatin and pancreatic polypeptide. Ultrastructure analysis of differentiated HDDCs showed both immature and mature insulin granules with light-backscattering properties. Furthermore, in vitro HDDC-derived β cells (called β-HDDCs) secreted human insulin and C-peptide in response to glucose, KCl, 3-isobutyl-1-methylxanthine, and tolbutamide stimulation. Transplantation of β-HDDCs into diabetic SCID-beige mice confirmed their functional glucose-responsive insulin secretion and their capacity to mitigate hyperglycemia. Our data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new β cells with potential to reverse diabetes.

  2. The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors

    PubMed Central

    Jensen, Kirsty; Makins, Giles D.; Kaliszewska, Anna; Hulme, Martin J.; Paxton, Edith; Glass, Elizabeth J.

    2009-01-01

    The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades bovine macrophages (mϕ) and induces host cell transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of characteristic mϕ functions and phenotypic markers, indicative of host cell de-differentiation. We have investigated the effect of T. annulata infection on the expression of the mϕ differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to mϕ was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived mϕ. Treatment of T. annulata-infected cells with the theileriacidal drug buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of down-stream target genes, e.g. up-regulation of integrin B7 and down-regulation of IL12A. Furthermore, T. annulata infection is associated with the suppression of the transcription factors, Pu.1 and RUNX1, and colony stimulating factor 1 receptor (CSF1R) which are also involved in the regulation of monocyte/mϕ differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host mϕ differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation. Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected mϕ. PMID:19303416

  3. The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors.

    PubMed

    Jensen, Kirsty; Makins, Giles D; Kaliszewska, Anna; Hulme, Martin J; Paxton, Edith; Glass, Elizabeth J

    2009-08-01

    The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades bovine macrophages (m phi) and induces host cell transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of characteristic m phi functions and phenotypic markers, indicative of host cell de-differentiation. We have investigated the effect of T. annulata infection on the expression of the m phi differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to m phi was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi. Treatment of T. annulata-infected cells with the theileriacidal drug buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of down-stream target genes, e.g. up-regulation of integrin B7 and down-regulation of IL12A. Furthermore, T. annulata infection is associated with the suppression of the transcription factors, Pu.1 and RUNX1, and colony stimulating factor 1 receptor (CSF1R) which are also involved in the regulation of monocyte/m phi differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation. Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.

  4. Karyotype analysis of the acute fibrosarcoma from chickens infected with subgroup J avian leukosis virus associated with v-src oncogene.

    PubMed

    Dong, Xuan; Ju, Sidi; Chen, Junxia; Meng, Fanfeng; Sun, Peng; Li, Yang; Wang, Xin; Wang, Yixin; Liu, Juan; Chang, Shuang; Zhao, Peng; Cui, Zhizhong

    2016-01-01

    To understand the cytogenetic characteristics of acute fibrosarcoma in chickens infected with the subgroup J avian leukosis virus associated with the v-src oncogene, we performed a karyotype analysis of fibrosarcoma cell cultures. Twenty-nine of 50 qualified cell culture spreads demonstrated polyploidy of some macrochromosomes, 21 of which were trisomic for chromosome 7, and others were trisomic for chromosomes 3, 4, 5 (sex chromosome w), and 10. In addition, one of them was trisomic for both chromosome 7 and the sex chromosome 5 (w). In contrast, no aneuploidy was found for 10 macrochromosomes of 12 spreads of normal chicken embryo fibroblast cells, although aneuploidy for some microchromosomes was demonstrated in five of the 12 spreads. The cytogenetic mosaicism or polymorphism of the aneuploidy in the acute fibrosarcoma described in this study suggests that the analysed cells are polyclonal.

  5. Overexpression of C-terminally but not N-terminally truncated Myb induces fibrosarcomas: a novel nonhematopoietic target cell for the myb oncogene.

    PubMed Central

    Press, R D; Reddy, E P; Ewert, D L

    1994-01-01

    The myb oncogene encodes a DNA-binding transcriptional transactivator which can become a hematopoietic cell-transforming protein following the deletion of amino acid sequences from either its amino or carboxyl terminus. Although a number of hematopoietic tumors express terminally deleted variants of Myb, the involvement of truncated Myb in nonhematopoietic tumors has not been adequately investigated. To assess the full spectrum of Myb's oncogenic capability, a replication-competent retroviral vector (RCAMV) was used to express a full-length protein (C-Myb), an amino-terminally truncated protein (VCC- or delta N-Myb), a carboxyl-terminally truncated protein (T-Myb), or a doubly truncated protein (VCT-Myb) in vivo. These viruses were injected intravenously into 10-day chicken embryos, and the infected chicks were monitored for tumors. Approximately 4 to 8 weeks after hatching, the majority (30 of 39 [77%]) of animals infected with the T-Myb retrovirus (without 214 carboxyl-terminal residues) developed nodular muscle tumors which could be identified by both morphologic and immunohistochemical criteria as fibrosarcomas. Identically appearing tumors could also be found in the kidney of some T-Myb-infected animals. The T-Myb-induced fibrosarcomas expressed the appropriately sized T-Myb protein, contained an unaltered proviral T-myb gene, and showed clonal proviral integration sites. In comparison, no sarcomas were observed in any of the animals infected with the amino-terminally truncated (VCC- and delta N-Myb) or doubly truncated (VCT-Myb) viruses. A loss of carboxyl-terminal but not amino-terminal sequences can thus convert Myb into a potent in vivo transforming protein for nonhematopoietic mesenchymal cells. In comparison, a truncation of either or both ends of the protein can activate Myb into a hematopoietic cell-transforming protein. Images PMID:8139533

  6. Oncogenes

    SciTech Connect

    Compans, R.W.; Cooper, M.; Koprowski, H.; McConell, I.; Melchers, F.; Nussenzweig, V.; Oldstone, M.; Olsnes, S.; Saedler, H.; Vogt, P.K.

    1989-01-01

    This book covers the following topics: Roles of drosophila proto-oncogenes and growth factor homologs during development of the fly; Interaction of oncogenes with differentiation programs; Genetics of src: structure and functional organization of a protein tyrosine kinase; Structures and activities of activated abl oncogenes; Eukaryotic RAS proteins and yeast proteins with which they interact. This book presents up-to-data review articles on oncogenes. The editor includes five contributions which critically evaluate recent research in the field.

  7. Generation of fibrosarcomas in vivo by a retrovirus that expresses the normal B chain of platelet-derived growth factor and mimics the alternative splice pattern of the v-sis oncogene

    SciTech Connect

    Pech, M.; Gazit, A.; Arnstein, P.; Aaronson, S.A. )

    1989-04-01

    A retrovirus containing the entire human platelet-derived growth factor B-chain (PDGF-B) gene was constructed in order to investigate the in vivo biological activity of its encoded growth factor. When this virus was introduced into newborn mice, it reproducibly generated fibrosarcomas at the site of inoculation. Proviruses in each fibrosarcoma analyzed had lost 149 nucleotides downstream of the PDGF-B coding region. This deletion originated from an alternative or aberrant splice event that occurred within exon 7 of the PDGF-B gene and mimicked the v-sis oncogene. Thus, deletion of this region may be necessary for efficient retrovirus replication or for more potent transforming function. Evidence that the normal growth factor coding sequence was unaltered derived from RNase protection studies and immunoprecipitation analysis. Tumors were generally polyclonal but demonstrated clonal subpopulations. Moreover, tumor-derived cell lines became monoclonal within a few tissue culture passages and rapidly formed tumors in vivo. These findings argue that overexpression of the normal human PDGF-B gene product under retrovirus control can induce the fully malignant phenotype.

  8. [MORPHOLOGICAL PECULIARITIES OF MUSCULO-APONEUROTIC TISSUES OF ANTERIOR ABDOMINAL WALL IN PATIENTS, SUFFERING MORBID OBESITY].

    PubMed

    Usenko, O Yu; Gomolyako, I V; Kondratenko, B M; Moskalenko, V V

    2015-11-01

    Results of morphological investigation of musculo-aponeurotic structures of anterior abdominal wall were presented in the morbid obesity patients. The role of obesity as a primary cause for morphofunctional insufficience of musculo-aponeurotic structures was established.

  9. Musculoaponeurotic Area of the Hip and Clinicophotographic Scaling System.

    PubMed

    Mena-Chávez, J Alejandro; Cárdenas-Camarena, Lázaro

    2015-06-01

    With the evolution of body contouring, few innovative alternatives have been developed for cosmetic treatment in the hip area. A multicenter controlled study was conducted, including a prior review of the literature regarding the hip area. Dissections were performed on 4 male cadavers, outlining the "musculoaponeurotic area of the hip." The area was subdivided into anterior and posterior surfaces. A clinical study was conducted in 79 patients, obtaining a scale by using the most prominent points on the sides of both thighs as the main reference. With the lines marked on photographs and the measurements, a "clinicophotographic scaling system" was designed. The anterior surface corresponds to the tensor fasciae latae and its tendon as well as to the aponeurosis of the gluteus medius. The posterior surface corresponds with the iliotibial tract and the tendon insertions of the gluteus maximus. The average dimensions of the cadaver "musculoaponeurotic area of the hip" are as follows: length, 17.5 cm, and width, 11.5 cm. Using the "clinicophotographic scaling system," the dimensions are as follows: length, 14.9 cm, and width, 10.3 cm. The "musculoaponeurotic area of the hip" was defined involving muscles, tendons, aponeurosis, fascia, subcutaneous cellular tissue, and skin. The borders were established using important anatomical points that determine the length and width of the area. The "clinicophotographic scaling system" was used to clinically calculate the length and width of the area. By examination and palpation, the borders and dimensions of this area could be determined.

  10. Musculoaponeurotic Area of the Hip and Clinicophotographic Scaling System

    PubMed Central

    Mena-Chávez, J. Alejandro

    2015-01-01

    Background: With the evolution of body contouring, few innovative alternatives have been developed for cosmetic treatment in the hip area. Methods: A multicenter controlled study was conducted, including a prior review of the literature regarding the hip area. Dissections were performed on 4 male cadavers, outlining the “musculoaponeurotic area of the hip.” The area was subdivided into anterior and posterior surfaces. A clinical study was conducted in 79 patients, obtaining a scale by using the most prominent points on the sides of both thighs as the main reference. With the lines marked on photographs and the measurements, a “clinicophotographic scaling system” was designed. Results: The anterior surface corresponds to the tensor fasciae latae and its tendon as well as to the aponeurosis of the gluteus medius. The posterior surface corresponds with the iliotibial tract and the tendon insertions of the gluteus maximus. The average dimensions of the cadaver “musculoaponeurotic area of the hip” are as follows: length, 17.5 cm, and width, 11.5 cm. Using the “clinicophotographic scaling system,” the dimensions are as follows: length, 14.9 cm, and width, 10.3 cm. Conclusions: The “musculoaponeurotic area of the hip” was defined involving muscles, tendons, aponeurosis, fascia, subcutaneous cellular tissue, and skin. The borders were established using important anatomical points that determine the length and width of the area. The “clinicophotographic scaling system” was used to clinically calculate the length and width of the area. By examination and palpation, the borders and dimensions of this area could be determined. PMID:26180724

  11. Absence of ras-gene hot-spot mutations in canine fibrosarcomas and melanomas.

    PubMed

    Murua Escobar, Hugo; Günther, Kathrin; Richter, Andreas; Soller, Jan T; Winkler, Susanne; Nolte, Ingo; Bullerdiek, Jörn

    2004-01-01

    Point mutations within ras proto-oncogenes, particularly within the mutational hot-spot codons 12, 13 and 61, are frequently detected in human malignancies and in different types of experimentally-induced tumours in animals. So far little is known about ras mutations in naturally occurring canine fibrosarcomas or K-ras mutations in canine melanomas. To elucidate whether ras mutations exist in these naturally occurring tumours in dogs, in the present study we screened 13 canine fibrosarcomas, 2 feline fibrosarcomas and 11 canine melanomas for point mutations, particularly within the mutational hot-spots, making this the first study to investigate a large number of canine fibrosarcomas. None of the samples showed a K- or N-ras hot spot mutation. Thus, our data strongly suggest that ras mutations at the hot-spot loci are very rare and do not play a major role in the pathogenesis of the spontaneously occurring canine tumours investigated.

  12. Corneal fibrosarcoma in a cat.

    PubMed

    Strong, Travis D; Tangeman, Sarah; Ben-Shlomo, Gil; Haynes, Joseph; Allbaugh, Rachel A

    2016-07-01

    To present the clinicopathologic features of a Domestic Short-haired cat with spontaneous, intermediate-grade corneal fibrosarcoma, possibly secondary to chronic corneal irritation associated with a corneal sequestrum. A 12-year-old, spayed female Domestic Short-haired cat was evaluated for a slowly growing, pink, exophytic mass affecting the left cornea. The cat had presented 6 years previously for bilateral brown corneal sequestra, as well as 3 years previously for a small pale growth on the left cornea hypothesized to be an epithelial inclusion cyst and a corneal ulcer affecting the right eye. Incisional biopsy of the corneal mass indicated intermediate-grade corneal fibrosarcoma within the corneal stroma. Owing to the potential for malignant behavior, the left globe was enucleated. Routine systemic staging was performed prior to surgery with no evidence of metastasis. Definitive diagnosis of corneal fibrosarcoma was made through histopathologic examination of the incisional biopsy. There was an elevated mitotic index, indicating an intermediate-grade phenotype. Histopathology of the enucleated globe substantiated the initial findings, and complete tumor resection was confirmed. Subjacent to the corneal fibrosarcoma, there was a region of necrotic tissue suggestive of a corneal sequestrum. Six months after diagnosis and enucleation, the patient remained healthy with no signs of local spread or distant metastasis. To the authors' knowledge, this is the first documented case of a corneal fibrosarcoma in a cat. © 2016 American College of Veterinary Ophthalmologists.

  13. Fibrosarcoma complicating irradiated pituitary adenoma

    SciTech Connect

    Shi, T.; Farrell, M.A.; Kaufmann, J.C.

    1984-09-01

    Eight years after radiation therapy (5000 rads of 60Co) for a pituitary adenoma, a patient developed a sellar fibrosarcoma. The tumor had an aggressive growth pattern: it infiltrated the optic nerve, sphenoidal air sinus, hypothalamus, and both cavernous sinuses, where compression of the left internal carotid artery resulted in a massive hemispheric infarction. Surgery was ineffective in arresting rapid growth of the lesion; death occurring 5 months after onset of symptoms.

  14. Facelift incision and superficial musculoaponeurotic system advancement in parotidectomy: case reports.

    PubMed

    Kim, Il-Kyu; Cho, Hyun-Woo; Cho, Hyun-Young; Seo, Ji-Hoon; Lee, Dong-Hwan; Park, Seung-Hoon

    2015-12-01

    Surgical procedures for parotidectomy had been developed to gain adequate approach, prevent morbidity of nerve, and give esthetic satisfaction. We performed two cases of parotidectomy through facelift incision. One case was reconstructed with superficial musculoaponeurotic system (SMAS) flap and sternocleidomastoid (SCM) muscle rotated flap at the parotid bed. In second case, same procedures were performed, but collagen membrane was additionally implanted for prevention of Frey's syndrome. After surgery, two cases showed esthetic results without neck scar and hollow defect on parotid bed area.

  15. Ameloblastic fibrosarcoma: a cytologist's perspective.

    PubMed

    Gupta, Nalini; Barwad, Adarsh; Kumar, Rajiv; Rijuneeta; Vaiphei, Kim

    2011-08-01

    Fine-needle aspiration cytology of a case of ameloblastic fibrosarcoma (AFS), an unusual odontogenic tumor related to ameloblastoma (AB), was performed in a 25-year-old female with a 1 cm swelling in the left lower orbital region along with involvement of zygomatic region. Aspiration of the tumor yielded a cellular sample composed predominantly of mesenchymal element and few clusters representing epithelial component showing tall columnar cells with peripheral palisading. Detailed cytomorphological features of AFS are discussed along with differential diagnosis from other tumors such as AB, desmoplastic AB, odontogenic fibroma, ameloblastic fibrodentinoma and ameloblastic fibro-odontoma, ameloblastic fibroma. Copyright © 2010 Wiley-Liss, Inc.

  16. Recurrent congenital fibrosarcoma with heart metastases.

    PubMed

    Lohi, Olli; Vornanen, Martine; Kähkönen, Marketta; Vettenranta, Kim; Parto, Katriina; Arola, Mikko

    2012-07-01

    Congenital fibrosarcomas are malignant tumors that arise in soft tissues. In infants this unique tumor does not commonly metastasize, even though there may be local recurrences. We report here a boy who had congenital fibrosarcoma in his right foot, which was completely excised at the age of 3 days. Four months later, a solitary encapsulated metastasis emerged in thoracic chest wall, which was operated. During adjuvant chemotherapy he developed histologically confirmed fibrosarcoma metastases in the heart. After extended treatment with cyclophosphamide/topotecan and gemcitabine/docetaxel, the heart tumors disappeared and he has been in complete remission for 3 years.

  17. Fibrosarcoma of the mandible: a diagnostic dilemma.

    PubMed

    Nanda, Kanwar Deep Singh; Mehta, Anurag; Nanda, Jasmine

    2013-08-01

    Fibrosarcoma is a malignant mesenchymal neoplasm of fibroblasts that rarely affects oral cavity and can cause local recurrences or metastasis. The aetiologic factors are still unknown, but many authors have reported the radiation therapy history as an important aetiological factor, followed by trauma and underlying conditions like Paget's disease, fibrous dysplasia or chronic osteomyelitis. Fibrosarcoma of mandible is rare, with an incidence which ranges from 0-6.1% of all primary fibrosarcomas of the bone. This paper has described a case of a swelling in the mandible of a 17-years old female who had a radiolucency in association with crown of an impacted tooth and foci of radiopacity, which led to a misdiagnosis of either an odontogenic lesion or a bone tumour, but proved to be a fibrosarcoma on histopathological and immunohistochemistry investigations.

  18. Andreas Vesalius' 500th Anniversary: Initiation of the Superficial Facial System and Superficial Musculoaponeurotic System Concepts.

    PubMed

    Brinkman, Romy J; Hage, J Joris

    2016-02-01

    Because of their relevance for liposuction and rhytidectomies, respectively, the superficial fascial system (SFS) and superficial musculoaponeurotic system (SMAS) have been thoroughly studied over the past decennia. Although it is well known that the SMAS concept was introduced by Tessier in 1974, it remains unknown who first properly described the stratum membranosum of the SFS. In light of the 500th birthday of Andreas Vesalius (1515-1564), we searched his 1543 masterwork De Humani Corporis Fabrica Libri Septem and related work for references to these structures. We found ample reference to both structures as the membrana carnosa (or fleshy membrane) in his works and concluded that Vesalius recognized the extension, nature, and functions of the stratum membranosum of the SFS, as well as its more musculous differentiation as the SMAS in the head and neck area, and the dartos in the perineogenital area. In doing so, Vesalius recorded most details of the SFS and SMAS concepts avant la lettre.

  19. Absent external oblique musculo-aponeurotic complex during inguinal hernioplasty: a case report and review of literature.

    PubMed

    Dsouza, Royson; Shankar, Nachiket; Gurubatham, Rohin; Rajaleelan, Wesley; Menon, Nandakumar

    2017-03-03

    The external oblique musculo-aponeurotic complex is an important contributor to the strength of the inguinal canal. The present case report describes the bilateral absence of the external oblique muscle in a patient. A 40-year-old male patient presented with a history of intermittent lower abdominal pain for 15 years which had increased over the past 2 years. Abdominal examination revealed bilateral reducible, incomplete, direct inguinal hernia. Elective bilateral Lichtenstein's mesh hernioplasty was planned for the patient. Intraoperatively, there was no evidence of the external oblique aponeurosis and the spermatic cord was noted deep to the membranous fascial layer. The inguinal ligament was thin and atrophic and was attached to the pubic tubercle medially and anterior superior iliac spine laterally. There was no evidence of any superior aponeurotic connection to the inguinal ligament. A postoperative ultrasound examination of the abdomen confirmed the bilateral absence of the external oblique musculo-aponeurotic complex. The isolated absence of the external oblique musculo-aponeurotic complex in adults is an exceedingly rare anomaly. The possibility of such an anomaly should be considered in patients without other risk factors for hernia.

  20. The superficial musculoaponeurotic system flap in the prevention of Frey syndrome: A meta-analysis.

    PubMed

    Dulguerov, Nicolas; Makni, Amir; Dulguerov, Pavel

    2016-07-01

    Evaluate the difference of the incidence in clinical Frey syndrome in studies comparing classical parotidectomy and parotidectomy with superficial musculoaponeurotic system (SMAS) flap elevation and suturing through meta-analysis methodology. Meta-analysis of controlled studies with and without SMAS flap. Database search with the following key word combination: "Frey syndrome" and "SMAS." parotidectomy, SMAS flap and control groups, minimal follow-up of 1 year. The outcome was the presence of clinical Frey syndrome. Eleven studies, mostly retrospective and not randomized. According to the fixed-effect model, SMAS technique is associated with a decrease of clinical Frey syndrome with an odds ratio (OR) of 0.42 (confidence interval [CI] 0.32-0.56). With the random-effect model, the difference remains significant (P = 0.006) with an OR of 0.25 (CI 0.09-0.66). The heterogeneity index I(2) is very high (85%). The use of SMAS flap and suturing is associated with a decreased incidence of Frey syndrome. Laryngoscope, 126:1581-1584, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  1. Wound tension in rhytidectomy. Effects of skin-flap undermining and superficial musculoaponeurotic system suspension.

    PubMed

    Burgess, L P; Casler, J D; Kryzer, T C

    1993-02-01

    This study was conducted to determine the effects of skin-flap undermining and superficial musculoaponeurotic system (SMAS) suspension on wound-closing tension. Nine sides from five fresh-frozen cadavers were used, with closing tension measured at the two main anchor points, anteriorly (A) and posteriorly (P), with and without SMAS plication for minimal (MIN), intermediate (INT), and maximal (MAX) skin-flap undermining. Results indicated that closing tension was significantly decreased with SMAS plication, both A and P, for all three levels of skin undermining. The average decrease in closing tension with SMAS plication was: A-MIN 191 g, A-INT 95 g, A-MAX 83 g, P-MIN 235 g, P-INT 68 g, and P-MAX 70 g (P < .001 for all). Considering the effect of skin-flap undermining alone, closing tension decreased with wider skin-flap undermining, both with and without SMAS plication. The tension-reducing effect of SMAS plication was decreased with wider skin-flap undermining. Regression analysis determined a second-order exponential curve relating closing tension to skin excision.

  2. A transition in transcriptional activation by the glucocorticoid and retinoic acid receptors at the tumor stage of dermal fibrosarcoma development.

    PubMed Central

    Vivanco, M D; Johnson, R; Galante, P E; Hanahan, D; Yamamoto, K R

    1995-01-01

    In transgenic mice harboring the bovine papillomavirus genome, fibrosarcomas arise along an experimentally accessible pathway in which normal dermal fibroblasts progress through two pre-neoplastic stages, mild and aggressive fibromatosis, followed by a final transition to the tumor stage. We found that the glucocorticoid receptor (GR) displays only modest transcriptional regulatory activity in cells derived from the three non-tumor stages, whereas it is highly active in fibrosarcoma cells. Upon inoculation into mice, the aggressive fibromatosis cells progress to tumor cells that have high GR activity; thus, the increased transcriptional regulatory activity of GR correlates with the cellular transition to the tumor stage. The intracellular levels of GR, as well as its hormone-dependent nuclear translocation and specific DNA binding activities, are unaltered throughout the progression. Strikingly, the low GR activity observed in the pre-neoplastic stages cannot be overcome by exogenous GR introduced by co-transfection. Moreover, comparisons of primary embryo fibroblasts and their transformed derivatives revealed a similar pattern--modest GR activity, unresponsive to overexpressed GR protein, in the normal cells was strongly increased in the transformed cells. Likewise, the retinoic acid receptor (RAR) displayed similar differential activity in the fibrosarcoma pathway. Thus, the oncogenic transformation of fibroblasts, and likely other cell types, is accompanied by a striking increase in the activities of transcriptional regulators such as GR and RAR. We suggest that normal primary cells have a heretofore unrecognized capability to limit the magnitude of induction of gene expression. Images PMID:7774580

  3. Congenital infantile fibrosarcoma: Association with bleeding diathesis

    PubMed Central

    Salman, Mayssaa; Khoury, Nabil J.; Khalifeh, Ibrahim; Abbas, Hussein A.; Majdalani, Marianne; Abboud, Miguel; Muwakkit, Samar; Solh, Hassan El; Saab, Raya

    2013-01-01

    Patient: Male, 2 month Final Diagnosis: Congenital infantile fibrosarcoma Symptoms: Bleeding Medication: Vincristine • actinomycin • cyclophosphamide Clinical Procedure: Surgical resection Specialty: Pediatric Oncology Objective: Diagnostic/therapeutic accidents Background: Congenital infantile fibrosarcoma (CIF) is a soft-tissue tumor occurring during the first 2 years of life, most commonly in the extremities. CIF is frequently initially misdiagnosed as a vascular tumor, but its association with bleeding and coagulopathy has not been well characterized. Case Reports: We describe 2 infants with CIF presenting with bleeding and coagulopathy, requiring urgent intervention. Both patients did well; one underwent partial resection followed by chemotherapy, and the other received 2 cycles of chemotherapy followed by gross total resection. We also provide a review of all reported cases of coagulopathy in the setting of CIF in the English literature, uncovering an association that seems to be more prevalent in patients diagnosed in the neonatal period, with associated anemia and thrombocytopenia, and a significant mortality rate. Conclusions: CIF needs to be considered in the differential diagnosis of vascular congenital tumors, especially when there is evidence of bleeding, anemia, or thrombocytopenia. PMID:24265847

  4. Ameloblastic Fibrosarcoma Arising in the Maxilla.

    PubMed

    Pillay, Rachael R; Bilski, Arthur; Batstone, Martin

    2016-01-01

    Ameloblastic fibrosarcoma (AFS) is a rare odontogenic neoplasm of the jaw that usually arises de novo or through a malignant change in the mesenchymal component of a preexisting or recurrent benign fibroma. The majority of AFS cases reported in the literature arise in the mandible. A 35-year-old male presented with an asymptomatic left maxillary mass that on imaging was found to be effacing most of his maxillary sinus. He underwent a left maxillectomy with free-flap reconstruction and adjuvant radiotherapy to the tumor bed. Wide local excision remains the treatment of choice for AFS, given the poor survival rates of patients with recurrent disease. However, long-term studies and follow-up are needed to elucidate the role of adjuvant therapies in the primary treatment of AFS.

  5. Ameloblastic Fibrosarcoma Arising in the Maxilla

    PubMed Central

    Pillay, Rachael R.; Bilski, Arthur; Batstone, Martin

    2016-01-01

    Background: Ameloblastic fibrosarcoma (AFS) is a rare odontogenic neoplasm of the jaw that usually arises de novo or through a malignant change in the mesenchymal component of a preexisting or recurrent benign fibroma. The majority of AFS cases reported in the literature arise in the mandible. Case Report: A 35-year-old male presented with an asymptomatic left maxillary mass that on imaging was found to be effacing most of his maxillary sinus. He underwent a left maxillectomy with free-flap reconstruction and adjuvant radiotherapy to the tumor bed. Conclusion: Wide local excision remains the treatment of choice for AFS, given the poor survival rates of patients with recurrent disease. However, long-term studies and follow-up are needed to elucidate the role of adjuvant therapies in the primary treatment of AFS. PMID:27303223

  6. Ameloblastic fibrosarcoma: a rare malignant odontogenic tumor.

    PubMed

    Gilani, S M; Raza, A; Al-Khafaji, B M

    2014-02-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumor. It can arise de novo, however one-third of cases may arise from a recurrent ameloblastic fibroma, in which case they appear to present at an older age. A 16-year-old female presented with one month history of right mandibular mass. Computerized tomography (CT) scan showed a large destructive mass. A biopsy of the mass was performed. Histologically, it consisted of a mixed epithelial-mesenchymal odontogenic neoplasm composed of benign islands of well-differentiated ameloblastic epithelium within a malignant fibrous stroma consisting of spindle cells or fibroblasts with a brisk mitotic activity. The malignant spindle cell proliferation showed positive staining with p-53 and a high proliferation index with ki-67. A diagnosis of AFS was rendered. The differential diagnosis includes other odontogenic sarcomas, ameloblastic carcinosarcoma and spindle cell carcinoma. Treatment of choice is wide surgical excision, with long-term follow-up. Postoperative chemotherapy and radiotherapy has been used successfully in a few reported cases. AFS is a locally aggressive malignant tumor, with regional and distant metastases being uncommon. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  7. In vitro irradiation is able to cause RET oncogene rearrangement.

    PubMed

    Ito, T; Seyama, T; Iwamoto, K S; Hayashi, T; Mizuno, T; Tsuyama, N; Dohi, K; Nakamura, N; Akiyama, M

    1993-07-01

    Elevated risk of thyroid cancers among the atomic bomb survivors as compared to the nonexposed population suggests that some genetic events related to thyroid cancer must be caused by ionizing radiation. Accordingly, inducibility of RET oncogene rearrangements, i.e., the generation of the RET-PTC oncogene, specific for thyroid cancer, was investigated among human undifferentiated thyroid carcinoma cells (8505C), which do not have RET oncogene rearrangement, after 0, 10, 50, and 100 Gy of in vitro X-irradiation by means of reverse transcription polymerase chain reaction. After testing 10(8) cells at each dose point, 3 independent samples obtained with 50 Gy of X-irradiation and 6 independent samples obtained with 100 Gy of X-irradiation showed a rearranged RET oncogene amplified band. No rearranged transcripts were obtained from cells irradiated with 0 or 10 Gy. All of the transcripts were sequenced and found to contain the D10S170 and RET sequence. Interestingly, two types of rearrangements were included in these transcripts: one is specific for thyroid cancer and the other, which contains a 150-base pair insert, is atypical, not usually seen in vivo. This insert was found to be the exon of D10S170. Furthermore, in fibrosarcoma cells (HT1080), X-irradiation also induced RET oncogene rearrangements, which included the same two types of rearrangements observed in the X-irradiated thyroid cells (8505C). These results are in favor of the hypothesis that some radiation-induced thyroid cancers, including those among atomic bomb survivors, might have developed when a growth advantage was obtained through a specific form of RET oncogene rearrangement induced by radiation exposure.

  8. Development of the Platysma Muscle and the Superficial Musculoaponeurotic System (Human Specimens at 8–17 Weeks of Development)

    PubMed Central

    De la Cuadra-Blanco, C.; Peces-Peña, M. D.; Carvallo-de Moraes, L. O.; Herrera-Lara, M. E.; Mérida-Velasco, J. R.

    2013-01-01

    There is controversy regarding the description of the different regions of the face of the superficial musculoaponeurotic system (SMAS) and its relationship with the superficial mimetic muscles. The purpose of this study is to analyze the development of the platysma muscle and the SMAS in human specimens at 8–17 weeks of development using an optical microscope. Furthermore, we propose to study the relationship of the anlage of the SMAS and the neighbouring superficial mimetic muscles. The facial musculature derives from the mesenchyme of the second arch and migrates towards the different regions of the face while forming premuscular laminae. During the 8th week of development, the cervical, infraorbital, mandibular, and temporal laminae are observed to be on the same plane. The platysma muscle derives from the cervical lamina and its mandibular extension enclosing the lower part of the parotid region and the cheek, while the SMAS derives from the upper region. During the period of development analyzed in this study, we have observed no continuity between the anlage of the SMAS and that of the superficial layer of the temporal fascia and the zygomaticus major muscle. Nor have we observed any structure similar to the SMAS in the labial region. PMID:24396304

  9. Development of the platysma muscle and the superficial musculoaponeurotic system (human specimens at 8-17 weeks of development).

    PubMed

    De la Cuadra-Blanco, C; Peces-Peña, M D; Carvallo-de Moraes, L O; Herrera-Lara, M E; Mérida-Velasco, J R

    2013-01-01

    There is controversy regarding the description of the different regions of the face of the superficial musculoaponeurotic system (SMAS) and its relationship with the superficial mimetic muscles. The purpose of this study is to analyze the development of the platysma muscle and the SMAS in human specimens at 8-17 weeks of development using an optical microscope. Furthermore, we propose to study the relationship of the anlage of the SMAS and the neighbouring superficial mimetic muscles. The facial musculature derives from the mesenchyme of the second arch and migrates towards the different regions of the face while forming premuscular laminae. During the 8th week of development, the cervical, infraorbital, mandibular, and temporal laminae are observed to be on the same plane. The platysma muscle derives from the cervical lamina and its mandibular extension enclosing the lower part of the parotid region and the cheek, while the SMAS derives from the upper region. During the period of development analyzed in this study, we have observed no continuity between the anlage of the SMAS and that of the superficial layer of the temporal fascia and the zygomaticus major muscle. Nor have we observed any structure similar to the SMAS in the labial region.

  10. Vaccine-associated fibrosarcoma with keloidal differentiation in a cat.

    PubMed

    Gumber, Sanjeev; Wakamatsu, Nobuko

    2011-09-01

    A 6-year-old Domestic Shorthair cat was presented with a history of subcutaneous mass of the lateral left hind limb. The subcutaneous mass developed over a period of approximately 16 months subsequent to administration of Feline leukemia virus vaccines. Based on the histopathological and immunohistochemical examination, the subcutaneous mass was diagnosed as vaccine-associated fibrosarcoma with keloidal differentiation.

  11. Congenital osteolytic dural fibrosarcoma presenting as a scalp swelling.

    PubMed

    Brohi, Shams Raza; Dilber, Muzamil

    2012-08-01

    An extremely rare case of congenital dural fibrosarcoma is reported in a 2 months old child who presented with scalp swelling since birth. CT scan revealed an osteolytic lesion compressing the underlying atrophic brain. Tumour was completely excised and duroplasty was done with a patch graft. Postoperative CSF leak was managed with aspirations and lumbar puncture.

  12. [Malignant fibrous histiocytoma: pleomorphic sarcoma NOS or pleomorphic fibrosarcoma].

    PubMed

    Meister, P

    2005-03-01

    The entity and nosology of pleomorphic malignant fibrous histiocytoma (MFH) is still ambiguous. The actual WHO-Classification uses pleomorphic malignant fibrous histiocytoma (MFH) and pleomorphic sarcoma NOS (not otherwise specified) synonymously. On the other hand text and illustrations convey the impression, that these tumors also could be pleomorphic lipo-, leio- or rhabdomyosarcomas etc. It would have been more informative to emphasize, that with the above mentioned specific sarcoma types MFH-like appearance may occur. Furthermore it would have been more up to date to consider pleomorphic sarcomas NOS as pleomorphic fibrosarcomas and include them in the chapter of fibroblastic and myofibroblastic tumors. This concept already has been carried out for the former myxoid variant of MFH, nowadays preferentially called myxofibrosarcoma. There is controversial discussion about the clinical significance of exact typing of pleomorphic sarcomas. Problems may also occur due to the lack of standards, which degree of desmin expression signifies leiomyosarcoma or just indicates myofibroblasts in MFH. The requirement of exclusion of other tumor-types before diagnosing pleomorphic fibrosarcoma still remains obligatory. After verification of the diagnosis pleomorphic sarcoma NOS or pleomorphic fibrosarcoma, grading e.g. according to criteria of the FFCCS can be carried out. Most cases of pleomorphic fibrosarcoma will qualify as high grade malignant.

  13. Rescue of avian leukosis subgroup-J-associated acutely transforming viruses carrying different lengths of the v-fps oncogene and analysis of their tumorigenicity.

    PubMed

    Wang, Yixin; Fang, Lichun; Li, Jianliang; Li, Yang; Cui, Shuai; Sun, Xiaolong; Chang, Shuang; Zhao, Peng; Cui, Zhizhong

    2016-12-01

    In our previous study, six subgroup J strains of avian leukosis virus (ALV-J)-associated acutely transforming viruses carrying different lengths of the v-fps oncogene, designated as Fu-J and Fu-J1-5, were isolated and characterized from fibrosarcomas in ALV-J-infected chickens. In the present study, the oncogenic potential of Fu-J and Fu-J1-5 was investigated using a reverse genetics technique. Six replication-defective viruses, named rFu-J and rFu-J1-5, were rescued with the replication-competent rescued ALV-J strain rSDAU1005 as a helper virus by co-transfection of chicken embryo fibroblast monolayers with infectious clone plasmids. Experimental bird studies were performed, demonstrating that only the rescued rFu-J virus carrying the complete v-fps oncogene with rSDAU1005 as the helper virus could induce acute fibrosarcoma after inoculation in specific-pathogen-free (SPF) chickens. These results provide direct evidence that the replication-defective acutely transforming Fu-J virus, with the complete v-fps oncogene, was associated with acute fibrosarcoma in chickens infected with ALV-J in the field, as reported previously.

  14. Plakoglobin is a new target gene of histone deacetylase in human fibrosarcoma HT1080 cells.

    PubMed

    Shim, Joong Sup; Kim, Dong Hoon; Kwon, Ho Jeong

    2004-03-04

    Histone deacetylase (HDAC) plays a key role in gene expression, by suppressing the transcription of a number of target genes. Identification of such genes is important for deciphering the functional role of HDAC. Here, using cancer gene-focused DNA microarray analysis, we identified plakoglobin as a new target gene of HDAC. Functional inhibition of HDAC by its specific inhibitors induced the expression of plakoglobin by eight-fold in human fibrosarcoma HT1080 cells. However, the expression of beta-catenin, which is closely related to plakoglobin, was not altered, implying the specific function of HDAC in plakoglobin expression. Using antiacetyl-H4 antibody, chromatin immunoprecipitation analysis revealed that the distal region (-945 approximately -646) of the promoter of plakoglobin is responsible for the HDAC-mediated repression of the gene. Moreover, the induced expression of plakoglobin by the inhibition of HDAC activated the Tcf/Lef-dependent luciferase reporter gene, a well-known downstream effector of the Wnt signaling pathway. Furthermore, transient transfection of plakoglobin also activated Tcf/Lef reporter gene expression. Taken together, our results demonstrate that plakoglobin is a new target gene governed by HDAC, and that it acts as an oncogene in HT1080 cells.

  15. Suprafibromuscular facelifting with periosteal suspension of the superficial musculoaponeurotic system and fat pad of Bichat rotation. Tightening the net.

    PubMed

    Keller, G S; Cray, J

    1996-04-01

    To design a facelifting technique that improves the safety of the facial nerve in extended facelifting; improves methods of fixation of the elevation of the nasolabial folds, the melolabial folds, the corner of the mouth and the malar fat pad; and augments the malar and submalar areas without implants. After a retrospective review of previous modified "composite" technique facelift results (307 patients over 4 years), a suprafibromuscular facelift technique was evolved through 22 fresh cadaver dissections. The resulting technique was applied to 73 patients, 61 females and 12 males, who were followed up for 6 to 18 months. Preauricular dissection was subcutaneous for about 4 cm. An incision was made through the superficial musculoaponeurotic system (SMAS) at the level of the body of the zygoma. Dissection over the malar eminence was performed under the orbicularis muscle. Mid-cheek dissection was performed over the fibromuscular SMAS in th layer of areolar tissues that lines it. A rotation of the fat pad of Bichat (or buccal fat pad) was used, when indicated, to augment the cheek. Stabilization of the elevation of the nasolabial fold, the melolabial fold, and the corner of the mouth was obtained by the use of suspension sutures from the SMAS to the malar eminence. Stabilization of the malar fat pad was provided by the laterally directed flap of SMAS that was sutured to the temporal fascia. The patients were followed up for 6 to 18 months and evaluated for stability of the correction and facial nerve complications. RESULTS AND CONCLUSION; The facelift corrections (nasolabial fold, melolabial fold, malar fat pad shift) were stable over the follow-up period. No facial nerve injuries were seen.

  16. Korean Sa-Ahm Acupuncture for Treating Canine Oral Fibrosarcoma.

    PubMed

    Choi, Keum Hwa; Flynn, Kristi

    2017-06-01

    A nine-year-old male neutered Golden Retriever presented with oral fibrosarcoma. Sa-Ahm Traditional Korean acupuncture was provided along with medicinal herb treatment. Based on Sa-Ahm's theory, the constitution of this case was hypoactive Large-Intestine (LI) meridian qi. The acupuncture treatment was focused on reinforcing LI meridian qi along with reinforcing Small-Intestine and Liver meridian qi. The necrosis of the tumor started from 8 months after treatments and was completely necrotized around 1 month after initiation of tumor necrosis. Karnofsky Performance Status score was 80 to 100 % throughout the treatment except during the active stage of tumor necrosis having KPS of 50%. In this study, oral fibrosarcoma was managed well by both Sa-Ahm acupuncture and medicinal herb treatment. The result suggested that Sa-Ahm acupuncture along with herbal treatment could be a potential medical option for canine oral FSA therapy. Copyright © 2017. Published by Elsevier B.V.

  17. Ameloblastic fibrosarcoma of the jaw: report of five cases.

    PubMed

    Dallera, P; Bertoni, F; Marchetti, C; Bacchini, P; Campobassi, A

    1994-12-01

    Five cases of ameloblastic fibrosarcomas (AFS) are reported. The tumour was characterized histologically by a biphasic pattern: the malignant mesenchymal component had the features of an intermediate grade fibrosarcoma in 3 cases, malignant fibrous histiocytoma and osteogenic sarcoma in 2 cases. The epithelial odontogenic component had a benign appearance cytologically. In 1 patient, in the recurrence only the malignant mesenchymal component was present. AFS is a fully malignant tumour, in fact 1 patient died of the tumour after inadequate surgical treatments, and 2 patients had a recurrence after intralesional surgery. The treatment of choice was achieved when surgery with wide surgical margins was performed. As MFH and OGS features are present in the malignant mesenchymal component of this tumour we prefer to use the broad term ameloblastic sarcoma instead of AFS.

  18. Fibrosarcoma of the trachea with severe tracheal obstruction

    PubMed Central

    Roncoroni, A. J.; Puy, R. J. M.; Goldman, E.; Fonseca, R.; Olmedo, Gloria

    1973-01-01

    Roncoroni, A. J., Puy, R. J. M., Goldman, E., Fonseca, R., and Olmedo, G. (1973).Thorax,28, 777-781. Fibrosarcoma of the trachea with severe tracheal obstruction. A patient with a tracheal fibrosarcoma is reported. The tumour was located just above the thoracic inlet and produced severe obstruction predominantly during expiration. An abnormal effort independent flow pattern was seen during inspiration in isovolume pressure-flow studies. Endoscopic resection induced temporary symptomatic remission, and airway resistance and expiratory flows became normal. Subsequently he required resection of eight tracheal rings with end-to-end tracheal anastomosis. Obstructive granulomata then developed at the suture sites, necessitating endoscopic removal. Later tracheal stenosis responded to periodic dilatation. Images PMID:4787990

  19. Fibrosarcoma after high energy radiation therapy for pituitary adenoma

    SciTech Connect

    Martin, W.H.; Cail, W.S.; Morris, J.L.; Constable, W.C.

    1980-11-01

    Pituitary sarcoma is a rare late complication of radiotherapy for pituitary tumors. Although early case reports involved multiple courses of relatively low-energy radiation therapy, pituitary sarcoma has been seen with single courses of high-energy x-ray or heavy particle radiotherapy. This report describes a fibrosarcoma of the pituitary occurring 5 years after 4,500 rad (45 Gy) of x-irradiation delivered in 20 treatments over 3 weeks by an 8 MeV linear accelerator.

  20. Electrochemical treatment of mouse and rat fibrosarcomas with direct current

    SciTech Connect

    Chou, C.K.; McDougall, J.A.; Ahn, C.; Vora, N.

    1997-03-01

    Electrochemical treatment (ECT) of cancer utilizes direct current to produce chemical changes in tumors. ECT has been suggested as an effective alternative local cancer therapy. However, a methodology is not established, and mechanisms are not well studied. In vivo studies were conducted to evaluate the effectiveness of ECT on animal tumor models. Radiation-induced fibrosarcomas were implanted subcutaneously in 157 female C3H/HeJ mice. Larger rat fibrosarcomas were implanted on 34 female Fisher 344 rats. When the spheroidal tumors reached 10 mm in the mice, two to five platinum electrodes were inserted into the tumors at various spacings and orientations. Ten rats in a pilot group were treated when their ellipsoidal tumors were about 25 mm long; electrode insertion was similar to the later part of the mouse study; i.e., two at the base and two at the center. A second group of 24 rats was treated with six or seven electrodes when their tumors were about 20 mm long; all electrodes were inserted at the tumor base. Of the 24 rats, 12 of these were treated once, 10 were treated twice, and 2 were treated thrice. All treated tumors showed necrosis and regression for both mice and rats; however, later tumor recurrence reduced long-term survival. When multiple treatments were implemented, the best 3 month mouse tumor cure rate was 59.3%, and the best 6 month rat tumor cure rate was 75.0%. These preliminary results indicate that ECT is effective on the radiation-induced fibrosarcoma (RIF-1) mouse tumor and rat fibrosarcoma. The effectiveness is dependent on electrode placement and dosage.

  1. Fibrosarcoma of the lung with extrapulmonary manifestations: case report.

    PubMed

    McLigeyo, S O; Mbui, J; Kungu, A; Amayo, E; Ogendo, S W

    1995-07-01

    A 50-year-old female presented with a five months history of recurrent attacks of dizziness, sweatiness, tremors and fainting with loss of consciousness. These were found to be due to hypoglycaemic episodes with blood sugars less than 1 mmol/l and were treated as such. A diagnosis of insulinoma was initially considered, but the patient turned out to have fibrosarcoma of the lung, a rare lung tumour. She also had finger and toe clubbing and features of hypertrophic pulmonary osteoarthropathy.

  2. Sclerosing epithelioid fibrosarcoma metastasizing to the penile shaft

    PubMed Central

    Bell, Michael D.; Brimo, Fadi; Jung, Sungmi; Aprikian, Armen G.

    2016-01-01

    We present the case of a 50-year-old man with a periurethral mass. He was previously known for sclerosing epithelioid fibrosarcoma (SEF) of the left foot, having an amputation for local recurrence with >2 cm negative margins. A solid periurethral mass was surgically excised seven months later, yielding the diagnosis of metastatic SEF. This is the first documented metastasis of SEF to the penis. These sarcomas have proven difficult to treat, with high recurrence rates despite a multimodal approach. PMID:28096927

  3. Fibrosarcoma arising from gouty tophi: report of a unique case and review of literature

    PubMed Central

    Wang, Jian-Jun; Wang, Hai-Yan; Cheng, Kai; Wang, Xuan; Yu, Bo; Shi, Shan-Shan; Zhou, Xiao-Jun; Shi, Qun-Li

    2015-01-01

    Fibrosarcoma is a malignant mesenchymal tumor. To the author’s best knowledge, no previous case of fibrosarcoma arising from gouty tophi has been reported. Here we reported the first case of fibrosarcoma arising from gouty tophi. A case of 58-year-old man was presented with a mass with ulcer and infection in the second joint of left middle finger for 2 months, with long standing gouty tophi. The tumor was biopsied and the biopsy showed complete excision of the tumor. With the pathological and immunohistochemical features considered, the diagnosis of fibrosarcoma associated with gouty tophi was made. The clinical findings, pathological characteristics and treatment were described. PMID:26097616

  4. Treatment of fibrosarcoma in a maned wolf (Chrysocyon brachyurus) by rostral maxillectomy.

    PubMed

    McNulty, E E; Gilson, S D; Houser, B S; Ouse, A

    2000-09-01

    A 12-yr-old captive intact male maned wolf (Chrysocyon brachyurus) was diagnosed with a fibrosarcoma of the incisive bones. The mass was excised by rostral maxillectomy, and the wolf remained normal and on display with good function and cosmetics for 7 mo. Subsequently, it became weak, ataxic, and dyspneic and was euthanatized. At necropsy, there was a small regrowth of the maxillary tumor, a metastatic mediastinal mass, and multiple metastatic lung masses, suggesting that oral fibrosarcoma in maned wolves behaves similarly to oral fibrosarcoma in domestic canines. Aggressive surgical treatment of oral fibrosarcoma in this species can achieve good functional and cosmetic results.

  5. Radiation-induced dural fibrosarcoma with unusually short latent period

    SciTech Connect

    Ghatak, N.R.; Aydin, F.; Leshner, R.T. Tulane Univ., New Orleans, LA )

    1993-05-01

    Although rare, the occurrence of radiation-induced intracranial neoplasms of various types is well known. Among these tumors, fibrosarcomas, especially in the region of seila turcica, seem to be the most common type. These tumors characteristically occur after a long latent period, usually several years, following radiation therapy. The authors now report a case of apparently radiation-induced fibrosarcoma with some unusual features in a 10-year-old boy who was treated with radiation for medulloblastoma. He received a total dose of 53.2 Gy radiation delivered at 1.8 per fraction with 6 MV acceleration using the standard craniospinal technique. An MRI at 15 months after the completion of radiotherapy showed a mass over the cerebral convexity, which increased two-fold in size within a period of 4 months. A well circumscribed tumor was removed from the fronto-parietal convexity. The tumor measured 5x4.5x1.5 cm and was attached to the dura with invasion of the overlying bone. Histologically, it displayed the characteristic features of a low-grade fibrosarcoma. The patient remains free of tumor 18 months after the surgery. This case emphasizes the potential risk for the development of a second neoplasm following therapeutic radiation and also documents, to the authors' knowledge, the shortest latent period reported so far between administration of radiotherapy and development of an intracranial tumor.

  6. Rare Undifferentiated Tumour of Thyroid: Primary Thyroid Fibrosarcoma

    PubMed Central

    Girgin, Sadullah; Göya, Cemil; Büyükbayram, Hüseyin; Urakçi, Zuhat

    2016-01-01

    Primary thyroid fibrosarcoma cases are very rare. Although it is a known fact that soft tissue sarcomas show slow growth, there have been some cases in literature similar to our case in which there was a fast-growing tumour tissue causing breathing and swallowing difficulties due to painless pressure. For diagnosis, there is no specific clinical or radiological finding. We report a 67-year-old male with a mobile fast-growing mass covering almost all over the neck that appeared 2 months prior to the admission. Laboratory findings showed that the patient was euthyroid. Fine needle aspiration biopsy results are consistent with suspicion of a mesenchymal, histiocytic, epithelial or lymphoid tissue origined malignancy. Patient was taken into surgical operation. The thyroid tissue invaded the main vascular structure, trachea and esophagus. Due to this situation R1 resection was applied. Immunohistopathological examination showed a conventional type of fibrosarcoma. After the surgery, radiotherapy and chemotherapy had been planned and applied. Patients died before the radiotherapy sessions ended. It should be kept in mind that a rapid growth in thyroid tissue can be thyroid fibrosarcoma, there could be a rapid clinical course and poor prognosis after operation. PMID:27504356

  7. Rare Undifferentiated Tumour of Thyroid: Primary Thyroid Fibrosarcoma.

    PubMed

    Bahadir, Mehmet Veysi; Girgin, Sadullah; Göya, Cemil; Büyükbayram, Hüseyin; Urakçi, Zuhat

    2016-06-01

    Primary thyroid fibrosarcoma cases are very rare. Although it is a known fact that soft tissue sarcomas show slow growth, there have been some cases in literature similar to our case in which there was a fast-growing tumour tissue causing breathing and swallowing difficulties due to painless pressure. For diagnosis, there is no specific clinical or radiological finding. We report a 67-year-old male with a mobile fast-growing mass covering almost all over the neck that appeared 2 months prior to the admission. Laboratory findings showed that the patient was euthyroid. Fine needle aspiration biopsy results are consistent with suspicion of a mesenchymal, histiocytic, epithelial or lymphoid tissue origined malignancy. Patient was taken into surgical operation. The thyroid tissue invaded the main vascular structure, trachea and esophagus. Due to this situation R1 resection was applied. Immunohistopathological examination showed a conventional type of fibrosarcoma. After the surgery, radiotherapy and chemotherapy had been planned and applied. Patients died before the radiotherapy sessions ended. It should be kept in mind that a rapid growth in thyroid tissue can be thyroid fibrosarcoma, there could be a rapid clinical course and poor prognosis after operation.

  8. Oncogenic human papillomaviruses.

    PubMed

    McBride, Alison A

    2017-10-19

    Human papillomaviruses (HPVs) are an ancient group of viruses with small, double-stranded DNA circular genomes. They are species-specific and have a strict tropism for mucosal and cutaneous stratified squamous epithelial surfaces of the host. A subset of these viruses has been demonstrated to be the causative agent of several human cancers. Here, we review the biology, natural history, evolution and cancer association of the oncogenic HPVs.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Authors.

  9. Oncogenic human papillomaviruses

    PubMed Central

    2017-01-01

    Human papillomaviruses (HPVs) are an ancient group of viruses with small, double-stranded DNA circular genomes. They are species-specific and have a strict tropism for mucosal and cutaneous stratified squamous epithelial surfaces of the host. A subset of these viruses has been demonstrated to be the causative agent of several human cancers. Here, we review the biology, natural history, evolution and cancer association of the oncogenic HPVs. This article is part of the themed issue ‘Human oncogenic viruses’. PMID:28893940

  10. Modified superficial musculoaponeurotic system face-lift: a review of 327 consecutive procedures and a patient satisfaction assessment.

    PubMed

    Castello, Manuel Francisco; Lazzeri, Davide; Silvestri, Alessandro; Agostini, Tommaso; Gigliotti, Diego; Marcelli, Claudio; D'Aniello, Carlo; Gasparotti, Marco

    2011-04-01

    A conventional superficial musculoaponeurotic system (SMAS) face-lift is well established because it allows the skin envelope to be rotated in a bit more lateral direction than the cephalad redirection of the SMAS flap. This ensures an individualization of the treatment plan according to the needs of the patient and avoids a postoperative stretched look. However, this technique has some limitations with respect to its long-term effects on the sagging tissue, inadequate lifting of the malar fat pad, and flattening of the nasolabial fold. The procedure described by the authors consisted of a modified approach to conventional SMAS flap dissection for 327 patients with facial aging signs undergoing a face-lift. A pointing tongue-shaped flap of zygomaticotemporal fascia was dissected and preserved in the posterior half of the upper edge of the SMAS flap and anchored to the deep temporal fascia, enhancing the vertical support of the facial soft tissues. Outcomes were determined by case notes, clinical review, and a questionnaire. The study investigated 327 consecutive modified SMAS face-lifting procedures. Few complications were observed. Only two patients experienced small hematomas needing evacuation. Some patients reported bearable pain in the temporal region and tension during mouth opening. Temporary weakness in the branches of the facial nerve experienced by two patients resolved completely within some months. Two patients presented with dehiscence of the scar, and one patient experienced punctual retroauricular skin necrosis, which healed uneventfully with conservative treatment. Two patients reported that the knot in the temporal region was palpable through the skin. One patient experienced retroauricular infection. Only two patients required additional procedures. One mild hypertrophic scar responding to steroid injection over the mastoid area was observed in the entire series. With the reported technique, the authors achieved pleasing, natural, durable results

  11. Long-term Analysis of Lip Augmentation With Superficial Musculoaponeurotic System (SMAS) Tissue Transfer Following Biplanar Extended SMAS Rhytidectomy.

    PubMed

    Richardson, Matthew Allen; Rousso, Daniel Elliott; Replogle, William H

    2017-01-01

    To our knowledge, long-term, objective results of lip augmentation using superficial musculoaponeurotic system (SMAS) tissue transfer beyond 1 year have not been previously described. To evaluate the efficacy, longevity, and safety of lip augmentation using SMAS tissue transfer. A retrospective single-blind cohort study was designed to evaluate all patients who underwent surgical lip augmentation using SMAS following rhytidectomy between January 1, 2000, and November, 16, 2015, at a private facial plastic surgery practice in Birmingham, Alabama. Preoperative photographs of each patient served as controls and were compared with postoperative photographs at 3 months, 1 year, and 5 years after lip augmentation. A total of 104 images (from 26 individual patients) were reviewed by 12 blinded observers using a validated lip augmentation grading scale. Lip augmentation using SMAS. Median lip volumes of all patients at each postoperative interval (3 months, 1 year, and 5 years) compared with preoperative lip volumes. Secondary outcome measures included postoperative complications. A total of 423 patients were identified who underwent surgical lip augmentation using SMAS. Sixty patients with approximately 5 years or more of postoperative photographs were reviewed for complications. Twenty-six patients had 3-month, 1-year, and 5-year postoperative follow-up photographs and were included in the photographic evaluation. The mean age of these patients at the time of surgery was 54.6 years (range, 41.2-80.6 years. Fifty-nine of the 60 patients (98.3%) were female. Two of 60 patients (3.3%) with 5 years or more of postoperative follow-up developed complications requiring intervention. Both the superior lip and the inferior lip showed statistically significant increases in volume at 3 months, 1 year, and 5 years (P ≤ .004 for the superior lip after 5 years; P ≤ .001 for all other comparisons) after SMAS lip augmentation. The greatest median increase was observed in the

  12. Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression

    PubMed Central

    Martinez-Pastor, Barbara; Ortega-Molina, Ana; Soria, Rebeca; Collado, Manuel; Fernandez-Capetillo, Oscar; Serrano, Manuel

    2009-01-01

    Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability. PMID:19421407

  13. Ameloblastic Fibrosarcoma of the Mandible With Distant Metastases.

    PubMed

    Pourdanesh, Fereydoun; Mohamadi, Mansoureh; Moshref, Mohammad; Soltaninia, Omid

    2015-10-01

    Ameloblastic fibrosarcoma is a mixed odontogenic tumor that can originate de novo or from a transformed ameloblastic fibroma. This report describes the case of a 34-year-old woman with a recurrent, rapidly growing, debilitating lesion. This lesion appeared as a large painful mandibular swelling that filled the oral cavity and extended to the infratemporal fossa. The lesion had been previously misdiagnosed as ameloblastoma. Twenty months after final surgery and postoperative chemotherapy, lung metastases were diagnosed after she reported respiratory signs and symptoms. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  14. Malignant transformation of ameloblastic fibro-odontoma to ameloblastic fibrosarcoma.

    PubMed

    Howell, R M; Burkes, E J

    1977-03-01

    Two cases of malignant transformation of ameloblastic fibro-odontomas are presented, along with a review of the literature on ameloblastic fibrosarcomas. The occurrence of this malignant transformation of ameloblastic fibromas, ameloblastic odontomas, and ameloblastic fibro-odontomas appears to be more frequent than previously thought. This potential transformation alone does not justify radical treatment of all these benign lesions. If there is recurrence accompanied by a histologic pattern change toward a more unorganized fibrous stroma with displacement of the epithelial component, however, then more extensive treatment procedures appear to be indicated.

  15. Endocardial fibrosarcoma in a reticulated python (Python reticularis).

    PubMed

    Gumber, Sanjeev; Nevarez, Javier G; Cho, Doo-Youn

    2010-11-01

    A female, reticulated python (Python reticularis) of unknown age was presented with a history of lethargy, weakness, and distended coelom. Physical examination revealed severe dystocia and stomatitis. The reticulated python was euthanized due to a poor clinical prognosis. Postmortem examination revealed marked distention of the reproductive tract with 26 eggs (10-12 cm in diameter), pericardial effusion, and a slightly firm, pale tan mass (3-4 cm in diameter) adhered to the endocardium at the base of aorta. Based on histopathologic and transmission electron microscopic findings, the diagnosis of endocardial fibrosarcoma was made.

  16. Oncogenes in retroviruses and cells

    NASA Astrophysics Data System (ADS)

    Kurth, Reinhard

    1983-09-01

    Oncogenes are genes that cause cancer. Retroviruses contain oncogenes and cause cancer in animals and, perhaps, in man. The viruses have appropriated their oncogenes from normal cellular DNA by genetic recombination. Correspondingly, uninfected vertebrate cells contain a family of evolutionary conserved cellular oncogenes. Retrovirus infection, introducing additional viral oncogenes into the cells, as well as carcinogen-mediated activation of cellular oncogenes may both lead to increased synthesis of oncogene encoded transforming proteins which convert normal cells to tumor cells. Unique retroviruses of human origin have recently been identified. They may, on occasion, directly cause tumors in man. However, the general significance of retroviruses may better be illustrated by their remarkable genetic composition which allows them to promote tumor growth by a variety of genetic mechanisms.

  17. The human oncogenic viruses

    SciTech Connect

    Luderer, A.A.; Weetall, H.H

    1986-01-01

    This book contains eight selections. The titles are: Cytogenetics of the Leukemias and Lymphomas; Cytogenetics of Solid Tumors: Renal Cell Carcinoma, Malignant Melanoma, Retinoblastoma, and Wilms' Tumor; Elucidation of a Normal Function for a Human Proto-Oncogene; Detection of HSV-2 Genes and Gene Products in Cervical Neoplasia; Papillomaviruses in Anogennital Neoplasms; Human Epstein-Barr Virus and Cancer; Hepatitis B Virus and Hepatocellular Carcinoma; and Kaposi's Sarcoma: Acquired Immunodeficiency Syndrome (AIDS) and Associated Viruses.

  18. Low-grade fibrosarcoma of the proximal humerus.

    PubMed

    Saito, Tsuyoshi; Oda, Yoshinao; Tanaka, Kazuhiro; Matsuda, Shuichi; Sakamoto, Akio; Yamamoto, Hidetaka; Iwamoto, Yukihide; Tsuneyoshi, Masazumi

    2003-02-01

    We present the clinical, radiographical and pathological features of low-grade fibrosarcoma of the left proximal humerus in a 23-year-old man in whom it was necessary to distinguish the tumor from desmoplastic fibroma, malignant fibrous histiocytoma and intramedullary well-differentiated osteosarcoma. The patient presented with a 10-day history of pain in his left upper arm sustained when trying to break his fall with his left hand when slipping in the street. Plain radiography revealed an expanding multilobular osteolytic lesion from the proximal metaphysis to the diaphysis of his left humerus, accompanied by a pathological fracture at the distal portion of the lesion. Open biopsy of the lesion was performed twice; however, a conclusive diagnosis could not be obtained. The patient underwent wide excision and prosthetic replacement of the left proximal humerus. Histologically, the resected tumor was composed of both cellular areas and hypocellular areas. Cellular areas revealed a proliferation of bundles of uniform fibroblastic spindle-shaped cells with minimal cellular atypia, mixed with abundant intercellular collagenization. Mitotic figures were occasionally seen. Hypocellular areas showed myxoid features with loose bundles of collagen fibers. The patient demonstrates no evidence of disease 42 months after surgery. It is important to detect the scant atypical cells for the differential diagnosis of low-grade fibrosarcoma and desmoplastic fibroma of bone.

  19. Radiosensitization of two murine fibrosarcomas with 6-thioguanine.

    PubMed

    Kim, J H; Alfieri, A A; Kim, S H; Hong, S S

    1990-03-01

    In Vivo murine tumor experiments were carried out to determine whether 6-thioguanine (6-TG) could enhance the cytotoxic effects of radiation on tumors. The combined effects of single and fractionated x-irradiation were evaluated on the transplanted methylcholanthrene induced fibrosarcoma (Meth-A) in BALB/c mice, a moderately radioresponsive tumor and on the radiation induced fibrosarcoma (RIF) in C3H/He mice, a highly radioresistant tumor. The combined treatment of single administration of 6-TG (25 mg/kg) and of x-irradiation (20 Gy) on Meth-A tumors produced more than 90% tumor control, whereas the radiation alone resulted in less than 5% tumor control. The radiosensitizing effect by 6-TG was higher when the drug was administered either 1 to 8 hr prior to or 24 hr after x-irradiation. The dose modification factor of single dose 6-TG (10 mg/kg) is estimated to be 1.47 for Meth-A tumor and 1.25 for RIF tumor. The tumor control rates of fractionated irradiation alone and with concomitant 6-TG in Meth-A tumors were 14% and 59%, respectively. Based on the studies reported here and well documented pharmacokinetics in humans, it is suggested that combined radiation therapy and 6-TG may provide an enhanced therapeutic effect even in tumor varieties where the drug has no apparent anti-tumor activity on non-irradiated cells.

  20. Treatment of a maxillary fibrosarcoma in an adult alpaca.

    PubMed

    Higginbotham, Mary Lynn; McCaw, Dudley L; Anderson, David E; Lattimer, Jimmy C; Armbrust, Laura; Andrews, Gordon A; McBride, Brandon D

    2015-03-15

    An approximately 5-year-old sexually intact male alpaca was evaluated because of a right-sided maxillary mass that had recurred after previous surgical debulking. Clinical, radiographic, and CT examination revealed an approximately 1.5-cm-diameter soft tissue mass associated with expansile osteolysis of the maxillary alveolar bone, beginning at the level of the right maxillary third premolar tooth extending caudally to the level of the rostral roots of the second molar tooth. Right partial maxillectomy was performed, and histologic examination revealed an incompletely excised fibrosarcoma with osseous metaplasia. External beam radiation therapy to the tumor bed was initiated 1 month after surgery. Computerized planning was performed, and a total radiation dose of 48 Gy was prescribed in eleven 4.4-Gy fractions. Follow-up CT evaluations 6 and 58 weeks after radiation therapy was completed revealed no evidence of tumor recurrence. No clinical evidence of tumor recurrence was detected through 110 weeks after radiation therapy. The oral fibrosarcoma in the alpaca described here was successfully treated with surgical excision and adjuvant radiation therapy, resulting in excellent quality of life of the treated animal.

  1. Infantile fibrosarcoma of ethmoid sinus, misdiagnosed as an adenoid in a 5-year-old child

    PubMed Central

    Geramizadeh, Bita; Khademi, Bijan; Karimi, Mehran; Shekarkhar, Golsa

    2015-01-01

    Infantile fibrosarcoma of head and neck is rare and the presence of this tumor in ethmoid sinus is even more uncommon. To the best of our knowledge, <5 cases have been reported in the last 20 years in the English literature, so far, only one of which has been infantile type in a 15 months old girl. In this case report, we will explain our experience with a rare case of infantile fibrosarcoma originating from ethmoid sinus in a 5-year-old boy who presented with dyspnea and epistaxis. After biopsy, it was diagnosed as fibrosarcoma of sinus origin. PMID:26604519

  2. Analysis of chromosomal aberrations involving chromosome 1q31-->q53 in a DMBA-induced rat fibrosarcoma cell line: amplification and overexpression of Jak2.

    PubMed

    Sjöling, A; Lindholm, H; Samuelson, E; Yamasaki, Y; Watanabe, T K; Tanigami, A; Levan, G

    2001-01-01

    In a study of DMBA-induced rat fibrosarcomas we repeatedly found deletions and/or amplifications in the long arm of rat chromosome 1 (RNO1). Comparative genome hybridization showed that there was amplification involving RNO1q31-->q53 in one of the DMBA-induced rat fibrosarcoma tumors (LB31) and a cell culture derived from it. To identify the amplified genes we physically mapped rat genes implicated in cancer and analyzed them for signs of amplification. The genes were selected based on their locations in comparative maps between rat and man. The rat proto-oncogenes Ccnd1, Fgf4, and Fgf3 (HSA11q13.3), were mapped to RNO1q43 by fluorescence in situ hybridization (FISH). The Ems1 gene was mapped by radiation hybrid (RH) mapping to the same rat chromosome region and shown to be situated centromeric to Ccnd1 and Fgf4. In addition, the proto-oncogenes Hras (HSA11p15.5) and Igf1r (HSA15q25-->q26) were mapped to RNO1q43 and RNO1q32 by FISH and Omp (HSA11q13.5) was assigned to RNO1q34. PCR probes for the above genes together with PCR probes for the previously mapped rat genes Bax (RNO1q31) and Jak2 (RNO1q51-->q53) were analyzed for signs of amplification by Southern blot hybridization. Low copy number increases of the Omp and Jak2 genes were detected in the LB31 cell culture. Dual color FISH analysis of tumor cells confirmed that chromosome regions containing Omp and Jak2 were amplified and were situated in long marker chromosomes showing an aberrant banding pattern. The configuration of the signals in the marker chromosomes suggested that they had arisen by a break-fusion-bridge (BFB) mechanism. Copyright 2002 S. Karger AG, Basel

  3. Retroviral Oncogenes: A Historical Primer

    PubMed Central

    Vogt, Peter K.

    2012-01-01

    Retroviruses are the original source of oncogenes. The discovery and characterization of these genes were made possible by the introduction of quantitative cell biological and molecular techniques for the study of tumor viruses. Key features of all retroviral oncogenes were first identified in src, the oncogene of Rous sarcoma virus. These include non-involvement in viral replication, coding for a single protein, and cellular origin. The myc, ras and erbB oncogenes quickly followed src, and these together with pi3k are now recognized as critical driving forces in human cancer. PMID:22898541

  4. Recurrent fusion oncogenes in carcinomas.

    PubMed

    Teixeira, Manuel R

    2006-12-01

    Chromosome structural aberrations giving rise to fusion oncogenes is one of the most common mechanisms in oncogenesis. Although this type of gene rearrangement has long been recognized as a fundamental pathogenetic mechanism in hematologi-cal malignancies and soft-tissue tumors, it has until recently only rarely been described in the common carcinomas. In this review, the existing information on recurrent fusion oncogenes characterizing carcinomas is summarized, namely, the RET and NTRK1 fusion oncogenes in papillary thyroid carcinoma, PAX8-PPARG in follicular thyroid carcinoma, MECT1-MAML2 in mucoepidermoid carcinoma, the TFE3 and TFEB fusion oncogenes in kidney carcinomas, BRD4-NUT in midline carcinomas, ETV6-NTRK3 in secretory breast carcinomas, and TMPRSS2-ETS fusion oncogenes in prostate carcinomas. As in hematological and soft-tissue malignancies, the most common types of genes involved in fusion oncogenes in carcinomas are transcription factors and tyrosine kinases. With a few exceptions, most fusion oncogenes are tumor type specific in carcinomas, as in other cancers. The mechanisms behind the relative specificity of this type of somatic mutation involve the cellular environment influencing the selection of oncogenic fusions, and the oncogenic fusions in turn driving differentiation programs that may alter the cellular environment. The data summarized on different types of carcinomas characterized by fusion oncogenes indicate that the pathogenetic mechanisms involved in epithelial carcino-genesis may be similar to those known to operate in hematological and soft-tissue malignancies, and further anticipates that many more fusion oncogenes await identification in the most common types of human cancer.

  5. Spontaneous generation of germline characteristics in mouse fibrosarcoma cells

    NASA Astrophysics Data System (ADS)

    Ma, Zhan; Hu, Yao; Jiang, Guoying; Hou, Jun; Liu, Ruilai; Lu, Yuan; Liu, Chunfang

    2012-10-01

    Germline/embryonic-specific genes have been found to be activated in somatic tumors. In this study, we further showed that cells functioning as germline could be present in mouse fibrosarcoma cells (L929 cell line). Early germline-like cells spontaneously appeared in L929 cells and further differentiated into oocyte-like cells. These germline-like cells can, in turn, develop into blastocyst-like structures in vitro and cause teratocarcinomas in vivo, which is consistent with natural germ cells in function. Generation of germline-like cells from somatic tumors might provide a novel way to understand why somatic cancer cells have strong features of embryonic/germline development. It is thought that the germline traits of tumors are associated with the central characteristics of malignancy, such as immortalization, invasion, migration and immune evasion. Therefore, germline-like cells in tumors might provide potential targets to tumor biology, diagnosis and therapy.

  6. A delayed presentation of ameloblastic fibrosarcoma in an African patient.

    PubMed

    Chauke, Nkhensani Yvonne; Sofianos, Chrysis; Liakos, Dimitri; Ndobe, Elias

    2017-08-01

    A 24-year-old womanpresented with ameloblastic fibrosarcoma arising from ameloblastic fibroma. The delayed presentation accounted for the extensive destruction of the mandible and complete occlusion of her oral cavity. This resulted in an inability to eat and maintain oral hygiene. A multidisciplinary team management approach involved nutritional optimisation, segmental mandibulectomy, reconstruction with a reconstructive plate and a free anterolateral thigh flap to line the the floor of mouth. Functional and aesthetic outcome was acceptable, and the patient is planned for secondary free fibular flap bony reconstruction. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  7. Ameloblastic fibroma or fibrosarcoma: A dilemma of oral surgeon.

    PubMed

    Verma, Nitin; Neha

    2016-01-01

    Ameloblastic fibroma (AF) is an uncommon true mixed odontogenic tumor, with a relative frequency between 1.5% and 4.5% of all odontogenic tumors. It may behave either as a true neoplasm or as a hamartomatous proliferation of odontogenic epithelium of the enamel organ and odontogenic mesenchyme of the primitive dental pulp. Frequently diagnosed between the first and second decades of life with 75% of cases was diagnosed before the age of 20 and present with a well-defined unilocular or multilocular radiolucencies. A conservative approach, enucleation with curettage, and long-term follow-up are absolutely necessary for any recurrence or change to fibrosarcoma. We report a case of AF in a 10-year-old male patient who presented with a chief complaint of swelling in the right mandibular posterior region. Enucleation and curettage were done under general anesthesia, followed by immunohistochemical markers (Ki-67, Mib-1) to assess the sarcomatous changes and aggressiveness of the tumor.

  8. Spontaneous generation of germline characteristics in mouse fibrosarcoma cells.

    PubMed

    Ma, Zhan; Hu, Yao; Jiang, Guoying; Hou, Jun; Liu, Ruilai; Lu, Yuan; Liu, Chunfang

    2012-01-01

    Germline/embryonic-specific genes have been found to be activated in somatic tumors. In this study, we further showed that cells functioning as germline could be present in mouse fibrosarcoma cells (L929 cell line). Early germline-like cells spontaneously appeared in L929 cells and further differentiated into oocyte-like cells. These germline-like cells can, in turn, develop into blastocyst-like structures in vitro and cause teratocarcinomas in vivo, which is consistent with natural germ cells in function. Generation of germline-like cells from somatic tumors might provide a novel way to understand why somatic cancer cells have strong features of embryonic/germline development. It is thought that the germline traits of tumors are associated with the central characteristics of malignancy, such as immortalization, invasion, migration and immune evasion. Therefore, germline-like cells in tumors might provide potential targets to tumor biology, diagnosis and therapy.

  9. Malignant transformation of ameloblastic fibroma to ameloblastic fibrosarcoma: case report and review of the literature.

    PubMed

    Kobayashi, Kazuo; Murakami, Ryuichi; Fujii, Tohru; Hirano, Akiyoshi

    2005-10-01

    Ameloblastic fibrosarcoma is a rare malignant odontogenic tumour and is regarded as the malignant counterpart of the ameloblastic fibroma. The epithelial component remains benign, but the mesenchymal component becomes malignant. The diagnosis is made by histopathology. The case of a 26-year-old man who underwent curettage of an ameloblastic fibroma and died of an ameloblastic fibrosarcoma is presented, and the course of malignant transformation is analysed retrospectively. One-third of ameloblastic fibrosarcoma cases seem to have developed from recurrent ameloblastic fibromas. Knowledge of the malignant potential in the mesenchymal spindle cells of ameloblastic fibroma will assist in determining the management of these benign tumours, and may prevent malignant transformation to ameloblastic fibrosarcoma.

  10. Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells.

    PubMed

    Harati, Kamran; Slodnik, Pawel; Chromik, Ansgar Michael; Goertz, Ole; Hirsch, Tobias; Kapalschinski, Nikolai; Klein-Hitpass, Ludger; Kolbenschlag, Jonas; Uhl, Waldemar; Lehnhardt, Marcus; Daigeler, Adrien

    2015-02-01

    Metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin have been proven effective in fewer than 30% of all cases disseminated of fibrosarcoma. Elderly patients with cardiac disease are not suitable for systemic chemotherapy with doxorubicin. We therefore tested the apoptotic effects of the natural and well-tolerated compound resveratrol on human fibrosarcoma cells (HT1080). Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarrays. Application of resveratrol induced apoptotic cell death and significantly reduced proliferation of HT1080 cells. Correspondingly, expression of apoptosis-associated genes was altered in microarray analysis. This in vitro study demonstrates the anticancer activity of resveratrol against human fibrosarcoma cells. These results provide experimental support for in vivo trials assessing the effect of the natural polyphenol resveratrol. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Sclerosing epithelioid fibrosarcoma of the cecum: a radiation-associated tumor in a previously unreported site.

    PubMed

    Frattini, Jared C; Sosa, Julie Ann; Carmack, Susanne; Robert, Marie E

    2007-12-01

    Data from the nuclear reactor explosion in Chernobyl and the atomic bomb detonations in Hiroshima and Nagasaki demonstrated an association between ionizing radiation and tumoriogenesis. There is a significant association between external beam radiation and radiation-induced sarcoma. Sclerosing epithelioid fibrosarcoma is a rare form of malignant fibrosarcoma that is low grade and indolent with distinct immunohistopathologic characteristics that usually occurs in the soft tissues of the extremities. A 62-year-old man from Kiev who aided in the cleanup at Chernobyl presented with crampy abdominal pain, nausea, and vomiting. His workup revealed a cecal mass, and the final pathology from his laparotomy confirmed sclerosing epithelioid fibrosarcoma with metastasis to the liver. In addition to a review of the literature, we report the first case of sclerosing epithelioid fibrosarcoma arising from the large bowel. Exposure to ionizing radiation from Chernobyl could have played a role in the development of his tumor.

  12. Oncogenes in melanoma: an update.

    PubMed

    Kunz, Manfred

    2014-01-01

    Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future.

  13. Chemotherapeutic Efficacy of Indigofera aspalathoides on 20-Methylcholanthrene-Induced Fibrosarcoma in Rats

    PubMed Central

    Sivagnanam, Selva Kumar; Rao, Mudiganti Ram Krishna; Balasubramanian, Maruthaiveeran Periyasamy

    2012-01-01

    The present study was undertaken to test the chemopreventive effects of one herbal medicinal plant, Indigofera aspalathoides, on chemically induced carcinogenesis in rats. A well-known polyaromatic hydrocarbon, namely, 20-methylcholanthrene, which is a known carcinogenic substance, was used to induce fibrosarcoma in Wistar strain of male albino rats. Fibrosarcoma rats were treated with aqueous extracts of Indigofera aspalathoides. The rats were divided into four groups, each consisting of six animals. Group I served as normal control, Group II served as fibrosarcoma-induced animals, Group III were fibrosarcoma-bearing animals treated with aqueous extracts of Indigofera aspalathoides, and Group IV animals, which were normal healthy animals treated with Indigofera aspalathoides aqueous extract, served as drug control set. Group III and Group IV animals were treated with aqueous extract of Indigofera aspalathoides intraperitoneally at a dose of 250 mg/kg. b.w. for 30 days. The fibrosarcoma was proved by pathological examinations. The activity levels of nucleic acids such as total DNA and RNA and hexose, hexosamine, and sialic acid in liver and kidney of treated rats were used to monitor the chemopreventive role of the plant extract. The observed increase in the levels of DNA, RNA, hexose, hexosamine, and sialic acid in liver and kidney tissues of fibrosarcoma-bearing animals reached near normal state after the treatment with aqueous extracts of Indigofera aspalathoides, suggesting that Indigofera aspalathoides does have a chemotherapeutic role. PMID:22530134

  14. Identification of ALV-J associated acutely transforming virus Fu-J carrying complete v-fps oncogene.

    PubMed

    Wang, Yixin; Li, Jianliang; Li, Yang; Fang, Lichun; Sun, Xiaolong; Chang, Shuang; Zhao, Peng; Cui, Zhizhong

    2016-06-01

    Transduction of oncogenes by ALVs and generation of acute transforming viruses is common in natural viral infections. In order to understand the molecular basis for the rapid oncogenicity of Fu-J, an acutely transforming avian leukosis virus isolated from fibrosarcomas in crossbreed broilers infected with subgroup J avian leukosis virus (ALV-J) in China, complete genomic structure of Fu-J virus was determined by PCR amplification and compared with those of Fu-J1, Fu-J2, Fu-J3, Fu-J4, and Fu-J5 reported previously. The results showed that the genome of Fu-J was defective, with parts of gag gene replaced by the complete v-fps oncogene and encoded a 137 kDa Gag-fps fusion protein. Sequence analysis revealed that Fu-J and Fu-J1 to Fu-J5 were related quasi-species variants carrying different lengths of v-fps oncogenes generated from recombination between helper virus and c-fps gene. Comparison of virus carrying v-fps oncogene also gave us a glimpse of the molecular characterization and evolution process of the acutely transforming ALV.

  15. Role of Phosphoinositide 3-Kinase in the Aggressive Tumor Growth of HT1080 Human Fibrosarcoma Cells

    PubMed Central

    Gupta, Swati; Stuffrein, Selma; Plattner, Rina; Tencati, Michael; Gray, Christa; Whang, Young E.; Stanbridge, Eric J.

    2001-01-01

    We have developed a model system of human fibrosarcoma cell lines that do or do not possess and express an oncogenic mutant allele of N-ras. HT1080 cells contain an endogenous mutant allele of N-ras, whereas the derivative MCH603 cell line contains only wild-type N-ras. In an earlier study (S. Gupta et al., Mol. Cell. Biol. 20:9294–9306, 2000), we had shown that HT1080 cells produce rapidly growing, aggressive tumors in athymic nude mice, whereas MCH603 cells produced more slowly growing tumors and was termed weakly tumorigenic. An extensive analysis of the Ras signaling pathways (Raf, Rac1, and RhoA) provided evidence for a potential novel pathway that was critical for the aggressive tumorigenic phenotype and could be activated by elevated levels of constitutively active MEK. In this study we examined the role of phosphoinositide 3-kinase (PI 3-kinase) in the regulation of the transformed and aggressive tumorigenic phenotypes expressed in HT1080 cells. Both HT1080 (mutant N-ras) and MCH603 (wild-type N-ras) have similar levels of constitutively active Akt, a downstream target of activated PI 3-kinase. We find that both cell lines constitutively express platelet-derived growth factor (PDGF) and PDGF receptors. Transfection with tumor suppressor PTEN cDNA into HT1080 and constitutively active PI 3-kinase–CAAX cDNA into MCH603 cells, respectively, resulted in several interesting and novel observations. Activation of the PI 3-kinase/Akt pathway, including NF-κB, is not required for the aggressive tumorigenic phenotype in HT1080 cells. Activation of NF-κB is complex: in MCH603 cells it is mediated by Akt, whereas in HT1080 cells activation also involves other pathway(s) that are activated by mutant Ras. A threshold level of activation of PI 3-kinase is required in MCH603 cells before stimulatory cross talk to the RhoA, Rac1, and Raf pathways occurs, without a corresponding activation of Ras. The increased levels of activation seen were similar to those observed

  16. Role of phosphoinositide 3-kinase in the aggressive tumor growth of HT1080 human fibrosarcoma cells.

    PubMed

    Gupta, S; Stuffrein, S; Plattner, R; Tencati, M; Gray, C; Whang, Y E; Stanbridge, E J

    2001-09-01

    We have developed a model system of human fibrosarcoma cell lines that do or do not possess and express an oncogenic mutant allele of N-ras. HT1080 cells contain an endogenous mutant allele of N-ras, whereas the derivative MCH603 cell line contains only wild-type N-ras. In an earlier study (S. Gupta et al., Mol. Cell. Biol. 20:9294-9306, 2000), we had shown that HT1080 cells produce rapidly growing, aggressive tumors in athymic nude mice, whereas MCH603 cells produced more slowly growing tumors and was termed weakly tumorigenic. An extensive analysis of the Ras signaling pathways (Raf, Rac1, and RhoA) provided evidence for a potential novel pathway that was critical for the aggressive tumorigenic phenotype and could be activated by elevated levels of constitutively active MEK. In this study we examined the role of phosphoinositide 3-kinase (PI 3-kinase) in the regulation of the transformed and aggressive tumorigenic phenotypes expressed in HT1080 cells. Both HT1080 (mutant N-ras) and MCH603 (wild-type N-ras) have similar levels of constitutively active Akt, a downstream target of activated PI 3-kinase. We find that both cell lines constitutively express platelet-derived growth factor (PDGF) and PDGF receptors. Transfection with tumor suppressor PTEN cDNA into HT1080 and constitutively active PI 3-kinase-CAAX cDNA into MCH603 cells, respectively, resulted in several interesting and novel observations. Activation of the PI 3-kinase/Akt pathway, including NF-kappaB, is not required for the aggressive tumorigenic phenotype in HT1080 cells. Activation of NF-kappaB is complex: in MCH603 cells it is mediated by Akt, whereas in HT1080 cells activation also involves other pathway(s) that are activated by mutant Ras. A threshold level of activation of PI 3-kinase is required in MCH603 cells before stimulatory cross talk to the RhoA, Rac1, and Raf pathways occurs, without a corresponding activation of Ras. The increased levels of activation seen were similar to those observed

  17. Antiproliferative role of Indigofera aspalathoides on 20 methylcholanthrene induced fibrosarcoma in rats

    PubMed Central

    Kumar, Sivagnanam Selva; Rao, Mudiganti Ram Krishna; Balasubramanian, Maruthaiveeran Periyasamy

    2012-01-01

    Objective To find out the anticancer effect of Indigofera aspalathoides (I. aspalathoides) on 20-methylcholanthrene induced fibrosarcoma in rats. Methods Fibrosarcoma was induced in Wistar strain male albino rats by 20-methylcholanthrene. Intraperitoneous (i.p.) administration of 250 mg/kg body weight/day of aqueous extract of I. aspalathoides for 30 d effectively suppressed chemically induced tumors. Parameters such as body weight, liver and kidney weight, tumor weight, mean survival time, behavioral changes, blood glucose, blood glycogen and marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), acid phosphatase (ACP) and 5′-nucleiotidase (5′-NT) in serum, liver and kidney and lipid profiles such as total cholesterol, phospholipids, free fatty acids in liver and kidney of control and experimental animals were studied. Results Fibrosarcoma bearing animals were ferocious and anxious. The mean survival time was found to increase after the treatment. The body weights were significantly decreased (P<0.001) in group II fibrosarcoma animals which steadily increased after the treatment with I. aspalathoides. The liver and kidney weights were significantly increased whereas the tumor weights decreased as compared to the weights in untreated fibrosarcoma bearing rats. The blood glucose and the liver and kidney glycogen levels were found to decrease significantly (P<0.001) in group II animals. Elevated activities of marker enzymes were observed in serum, liver and kidney of fibrosarcoma bearing Group II animals which were normalize after I. aspalathoides treatment. In the liver and kidney of Group II animals the total cholesterol increased whereas the phospholipids and free fatty acid levels decreased (P<0.001) which were normalized after treatment. Conclusions The treatment by I. aspalathoides on fibrosarcoma bearing rats has improved the levels of various parameters indicating its antiproliferative and

  18. Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin.

    PubMed

    Bao, Q; Niess, H; Djafarzadeh, R; Zhao, Y; Schwarz, B; Angele, M K; Jauch, K-W; Nelson, P J; Bruns, C J

    2014-09-01

    Fibrosarcomas show a high incidence of recurrence and general resistance to apoptosis. Limiting tumor regrowth and increasing their sensitivity to chemotherapy and apoptosis represent key issues in developing more effective treatments of these tumors. Tissue inhibitor of metalloproteinase 1 (TIMP-1) broadly blocks matrix metalloproteinase (MMP) activity and can moderate tumor growth and metastasis. We previously described generation of a recombinant fusion protein linking TIMP-1 to glycosylphophatidylinositol (GPI) anchor (TIMP-1-GPI) that efficiently directs the inhibitor to cell surfaces. In the present report, we examined the effect of TIMP-1-GPI treatment on fibrosarcoma biology. Exogenously applied TIMP-1-GPI efficiently incorporated into surface membranes of human HT1080 fibrosarcoma cells. It inhibited their proliferation, migration, suppressed cancer cell clone formation, and enhanced apoptosis. Doxorubicin, the standard chemotherapeutic drug for fibrosarcoma, was tested alone or in combination with TIMP-1-GPI. In parallel, the influence of treatment on HT1080 side population cells (exhibiting tumor stem cell-like characteristics) was investigated using Hoechst 33342 staining. The sequential combination of TIMP-1-GPI and doxorubicin showed more than additive effects on apoptosis, while TIMP-1-GPI treatment alone effectively decreased "stem-cell like" side population cells of HT1080. TIMP-1-GPI treatment was validated using HT1080 fibrosarcoma murine xenografts. Growing tumors treated with repeated local injections of TIMP-1-GPI showed dramatically inhibited fibrosarcoma growth and reduced angiogenesis. Intraoperative peritumoral application of GPI-anchored TIMP-1 as an adjuvant to surgery may help maintain tumor control by targeting microscopic residual fibrosarcoma cells and increasing their sensitivity to chemotherapy.

  19. Analysis of Multiple Sarcoma Expression Datasets: Implications for Classification, Oncogenic Pathway Activation and Chemotherapy Resistance

    PubMed Central

    Goldsmith, Jeffrey D.; Bhasin, Manoj; Pillay, Kamana; Francoeur, Nancy; Libermann, Towia A.; Gebhardt, Mark C.; Spentzos, Dimitrios

    2010-01-01

    Background Diagnosis of soft tissue sarcomas (STS) is challenging. Many remain unclassified (not-otherwise-specified, NOS) or grouped in controversial categories such as malignant fibrous histiocytoma (MFH), with unclear therapeutic value. We analyzed several independent microarray datasets, to identify a predictor, use it to classify unclassifiable sarcomas, and assess oncogenic pathway activation and chemotherapy response. Methodology/Principal Findings We analyzed 5 independent datasets (325 tumor arrays). We developed and validated a predictor, which was used to reclassify MFH and NOS sarcomas. The molecular “match” between MFH and their predicted subtypes was assessed using genome-wide hierarchical clustering and Subclass-Mapping. Findings were validated in 15 paraffin samples profiled on the DASL platform. Bayesian models of oncogenic pathway activation and chemotherapy response were applied to individual STS samples. A 170-gene predictor was developed and independently validated (80-85% accuracy in all datasets). Most MFH and NOS tumors were reclassified as leiomyosarcomas, liposarcomas and fibrosarcomas. “Molecular match” between MFH and their predicted STS subtypes was confirmed both within and across datasets. This classification revealed previously unrecognized tissue differentiation lines (adipocyte, fibroblastic, smooth-muscle) and was reproduced in paraffin specimens. Different sarcoma subtypes demonstrated distinct oncogenic pathway activation patterns, and reclassified MFH tumors shared oncogenic pathway activation patterns with their predicted subtypes. These patterns were associated with predicted resistance to chemotherapeutic agents commonly used in sarcomas. Conclusions/Significance STS profiling can aid in diagnosis through a predictor tracking distinct tissue differentiation in unclassified tumors, and in therapeutic management via oncogenic pathway activation and chemotherapy response assessment. PMID:20368975

  20. Ameloblastic fibroma or fibrosarcoma: A dilemma of oral surgeon

    PubMed Central

    Verma, Nitin; Neha

    2016-01-01

    Ameloblastic fibroma (AF) is an uncommon true mixed odontogenic tumor, with a relative frequency between 1.5% and 4.5% of all odontogenic tumors. It may behave either as a true neoplasm or as a hamartomatous proliferation of odontogenic epithelium of the enamel organ and odontogenic mesenchyme of the primitive dental pulp. Frequently diagnosed between the first and second decades of life with 75% of cases was diagnosed before the age of 20 and present with a well-defined unilocular or multilocular radiolucencies. A conservative approach, enucleation with curettage, and long-term follow-up are absolutely necessary for any recurrence or change to fibrosarcoma. We report a case of AF in a 10-year-old male patient who presented with a chief complaint of swelling in the right mandibular posterior region. Enucleation and curettage were done under general anesthesia, followed by immunohistochemical markers (Ki-67, Mib-1) to assess the sarcomatous changes and aggressiveness of the tumor. PMID:28356692

  1. Ameloblastic fibroma and ameloblastic fibrosarcoma: A systematic review.

    PubMed

    Chrcanovic, Bruno Ramos; Brennan, Peter A; Rahimi, Siavash; Gomez, Ricardo Santiago

    2017-08-04

    To integrate the available data published to date on ameloblastic fibromas (AF) and ameloblastic fibrosarcomas (AFS) into a comprehensive analysis of their clinical/radiological features. An electronic search was undertaken in July 2017. Eligibility criteria included publications having enough clinical, radiological and histological information to confirm a definite diagnosis. A total of 244 publications (279 central AF tumours, 10 peripheral AF, 103 AFS) were included. AF and AFS differed significantly with regard to the occurrence of patients' mean age, bone expansion, cortical bone perforation and lesion size. Recurrence rates were as follows: central AF (19.2%), peripheral AF (12.5%), AFS (all lesions, 35%), primary (de novo) AFS (28.8%) and secondary AFS (occurring after an AF, 50%). Larger lesions and older patients were more often treated by surgical resections for central AF. Segmental resection resulted in the lowest rate of recurrence for most of the lesion types. AFS treated by segmental resection had a 70.5% lower probability to recur (OR 0.295; P = .049) than marginal resection; 21.3% of the AFS patients died due to complications related to the lesion. Very long follow-up is recommended for AF lesions, due to the risk of recurrence and malignant change into AFS. Segmental resection is the most recommended therapy for AFS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Congenital Fibrosarcoma and History of Prenatal Exposure to Petroleum Derivatives

    PubMed Central

    Soldin, Offie P.; López-Hernández, Fernando A.; Trasande, Leonardo; Ferrís-Tortajada, Josep

    2012-01-01

    Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame–an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy. PMID:22945410

  3. [Functional regulation of endothelial Myosin light chain kinase in extravascular migration of fibrosarcoma cells].

    PubMed

    Xin, Hua; Han, Zhen-guo

    2009-03-01

    To evaluate the functional regulation of endothelial Myosin light chain kinase (MLCK) in extravascular migration of fibrosarcoma HT1080 cells. An in vitro model of fibrosarcoma cell transmigration across a monolayer of HUVEC cultured on collagen gel was applied to observe extravascular migration of HT1080 cells,and were the electrical resistance of HUVEC monolayer and endothelial MLC phosphorylation in extravascular migration of HT1080 cells. HT1080 cells migrated through endothelial cells into collagen gel, the electrical resistance of a HUVEC monolayer was reduced and endothelial MLC phosphorylation was enhanced in extravascular migration of fibrosarcoma cells. Endothelial MLCK inhibitor (ML-7) blocked extravascular migration of HT1080 cells and inhibited reduction of electrical resistance of a HUVEC monolayer and enhancement of endothelial MLC phosphorylation in extravascular migration of HT1080 cells in a dose-dependent manner. Endothelial MLCK regulates fibrosarcoma cell transendothelial migration through MLC phosphorylation, leading to cytoskeletal reorganization and endothelial cell constriction, then fibrosarcoma cells migrate into extravascular tissue through the gaps between endothelial cells.

  4. Bilateral subcutaneous fibrosarcomas in a cat following feline parvo-, herpes- and calicivirus vaccination.

    PubMed

    De Man, Marc M G; Ducatelle, Richard V

    2007-10-01

    A crossbred cat developed a subcutaneous fibrosarcoma on the left side of the thorax at the site of previous administration of a feline parvo-, herpes- and calicivirus vaccine. A few months later the cat developed a second mass on the right side of the thorax after a booster vaccine had been administered at this site. This unique case of bilateral fibrosarcomas in a cat shortly after vaccination with parvo-, herpes- and caliciviruses suggests an individual disposition for the development of vaccine-associated sarcomas and a possible triggering of this type of pathological response which could have precipitated the development of the second tumour. To the authors' knowledge, this is the first case of vaccine-induced fibrosarcomas occurring bilaterally after injection of a feline parvo-, herpes- and calicivirus containing vaccine at different sides of the thorax.

  5. Ameloblastic fibrosarcoma: report of a case. Immunohistochemical study and review of the literature.

    PubMed

    Huguet, P; Castellví, J; Avila, M; Alejo, M; Autonell, F; Basas, C; Bescos, M S

    2001-01-01

    Ameloblastic fibrosarcoma is a rare malignant odontogenic tumour characterized by a benign epithelial component within a malignant fibrous stroma. Its behaviour is relatively benign, with absence of metastatic disease, and the prognosis is reported to be good. It is a paradoxical neoplasm with "sarcomatous" morphological and immunohistochemical patterns but with a favourable clinical course. We report a new case of this tumour in a mandibular ramus of a 31-years-old male patient, that was surgically excised and treated with adjuvant chemotherapy and radiotherapy. Five years later the patient is free of disease. The growth potential of ameloblastic fibrosarcoma is evaluated and compared with a related lesion, the ameloblastic fibroma. The sarcomatous mesenchymal component of ameloblastic fibrosarcoma is positive to Ki67, PCNA and p53, in front of the negativity of ameloblastic fibroma.

  6. Retroperitoneal Malignant Mesenchymoma: A Case of Mesenchymal Mixed Tumor with Osteosarcoma, Leiomyosarcoma, Liposarcoma and Fibrosarcoma

    PubMed Central

    Choi, Jung Eun; Yoo, Won Jong; Chung, Myung Hee; Sung, Mi Sook; Lee, Hae Giu; Park, Il Young; Kim, Jeana

    2002-01-01

    Malignant mesenchymoma is an interesting but very rare tumor in which malignant differentiation has occurred twice or more. We report a case of retroperitoneal malignant mesenchymoma consisting of osteosarcoma, leiomyosarcoma, liposarcoma and fibrosarcoma. Abdominal CT showed a large retroperitoneal mass with two separate and distinct parts, namely an area of prominent calcification and one of clearly enhancing solid components. The mass contained histologically distinct tumorous components with no histologic admixure at the interfaces. The densely calcified nodule corresponded to osteosarcoma, and the non-calcified clearly enhancing nodules to leiomyosarcoma, liposarcoma and fibrosarcoma. PMID:12514345

  7. Combined sellar fibrosarcoma and prolactinoma with neuronal metaplasia: report of a case unassociated with radiotherapy.

    PubMed

    Moro, Mario; Giannini, Caterina; Scheithauer, Bernd W; Lloyd, Ricardo V; Restall, Paul; Eagleton, Carl; Law, Andrew J; Kovacs, Kalman

    2004-01-01

    We report the occurrence of a primary pituitary fibrosarcoma causally unrelated to radiotherapy, admixed in association with a prolactin cell pituitary adenoma showing neuronal metaplasia. These unique findings were associated with multiple endocrine neoplasia type 1 (MEN 1). Primary fibrosarcoma involving the sella is a very rare tumor. The majority of cases have been associated with prior irradiation of either a pituitary adenoma or a craniopharyngioma. Pituitary adenoma with neuronal metaplasia is also rare and usually occurs in the setting of acromegaly. Despite the intimate association of both elements in our lesion, no transition of adenoma to sarcoma was demonstrable by immunohistochemistry or in situ hybridization studies.

  8. A Comparison Between Two Methods of Face-Lift Surgery in Nine Cadavers: SMAS (Superficial Musculo-Aponeurotic System) Versus MACS (Minimal Access Cranial Suspension).

    PubMed

    Mohammadi, Shabahang; Ahmadi, Aslan; Salem, Mohammad Mahdi; Safdarian, Mahdi; Ilkhani, Shahriar

    2015-10-01

    This study aimed to compare the average amounts of facial skin and muscle lifting in two different face-lift methods, superficial musculo-aponeurotic system (SMAS) plication and minimal access cranial suspension (MACS), to evaluate the effectiveness of each method in facial excursion. Thirty-six face-lift surgeries were performed on nine cadavers between October and December 2010. Both SMAS and MACS surgeries were done on each side of the cadaver faces. The average amounts of skin and muscle lifting up and out in three defined anatomical landmarks were compared between the two methods, SMAS plication and MACS lift procedure. Nine fresh cadavers with the mean age of 53 ± 6.7 years entered the study. Seven (77.8 %) were males and two (22.2 %) were females. The average amounts of lifting of the anatomical landmarks up and out were significantly greater in the SMAS plication method compared to the MACS lift procedure (P values <0.05), whereas facial symmetry was not significantly different between the two methods. The overall amounts of facial skin and muscle lifting by the SMAS plication method were greater than the MACS lift procedure. However, it does not justify ignoring the benefits of the MACS lift procedure in terms of less invasiveness and quicker recovery. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

  9. Ameloblastic fibrosarcoma involving the anterior and middle skull base with intradural extension.

    PubMed

    Guthikonda, Bharat; Hanna, Ehab Y; Skoracki, Roman J; Prabhu, Sujit S

    2009-11-01

    Ameloblastic fibrosarcoma is a malignant odontogenic tumor that rarely affects the skull base and surrounding regions. We present a case of a 48-year-old man with histologically confirmed malignant transformation of a benign ameloblastic fibroma 10 years after initial presentation of a localized facial mass. The ameloblastic fibrosarcoma extended from the facial region to the orbit, anterior and middle fossa skull base, the infratemporal fossa, and the cavernous sinus. Progressive proptosis with complete monocular vision loss was the presenting symptom. To our review, our case represents the first report of intradural extension of ameloblastic fibrosarcoma. Using a multidisciplinary skull base approach, resection of all tumors except that in the cavernous sinus was achieved with the resulting defect reconstructed with an anterolateral thigh free flap. The patient had no new neurologic deficits after surgery and underwent adjuvant fractionated radiation therapy. Malignant transformation of ameloblastic fibroma into ameloblastic fibrosarcoma can occur many years after initial presentation. Thus, vigilant long-term follow-up is essential despite the benign nature of the initial pathologic lesion. Use of a multidisciplinary approach is critical in obtaining the optimal outcome in these complex cases.

  10. Computed tomography characteristics of fibrosarcoma -- a histological subtype of feline injection-site sarcoma.

    PubMed

    Travetti, Olga; di Giancamillo, Mauro; Stefanello, Damiano; Ferrari, Roberta; Giudice, Chiara; Grieco, Valeria; Saunders, Jimmy H

    2013-06-01

    Feline injection-site sarcoma (FISS) may be a consequence of subcutaneous injection. In the present study, the medical records and the computed tomography (CT) features of 22 cats with a FISS, histopathological subtype fibrosarcoma, were used. The majority of the fibrosarcomas (45%) were located in the interscapular region. All fibrosarcomas, except one with mild enhancement, showed strong contrast uptake, characterised as ring (42%), heterogeneous (36%), homogeneous (9%), heterogeneous/ring (6.5%) or mixed heterogeneous/homogeneous enhancement (6.5%). The longest axis of the mass was in a cranio-caudal (68%) or dorso-ventral (32%) direction. The median volume calculated on CT was 7.57 cm(3). Common features were a marked local invasiveness of the musculature and heterogeneity of the tissue in the periphery of the neoplasia. When the fibrosarcoma was interscapular, performing an additional post-contrast scan with the forelimbs positioned caudally along the body, in addition to the standard protocol with the forelimbs extended cranially, allowed better evaluation of the actual relationship between the tumour and the surrounding tissues. The mean number of muscles involved with the tumour was 2.09 with extended and 1.95 with flexed forelimbs. When a lower number of structures was considered infiltrated through the double positioning, a less invasive surgical approach to underlying muscles and scapula was performed.

  11. Unusual Synchronous Presentation of Maxillary Sinus Fibrosarcoma and Gemistocytic Astrocytoma with a Complication Called Leukocytoclastic Vasculitis: A Case Report

    PubMed Central

    Cadir, Bilge; Karahan, Nermin; Nasir, Serdar; Aydin, M. Asim; Turkaslan, S. Suha

    2009-01-01

    Fibrosarcoma of the paranasal sinuses is extremely rare pathology and there is limited report in the literature. We report synchronous presentation of maxillary sinus fibrosarcoma and gemistocytic astrocytoma which is, to our knowledge, unique in the literature. Both tumors metastases to other organ rarely and the metastatic spread of gemistocytic astrocytoma to fibrosarcoma or vice versa have also not been reported in the literature yet. This report discusses the clinical course of the disease, outcome of the treatment approach and survival as well as an unusual occurrence of leukocytoclastic vasculitis during the course of radiotherapy in such unusual presentation. PMID:19756200

  12. Pro‑apoptotic effects of pycnogenol on HT1080 human fibrosarcoma cells.

    PubMed

    Harati, Kamran; Slodnik, Pawel; Chromik, Ansgar Michael; Behr, Björn; Goertz, Ole; Hirsch, Tobias; Kapalschinski, Nicolai; Klein-Hitpass, Ludger; Kolbenschlag, Jonas; Uhl, Waldemar; Lehnhardt, Marcus; Daigeler, Adrien

    2015-04-01

    Complete surgical resection with clear margins remains the mainstay of therapy for localised fibrosarcomas. Nevertheless, metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents like doxorubicin have proven to be effective in <30% of all cases of disseminated fibrosarcoma. Especially elderly patients with cardiac subdisease are not suitable for systemic chemotherapy with doxorubicin. Therefore we tested the apoptotic effects of the well-tolerated pine bark extract pycnogenol and its constituents on human fibrosarcoma cells (HT1080). Ten healthy subjects (six females, four males, mean age 24.8 ± 6 years) received a single dose of 300 mg pycnogenol orally. Blood plasma samples were obtained before and 6 h after intake of pycnogenol. HT1080 cells were treated with these plasma samples. Additionally, HT1080 were incubated separately with catechin, epicatechin and taxifolin that are known as the main constituents of pycnogenol. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarray. The results showed that single application of taxifolin, catechin and epicatechin reduced cell viability of HT1080 cells only moderately. A single dose of 300 mg pycnogenol given to 10 healthy adults produced plasma samples that led to significant apoptotic cell death ex vivo whereas pycnogenol-negative serum displayed no apoptotic activity. Microarray analysis revealed remarkable expression changes induced by pycnogenol in a variety of genes, which are involved in different apoptotic pathways of cancer cells [Janus kinase 1 (JAK1), DUSP1, RHOA, laminin γ1 (LAMC1), fibronectin 1 (FN1), catenin α1 (CTNNA1), ITGB1]. In conclusion, metabolised pycnogenol induces apoptosis in human fibrosarcoma cells. Pycnogenol exhibits its pro-apoptotic activity as a mixture and is more effective than its main constituents catechin, epicatechin and taxifolin indicating that the

  13. Perturbed MafB/GATA1 axis after burn trauma bares the potential mechanism for immune suppression and anemia of critical illness.

    PubMed

    Johnson, Nicholas B; Posluszny, Joseph A; He, Li K; Szilagyi, Andrea; Gamelli, Richard L; Shankar, Ravi; Muthumalaiappan, Kuzhali

    2016-10-01

    Patients who survive initial burn injury are susceptible to nosocomial infections. Anemia of critical illness is a compounding factor in burn patients that necessitates repeated transfusions, which further increase their susceptibility to infections and sepsis. Robust host response is dependent on an adequate number and function of monocytes/macrophages and dendritic cells. In addition to impaired RBC production, burn patients are prone to depletion of dendritic cells and an increase in deactivated monocytes. In steady-state hematopoiesis, RBCs, macrophages, and dendritic cells are all generated from a common myeloid progenitor within the bone marrow. We hypothesized in a mouse model of burn injury that an increase in myeloid-specific transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homolog B at the common myeloid progenitor stage steers their lineage potential away from the megakaryocyte erythrocyte progenitor production and drives the terminal fate of common myeloid progenitors to form macrophages vs. dendritic cells, with the consequences being anemia, monocytosis, and dendritic cell deficits. Results indicate that, even though burn injury stimulated bone marrow hematopoiesis by increasing multipotential stem cell production (Lin(neg)Sca1(pos)cKit(pos)), the bone marrow commitment is shifted away from the megakaryocyte erythrocyte progenitor and toward granulocyte monocyte progenitors with corresponding alterations in peripheral blood components, such as hemoglobin, hematocrit, RBCs, monocytes, and granulocytes. Furthermore, burn-induced V-maf musculoaponeurotic fibrosarcoma oncogene homolog B in common myeloid progenitors acts as a transcriptional activator of M-CSFR and a repressor of transferrin receptors, promoting macrophages and inhibiting erythroid differentiations while dictating a plasmacytoid dendritic cell phenotype. Results from small interfering RNA and gain-of-function (gfp-globin transcription factor 1 retrovirus) studies

  14. Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors

    SciTech Connect

    Souyri, M.; Vigon, I.; Charon, M.; Tambourin, P. )

    1989-09-01

    The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, the authors have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10{sup 4} foci per {mu}g of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, they found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which the authors had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

  15. Primary fibrosarcoma of the urinary bladder in a cat: follow-up after incomplete surgical excision.

    PubMed

    Greci, Valentina; Rocchi, Paola M; Sontuoso, Antonio F; Olivero, Daniela; Capasso, Angelo; Raiano, Vera

    2017-01-01

    An 11-year-old female spayed domestic shorthair cat was presented with haematuria of 2 months' duration followed by pollakiuria and stranguria. A firm, non-painful mass in the urinary bladder was palpated. Abdominal radiographs and ultrasound were suggestive of a urinary neoplasia. During explorative laparotomy, a partial cystectomy and surgical debulking were performed. Histopathology and immunostaining were consistent with a fibrosarcoma. The cat was discharged 10 days after surgery with a residual mass of about 1.8 cm on ultrasound re-examination. The cat was not given adjuvant therapy. The cat was euthanased 8 months after surgery because of tumour invasion of the urinary trigone and subsequent ureter dilation, hydronephrosis and severe azotaemia. Malignant urinary fibrosarcoma in this cat appeared to be only locally invasive. Palliative surgery without adjuvant postoperative chemotherapy in this cat resulted in an 8 month period of good quality of life.

  16. Electrochemotherapy increases local control after incomplete excision of a recurring penile fibrosarcoma in a stallion

    PubMed Central

    Spugnini, E.P.; Bolaffio, C.; Scacco, L.; Baldi, A.

    2016-01-01

    An eleven-year-old stallion was referred for adjuvant treatment of an incompletely excised, recurring penile fibrosarcoma. The horse was bright, alert and responsive with a 15 x 12 cm ulcerated lesion on the ventral side of the penis. The lesion was the tumor bed of an incompletely excised fibrosarcoma. After complete staging procedures, the owner elected to treat the horse with electrochemotherapy (ECT) using cisplatin as chemotherapy agent. Two sessions of ECT were performed at two-week intervals using local cisplatin followed by trains of biphasic electric pulses applied using different electrodes until complete coverage of the area was achieved. The treatment was well tolerated, and the patient is still disease free after 12 months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in equines carrying soft tissue tumors. PMID:27995080

  17. Fibrosarcoma adjacent to the site of microchip implantation in a cat.

    PubMed

    Daly, Meighan K; Saba, Corey F; Crochik, Sonia S; Howerth, Elizabeth W; Kosarek, Carrie E; Cornell, Karen K; Roberts, Royce E; Northrup, Nicole C

    2008-04-01

    A 14-year-old spayed female domestic shorthair cat presented with an interscapular mass. A computed tomography scan, biopsy, and histological examination revealed a fibrosarcoma adjacent to a pet identification microchip. Because the cat was previously vaccinated at this site, it is not possible to establish definitive causation of the fibrosarcoma, but this is the first report of a tumor in the vicinity of a microchip in a cat. Microchip-associated tumors have been reported in rodents and dogs. Veterinarians should be aware that because inflammation may predispose felines to tumor formation, separation and observation of vaccination and implantation sites are indicated. Adherence to American Association of Feline Practitioners (AAFP) vaccination guidelines and monitoring of microchip implantation sites are recommended.

  18. [Sclerosing epithelioid fibrosarcoma of the paravertebral column. Case report and literature review].

    PubMed

    Puerta Roldán, Patricia; Rodríguez Rodríguez, Rodrigo; Bagué Rossell, Silvia; de Juan Delago, Manel; Molet Teixidó, Joan

    2013-01-01

    Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of low-grade fibrosarcoma, with specific histological and immunohistochemical features and a poor prognosis. We report a case of SEF of the paravertebral column in a 49-year old male who presented a paraspinal mass with extension into the L4-L5 neural foramen and invasion of the L5 nerve root. Histology of the tumourectomy specimen and its immunohistochemical study led to the diagnosis of SEF. This case was particularly unusual due to its paravertebral column location and, despite its low grade, illustrates the malignant potential of SEF. Copyright © 2012 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  19. Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

    PubMed

    Maswadeh, Hamzah M; Aljarbou, Ahmad N; Alorainy, Mohammed S; Alsharidah, Mansour S; Khan, Masood A

    2015-01-01

    Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs.

  20. Immunomodulatory properties of silver nanoparticles contribute to anticancer strategy for murine fibrosarcoma

    PubMed Central

    Chakraborty, Biswajit; Pal, Ramkrishna; Ali, Mohammed; Singh, Leichombam Mohindro; Shahidur Rahman, Dewan; Kumar Ghosh, Sujit; Sengupta, Mahuya

    2016-01-01

    The use of nanotechnology in nanoparticle-based cancer therapeutics is gaining impetus due to the unique biophysical properties of nanoparticles at the quantum level. Silver nanoparticles (AgNPs) have been reported as one type of potent therapeutic nanoparticles. The present study is aimed to determine the effect of AgNPs in arresting the growth of a murine fibrosarcoma by a reductive mechanism. Initially, a bioavailability study showed that mouse serum albumin (MSA)-coated AgNPs have enhanced uptake; therefore, toxicity studies of AgNP-MSA at 10 different doses (1–10 mg/kg b.w.) were performed in LACA mice by measuring the complete blood count, lipid profile and histological parameters. The complete blood count, lipid profile and histological parameter results showed that the doses from 2 to 8 mg (IC50: 6.15 mg/kg b.w.) sequentially increased the count of leukocytes, lymphocytes and granulocytes, whereas the 9- and 10-mg doses showed conclusive toxicity. In an antitumor study, the incidence and size of fibrosarcoma were reduced or delayed when murine fibrosarcoma groups were treated by AgNP-MSA. Transmission electron micrographs showed that considerable uptake of AgNP-MSA by the sentinel immune cells associated with tumor tissue and a morphologically buckled structure of the immune cells containing AgNP-MSA. Because the toxicity studies revealed a relationship between AgNPs and immune function, the protumorigenic cytokines TNF-α, IL-6 and IL-1β were also assayed in AgNP-MSA-treated and non-treated fibrosarcoma groups, and these cytokines were found to be downregulated after treatment with AgNP-MSA. PMID:25938978

  1. Targeting androgen receptor/Src complex impairs the aggressive phenotype of human fibrosarcoma cells.

    PubMed

    Castoria, Gabriella; Giovannelli, Pia; Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer

  2. Fourier-transform infrared spectroscopic comparison of cultured human fibroblast and fibrosarcoma cells

    NASA Astrophysics Data System (ADS)

    Yang, Difei; Castro, Dan J.; El-Sayed, Ivan H.; El-Sayed, Mostafa A.; Saxton, Romaine E.; Zhang, Nancy Y.

    1995-05-01

    Infrared vibration spectroscopy appears to be a more powerful technique for diagnosis than visible or UV spectroscopy. Advantages of IR spectra include: 1) vibrational motion has a smaller tissue absorption coefficient than electronic motion, 2) scattering of infrared radiation has a lower cross section than visible or UV light, (these two facts allow deeper penetration of IR radiation) and 3) vibration spectra provide a better fingerprint of chemical groups present in cells than the unresolved broad electronic spectrum of biological molecules. In the present work, Fourier-transform IR spectroscopy was used to compare cultured human fibroblast and malignant fibrosarcoma cells. Significant differences were observed by comparing the spectra of the normal cells with that of the cancer cells. the PO2 symmetric stretching mode at 1082cm-1 in the cancer cell is reduced in intensity. These observations are similar to those reported previously by Wong et al in comparing the IR spectra of pairs of normal and cancerous cells from the colon and cervix. However, the observed increase in the relative intensity of the symmetric to antisymmetric CH3 bending mode are only found in fibrosarcoma and basal cell carcinoma. The decrease in intensity of the CH2 bending mode relative to that of CH3 mode was observed only for fibrosarcoma cells. This finding with paired human fibroblast and fibrosarcoma cells suggests that fatty acid chains or side chains of protein in the cancer cells are partially degraded leading to more terminal carbon. It is also possible that changes in the environment upon carcinogenesis induces a change in the relative absorption cross sections for the CH3 and CH2 bending vibrations.

  3. Fibrosarcoma of the brood pouch in an aquarium-reared lined seahorse (Hippocampus erectus).

    PubMed

    Willens, Scott; Dunn, J Lawrence; Frasca, Salvatore

    2004-03-01

    An adult, male, captive lined seahorse (Hippocampus erectus) was presented with weight loss, anorexia, and brood pouch distention. Initial treatments included manual expression of the brood pouch followed by saline flushes and enrofloxacin infusions. Radiographs and physical examination identified a nodular swelling in the brood pouch wall. The mass was excised, but the seahorse died. Necropsy and histopathology revealed a malignant mesenchymal tumor with a collagenous stroma, and a brood pouch fibrosarcoma was diagnosed.

  4. Scutellarein inhibits cancer cell metastasis in vitro and attenuates the development of fibrosarcoma in vivo.

    PubMed

    Shi, Xiujuan; Chen, Guangfeng; Liu, Xiaoqiang; Qiu, Yu; Yang, Shuzhang; Zhang, Yan; Fang, Xuexun; Zhang, Chen; Liu, Xiaoqing

    2015-01-01

    Fibrosarcoma is an aggressive and highly metastatic cancer of the connective tissue, for which effective therapeutic methods are limited. Recently, there has been a renewed interest in small molecular compounds from natural products in the treatment of cancer. In the present study, we investigated the compound, scutellarein, extracted from the perennial herb Scutellaria lateriflora, and it was found to possess anticancer potential. Cell proliferation assay and cell cycle analysis revealed that the proliferation rate of HT1080 human fibrosarcoma cells was significantly suppressed by treatment with scutellarein through the induction of apoptosis. Moreover, an in vivo experiment using Balb/c nude mice revealed that the volume and weight of the tumors were markedly reduced following treatment with scutellarein. We also analyzed the effects of scutellarein on the markers of metastasis, using the HT1080 cells. The results indicated that scutellarein potently inhibited cell migration, invasion and the expression and activity of matrix metalloproteinase (MMP)-2, -9 and -14. Furthermore, MMP activation and cell survival were suppressed due to the scutellarein-mediated downregulation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation. In conclusion, our data suggest that scutellarein has the ability to attenuate the development of fibrosarcoma and inhibit cancer cell metastasis.

  5. Scutellarein inhibits cancer cell metastasis in vitro and attenuates the development of fibrosarcoma in vivo

    PubMed Central

    SHI, XIUJUAN; CHEN, GUANGFENG; LIU, XIAOQIANG; QIU, YU; YANG, SHUZHANG; ZHANG, YAN; FANG, XUEXUN; ZHANG, CHEN; LIU, XIAOQING

    2015-01-01

    Fibrosarcoma is an aggressive and highly metastatic cancer of the connective tissue, for which effective therapeutic methods are limited. Recently, there has been a renewed interest in small molecular compounds from natural products in the treatment of cancer. In the present study, we investigated the compound, scutellarein, extracted from the perennial herb Scutellaria lateriflora, and it was found to possess anticancer potential. Cell proliferation assay and cell cycle analysis revealed that the proliferation rate of HT1080 human fibrosarcoma cells was significantly suppressed by treatment with scutellarein through the induction of apoptosis. Moreover, an in vivo experiment using Balb/c nude mice revealed that the volume and weight of the tumors were markedly reduced following treatment with scutellarein. We also analyzed the effects of scutellarein on the markers of metastasis, using the HT1080 cells. The results indicated that scutellarein potently inhibited cell migration, invasion and the expression and activity of matrix metalloproteinase (MMP)-2, -9 and -14. Furthermore, MMP activation and cell survival were suppressed due to the scutellarein-mediated downregulation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation. In conclusion, our data suggest that scutellarein has the ability to attenuate the development of fibrosarcoma and inhibit cancer cell metastasis. PMID:25394920

  6. Focal adhesion kinase regulates syndecan-2-mediated tumorigenic activity of HT1080 fibrosarcoma cells.

    PubMed

    Park, Haein; Han, Innoc; Kwon, Ho Jeong; Oh, Eok-Soo

    2005-11-01

    Expression of syndecan-2, a transmembrane heparan sulfate proteoglycan, is crucial for the tumorigenic activity in colon carcinoma cells. However, despite the high-level expression of syndecan-2 in mesenchymal cells, few studies have addressed the function of syndecan-2 in sarcoma cells. In HT1080 fibrosarcoma cells, we found that syndecan-2 regulated migration, invasion into Matrigel, and anchorage-independent growth but not cell-extracellular matrix adhesion or proliferation, suggesting that syndecan-2 plays different functional roles in fibrosarcoma and colon carcinoma cells. Consistent with the increased cell migration/invasion of syndecan-2-overexpressing HT1080 cells, syndecan-2 overexpression increased phosphorylation and interaction of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K), membrane localization of T-lymphoma invasion and metastasis gene-1 (Tiam-1), and activation of Rac. Syndecan-2-mediated cell migration/invasion of HT1080 cells was diminished when (a) cells were cotransfected with nonphosphorylatable mutant FAK Y397F or with other FAK mutants lacking PI3K interactions, (b) cells were treated with a specific PI3K inhibitor, or (c) levels of Tiam-1 were knocked down with small interfering RNAs. Furthermore, expression of several FAK mutants inhibited syndecan-2-mediated enhancement of anchorage-independent growth in HT1080 cells. Taken together, these data suggest that syndecan-2 regulates the tumorigenic activities of HT1080 fibrosarcoma cells and that FAK is a key regulator of syndecan-2-mediated tumorigenic activities.

  7. (Oncogenic action of ionizing radiation)

    SciTech Connect

    Not Available

    1990-01-01

    An extensive experiment involving approximately 400 rats exposed to the neon ion beam at the Bevalac in Berkeley, CA and to electrons is nearing completion. The carcinogenicity of energetic electrons was determined for comparison with the neon ion results. As in past reports we will describe progress in three areas corresponding to the specific aims of the proposal: (1) carcinogenesis and DNA strand breaks in rat skin following exposure by the neon ions or electrons; (2) DNA strand breaks in the epidermis as a function of radiation penetration; (3) oncogene activation in radiation-induced rat skin cancers. 72 refs., 6 tabs.

  8. Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents.

    PubMed

    Koto, Kazutaka; Murata, Hiroaki; Kimura, Shinya; Horie, Naoyuki; Matsui, Takaaki; Nishigaki, Yasunori; Ryu, Kazuteru; Sakabe, Tomoya; Itoi, Megumi; Ashihara, Eishi; Maekawa, Taira; Fushiki, Shinji; Kubo, Toshikazu

    2010-07-01

    Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with

  9. Sphere-forming tumor cells possess stem-like properties in human fibrosarcoma primary tumors and cell lines

    PubMed Central

    LIU, WEI-DONG; ZHANG, TAO; WANG, CHUN-LEI; MENG, HONG-MEI; SONG, YU-WEN; ZHAO, ZHE; LI, ZHENG-MIN; LIU, JIANG-KUN; PAN, SHANG-HA; WANG, WEN-BO

    2012-01-01

    Fibrosarcoma is a malignant soft tissue tumor of mesenchymal origin. Despite advances in medical and surgical treatment, patient survival rates have remained poor. According to the cancer stem cell hypothesis, tumors are comprised of heterogeneous cell populations that have different roles in tumor formation and growth. Cancer stem cells are a small cell subpopulation that exhibits stem-like properties to gain aggressiveness and recurrence. These cells have been identified in a variety of cancerous tumors, but not in human fibrosarcoma. In this study, we observed that HT1080 cells and primary fibrosarcoma cells formed spheres and showed higher self-renewal capacity, invasiveness and drug resistance compared with their adherent counterparts. Moreover, we demonstrated that the cells showed higher expression of the embryonic stem cell-related genes Nanog, Oct3/4, Sox2, Sox10 and their encoding proteins, as well as greater tumorigenic capacity in nude mice. In conclusion, our data suggest the presence of a stem-like cell population in human fibrosarcoma tumors, which provides more evidence for the cancer stem cell hypothesis and assistance in designing new therapeutic strategies against human fibrosarcoma. PMID:23205129

  10. Expression of Cellular Oncogenes in Human Malignancies

    NASA Astrophysics Data System (ADS)

    Slamon, Dennis J.; Dekernion, Jean B.; Verma, Inder M.; Cline, Martin J.

    1984-04-01

    Cellular oncogenes have been implicated in the induction of malignant transformation in some model systems in vitro and may be related to malignancies in vivo in some vertebrate species. This article describes a study of the expression of 15 cellular oncogenes in fresh human tumors from 54 patients, representing 20 different tumor types. More than one cellular oncogene was transcriptionally active in all of the tumors examined. In 14 patients it was possible to study normal and malignant tissue from the same organ. In many of these patients, the transcriptional activity of certain oncogenes was greater in the malignant than the normal tissue. The cellular fes (feline sarcoma) oncogene, not previously known to be transcribed in mammalian tissue, was found to be active in lung and hematopoietic malignancies.

  11. Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells by activation of the p38 MAPK pathway.

    PubMed

    KADOWAKI, Shingo; ENDOH, Daiji; OKUI, Toyo; HAYASHI, Masanobu

    2009-11-01

    We have reported that treatment with trientine, Cu-chelating agent, inhibits tumor growth in a murine transplantation model using fibrosarcoma and induces apoptosis in tumor cells in vivo and in vitro. When fibrosarcoma cells were treated with 10 mM trientine, the activities of p38 MAPK in treated cells were approximately 3-4 times higher than those in untreated cells. Proportions of cells in which apoptosis was induced by trientine increased in an incubation time-dependent manner from days 2 to 6. The proportions of apoptotic cells in the cells treated with trientine and SB203580, an inhibitor of p38 MAPK, were approximately 50% in those of cells treated with trientine alone. The present results showed that the p38 MAPK pathway may play an important role in induction of apoptosis in fibrosarcoma cells by trientine.

  12. TRAIL and taurolidine enhance the anticancer activity of doxorubicin, trabectedin and mafosfamide in HT1080 human fibrosarcoma cells.

    PubMed

    Harati, K; Chromik, A M; Bulut, D; Goertz, O; Hahn, S; Hirsch, T; Klein-Hitpass, L; Lehnhardt, M; Uhl, W; Daigeler, A

    2012-07-01

    Disseminated fibrosarcoma still represents a therapeutic dilemma because of lack of effective cytostatics. Therefore we tested tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and taurolidine, in combination with established and new chemotherapeutic agents on human fibrosarcoma (HT1080). Human fibrosarcoma cells (HT1080) were incubated with doxorubicin, mafosfamide and trabectedin both alone and in combination with taurolidine and TRAIL. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Cell proliferation was analysed using a bromodeoxyuridine (BrdU) ELISA assay. Single application of doxorubicin and trabectedin induced apoptotic cell death and significantly reduced the proliferation of HT1080 cells. In combination treatment, the addition of taurolidine and TRAIL resulted in a stronger reduction in the degree of cell viability when compared to single treatment. Trabectedin and taurolidine displayed a greater potential for inhibiting proliferation than did doxorubicin alone. When combined with TRAIL and taurolidine, treatment with doxorubicin and trabectedin demonstrated stronger apoptosis-inducing and antiproliferative effects.

  13. Antitumor effectiveness of different amounts of electrical charge in Ehrlich and fibrosarcoma Sa-37 tumors

    PubMed Central

    Ciria, HC; Quevedo, MS; Cabrales, LB; Bruzón, RP; Salas, MF; Pena, OG; González, TR; López, DS; Flores, JM

    2004-01-01

    Background In vivo studies were conducted to quantify the effectiveness of low-level direct electric current for different amounts of electrical charge and the survival rate in fibrosarcoma Sa-37 and Ehrlich tumors, also the effect of direct electric in Ehrlich tumor was evaluate through the measurements of tumor volume and the peritumoral and tumoral findings. Methods BALB/c male mice, 7–8 week old and 20–22 g weight were used. Ehrlich and fibrosarcoma Sa-37 cell lines, growing in BALB/c mice. Solid and subcutaneous Ehrlich and fibrosarcoma Sa-37 tumors, located dorsolaterally in animals, were initiated by the inoculation of 5 × 106 and 1 × 105 viable tumor cells, respectively. For each type of tumor four groups (one control group and three treated groups) consisting of 10 mice randomly divided were formed. When the tumors reached approximately 0.5 cm3, four platinum electrodes were inserted into their bases. The electric charge delivered to the tumors was varied in the range of 5.5 to 110 C/cm3 for a constant time of 45 minutes. An additional experiment was performed in BALB/c male mice bearing Ehrlich tumor to examine from a histolological point of view the effects of direct electric current. A control group and a treated group with 77 C/cm3 (27.0 C in 0.35 cm3) and 10 mA for 45 min were formed. In this experiment when the tumor volumes reached 0.35 cm3, two anodes and two cathodes were inserted into the base perpendicular to the tumor long axis. Results Significant tumor growth delay and survival rate were achieved after electrotherapy and both were dependent on direct electric current intensity, being more marked in fibrosarcoma Sa-37 tumor. Complete regressions for fibrosarcoma Sa-37 and Ehrlich tumors were observed for electrical charges of 80 and 92 C/cm3, respectively. Histopathological and peritumoral findings in Ehrlich tumor revealed in the treated group marked tumor necrosis, vascular congestion, peritumoral neutrophil infiltration, an acute

  14. Natural cytotoxicity of NC-2+ cells against the growth and metastasis of WEHI-164 fibrosarcoma.

    PubMed

    Shirzad, H; Burton, R C; Smart, Y C; Rafieian-kopaei, M; Shirzad, M

    2011-02-01

    We have previously reported a new receptor (NC-2) for natural cytotoxicity (NC) on murine leucocytes, identified by monoclonal antibody D9 (mAb D9). Pretreatment of mouse spleen cells with different concentrations of mAb D9 in vitro blocked NC against WEHI-164, whereas natural killing (NK) activity against YAC-1 was unaffected. This paper reports the immune surveillance against the growth of WEHI-164 tumour cells in mice by NC-2(+) Cells. The kinetics of in vivo reduction in NC activity were investigated by treating BALB/c and (CBA × C57BL/6) F1 mice with a single injection of 40 μg of mAb D9 and monitoring splenic NC activity by (51) Cr-release assay at intervals from 24 h to 3 weeks. Control mice were injected with OKT8 irrelevant antibody. Results showed a significant (P < 0.05) reduction in splenic NC activity within 24 h which persisted for up to 1 week. Similar results were also obtained when (CBA × C57BL/6) F1 mice were employed (P<0.001). In vivo tumour studies were undertaken to investigate the role of NC-2(+) cells in surveillance against tumour growth and metastasis of the WEHI-164 fibrosarcoma. When syngeneic BALB/c mice were injected with 40 μg of mAb D9 and then challenged with 5 × 10(5) WEHI-164 cells, results showed significantly increased growth rate of the transplanted WEHI-164 fibrosarcoma and tumour nodules in the lungs of animals, when compared to control mice with normal NC activity. Our data support an innate surveillance in metastasis and growth of WEHI-164 fibrosarcoma in mice. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

  15. Epigenetically induced changes in nuclear textural patterns and gelatinase expression in human fibrosarcoma cells.

    PubMed

    Poplineau, M; Doliwa, C; Schnekenburger, M; Antonicelli, F; Diederich, M; Trussardi-Régnier, A; Dufer, J

    2013-04-01

    Chromatin texture patterns of tumour cell nuclei can serve as cancer biomarkers, either to define diagnostic classifications or to obtain relevant prognostic information, in a large number of human tumours. Epigenetic mechanisms, mainly DNA methylation and histone post-translational modification, have been shown to influence chromatin packing states, and therefore nuclear texture. The aim of this study was to analyse effects of these two mechanisms on chromatin texture, and also on correlation with gelatinase expression, in human fibrosarcoma tumour cells. We investigated effects of DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-azadC) and histone deacetylase inhibitor trichostatin A (TSA) on nuclear textural characteristics of human HT1080 fibrosarcoma cells, evaluated by image cytometry, and expression of gelatinases MMP-2 and MMP-9, two metalloproteinases implicated in cancer progression and metastasis. 5-azadC induced significant variation in chromatin higher order organization, particularly chromatin decondensation, associated with reduction in global DNA methylation, concomitantly with increase in MMP-9, and to a lesser extent, MMP-2 expression. TSA alone did not have any effect on HT1080 cells, but exhibited differential activity when added to cells treated with 5-azadC. When treated with both drugs, nuclei had higher texture abnormalities. In this setting, reduction in MMP-9 expression was observed, whereas MMP-2 expression remained unaffected. These data show that hypomethylating drug 5-azadC and histone deacetylase inhibitor TSA were able to induce modulation of higher order chromatin organization and gelatinase expression in human HT1080 fibrosarcoma cells. © 2013 Blackwell Publishing Ltd.

  16. Functional and biochemical studies of CD9 in fibrosarcoma cell line.

    PubMed

    Chen, Shuli; Sun, Yingxia; Jin, Zhigao; Jing, Xianghong

    2011-04-01

    CD9, a member of the tetraspanin family, plays important roles in a variety of cell activities. Fibrosarcoma is a malignant tumor that arises from fibroblasts. Low CD9 expression is found in fibrosarcoma tumor, but function of CD9 in fibrosarcoma has been rarely studied. In this study, stable cell lines for CD9 overexpression and vector were generated in HT1080, a human fibroscarcoma cell line, and cellular functions were widely investigated. In CD9-HT1080 cells, CD9 mainly localized in the membrane and co-localized with F-actin in the filopodia of cell surface. In functional assays, we demonstrated that CD9 could up-regulate total and active caspase-3 expression and induce cell apoptosis, but cell proliferation remained unchanged. CD9 overexpression inhibited HT1080 cell adhesion to FN but promoted cell spreading on FN. We also observed CD9 reduced cell migration using FN a chemoattractant and inhibited cell colony formation in soft agar medium. To explore the biochemical mechanism for functional changes, we investigated the effects of CD9 overexpression on cellular pathways and protein association. CD9 overexpression induced Akt phosphorylation on FN but did not change total Akt expression. Phosphorylation of p38 but not ERK was increased by CD9 overexpression, total p38 and ERK were not affected. CD9 overexpression did not affect the expression of TGFα, EGFR, β1, and EWI-2, but EWI-F expression was up-regulated. Moreover, CD9 could associate with TGFα, EGFR, β1, EWI-2, and EWI-F in HT1080 cell line. Take together, CD9 overexpression had promoting effects on cell apoptosis and cell spreading, but had inhibitory effects on cell adhesion, migration, and cell colony formation. These effects might be ascribed to CD9 associations with EWI-2/EWI-F/β1 complex and EGFR pathway, and the activation of Akt and p38 signalings as well.

  17. Gene therapy with IL-12 induced enhanced anti-tumor activity in fibrosarcoma mouse model.

    PubMed

    Razi Soofiyani, Saiedeh; Kazemi, Tohid; Lotfipour, Farzaneh; Mohammad Hosseini, Akbar; Shanehbandi, Dariush; Hallaj-Nezhadi, Somayeh; Baradaran, Behzad

    2016-12-01

    Context Immunotherapy is among the most promising modalities for treatment of cancer. Recently, interleukin 12 (IL-12) has been used as an immunotherapeutic agent in cancer gene therapy. IL-12 can activate dendritic cells (DCs) and boost anti-tumor immune responses. Objective In the current study, we have investigated if IL-12 gene therapy can lead to the regression of tumor mass in a mouse model of fibrosarcoma. Material and methods To investigate the therapeutic efficacy of IL-12, WEHI-164 tumor cells were transfected with murine-IL12 plasmids using Lipofectamine. Enzyme linked immunosorbent assay (ELISA) was used to confirm IL-12 expression in transfected cells. The fibrosarcoma mouse model was established by subcutaneous injection of transfected cells to Balb/C mice. Mice were sacrificed and the tumors were extracted. Tumor sizes were measured by caliper. The expression of IL-12 and IFN-γ was studied with real-time PCR and western blotting. The expression of Ki-67(a tumor proliferation marker) in tumor mass was studied by immunohistochemistry staining. Results and discussion The group treated with IL-12 showed a significant decrease in tumor mass volume (P: 0.000). The results of real-time PCR and western blotting showed that IL-12 and IFN-γ expression increased in the group treated with IL-12 (relative expression of IL-12: 1.9 and relative expression of IFN-γ: 1.766). Immunohistochemistry staining showed that Ki-67 expression was reduced in the group treated with IL-12. Conclusion IL-12 gene therapy successfully led to regress of tumor mass in the fibrosarcoma mouse model. This may serve as a candidate therapeutic approach for treatment of cancer.

  18. Feline vaccine-associated fibrosarcoma induced by aluminium compound in two cats: short communication.

    PubMed

    Deim, Zoltán; Palmai, Nimród; Cserni, Gábor

    2008-03-01

    Two cases of feline vaccine-associated fibrosarcoma (FVAF) are reported. The excised tumours were both characterised as well circumscribed, subcutaneous, firm and white with central necrosis. Histopathologically, they consisted of well-differentiated and variably sized and shaped anaplastic cells, characterised by marked nuclear and cellular pleomorphism including giant cells. The mitotic activity was low. Aluminium was demonstrated in the central necrosis and giant cells. Neoplastic cells were positive for vimentin and negative for desmin and cytokeratin. The presence of feline sarcoma virus and feline immunodeficiency virus could not be detected by PCR in either case.

  19. Ameloblastic fibrosarcoma of the mandible: report of 2 chemosensitive pediatric cases.

    PubMed

    Demoor-Goldschmidt, Charlotte; Minard-Colin, Veronique; Cassagneau, Elizabeth; Supiot, Stephane; Oberlin, Odile; D'hautuille, Cedric; Corradini, Nadege

    2012-03-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumor. We report 2 pediatric cases of AFS from 2 different centers but reviewed by the same pathologist, which were unusual in that they were chemosensitive. Management was wide surgical resection, chemotherapy, and adjuvant radiotherapy. One case was a local AFS recurrence after incomplete surgery and the other was an AFS that was overlooked during earlier diagnosis of an ameloblastic fibroma. Both tumors responded very well to preoperative chemotherapy, with a reduction in tumor size and histologically proven decrease in viable tumor cell number. Both patients are well after 13 and 14 months of follow-up.

  20. [An immunohistochemical study of the proliferating activity of ameloblastic fibroma and ameloblastic fibrosarcoma].

    PubMed

    Lu, Y; Takata, T; Wang, L; Zhou, Z; Wu, L; Zhao, M; Nikai, H

    1998-12-01

    Six cases of ameloblastic fibroma (AF) and three cases of ameloblastic fibrosarcoma (AFS) were immunohistochemically investigated with a proliferating cell nuclear antigen (PCNA) monoclone antibody. Data on the PCNA labeling index (LI) of both epithelial and mesenchymal components were analyzed. The results showed that the PCNA LI of mesenchymal component of AFS (40.8%) was significantly higher than that of AF (3.2%) (P < 0.01) and that of the epithelial component of AFS (5.3%) was significantly lower than that of the mesenchymal one of AFS (P < 0.01). The results suggested that PCNA LI be a useful marker for the differentiation diagnosis of AF and AFS.

  1. Targeting Androgen Receptor/Src Complex Impairs the Aggressive Phenotype of Human Fibrosarcoma Cells

    PubMed Central

    Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Background Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). Experimental Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. Conclusion This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the

  2. Oncogene addiction: sometimes a temporary slavery.

    PubMed

    Jonkers, Jos; Berns, Anton

    2004-12-01

    Tumors induced in conditional oncomice can show remarkable different responses to subsequent oncogene deprivation. Complete sustained regression, concomitant with massive differentiation and/or apoptosis, and partial regression are both observed. In the latter case, tumor growth either resumes without being dependent any longer on the oncogene, or requires reactivation of the oncogene in cells that have become dormant. These models reflect many of the features we also witness in human cancer and can therefore assist us in understanding the underlying mechanisms and in designing more effective treatment protocols.

  3. Dissection of Ras-Dependent Signaling Pathways Controlling Aggressive Tumor Growth of Human Fibrosarcoma Cells: Evidence for a Potential Novel Pathway

    PubMed Central

    Gupta, Swati; Plattner, Rina; Der, Channing J.; Stanbridge, Eric J.

    2000-01-01

    Activation of multiple signaling pathways is required to trigger the full spectrum of in vitro and in vivo phenotypic traits associated with neoplastic transformation by oncogenic Ras. To determine which of these pathways are important for N-ras tumorigenesis in human cancer cells and also to investigate the possibility of cross talk among the pathways, we have utilized a human fibrosarcoma cell line (HT1080), which contains an endogenous mutated allele of the N-ras gene, and its derivative (MCH603c8), which lacks the mutant N-ras allele. We have stably transfected MCH603c8 and HT1080 cells with activating or dominant-negative mutant cDNAs, respectively, of various components of the Raf, Rac, and RhoA pathways. In previous studies with these cell lines we showed that loss of mutant Ras function results in dramatic changes in the in vitro phenotypic traits and conversion to a weakly tumorigenic phenotype in vivo. We report here that only overexpression of activated MEK contributed significantly to the conversion of MCH603c8 cells to an aggressive tumorigenic phenotype. Furthermore, we have demonstrated that blocking the constitutive activation of the Raf-MEK, Rac, or RhoA pathway alone is not sufficient to block the aggressive tumorigenic phenotype of HT1080, despite affecting a number of in vitro-transformed phenotypic traits. We have also demonstrated the possibility of bidirectional cross talk between the Raf-MEK-ERK pathway and the Rac-JNK or RhoA pathway. Finally, overexpression of activated MEK in MCH603c8 cells appears to result in the activation of an as-yet-unidentified target(s) that is critical for the aggressive tumorigenic phenotype. PMID:11094080

  4. Indocyanine Green Derivative Covalently Conjugated with Gold Nanorods for Multimodal Phototherapy of Fibrosarcoma Cells.

    PubMed

    Luo, Teng; Qian, Xiaoqing; Lu, Zhiyong; Shi, Yiwen; Yao, Zhirong; Chai, Xinyu; Ren, Qiushi

    2015-04-01

    A hydrophilic indocyanine green derivative (ICG-Der-02) was covalently doped into mesoporous silica-coated gold nanorods (AuNRs/mSiO2). The self-synthesized derivative offers one carboxyl functional group on a side chain, which enables ICG-Der-02 to be covalently linked to nanomaterials and reduces the probability of leakage/desorption of the dye. The detection of infrared luminescence around 1270 nm confirmed that 102 is efficiently generated by the nanocomposite (AuNRs/mSiO2-ICG-Der-02). Furthermore, a second layer of silica was coated onto the nanocomposite, which then was conjugated with the α(v) integrin-targeting cyclic peptide (RGD-4C). The cell tests showed that the resulting nanoconjugate (AuNRs/mSiO2-ICG-Der-02/RGD-4C) was able to bind preferentially to HT-1080 human fibrosarcoma cells. Due to the synergistic effect of the produced nanoconjugates, a dual-modality photothermal and photochemical therapy was successfully achieved by 808 nm irradiation. Compared to using photothermal or photochemical therapy alone, the dual-modality photothermal/photochemical therapeutic strategy proved to be more damaging to HT-1080 cells and enhanced the effectiveness of photodestruction. Our work presents a novel approach to the multimodal treatment of fibrosarcoma and shows promise for future use in cancer theranostics.

  5. Anti-metastatic activity of biologically synthesized gold nanoparticles on human fibrosarcoma cell line HT-1080.

    PubMed

    Karuppaiya, Palaniyandi; Satheeshkumar, Elumalai; Chao, Wei-Ting; Kao, Lin-Yi; Chen, Emily Chin-Fun; Tsay, Hsin-Sheng

    2013-10-01

    Plants are exploited as a potential source for the large-scale production of noble gold nanoparticles in the recent years owing to their various potential applications in nanobiotechnology and nanomedicine. The present work describes green biosynthetic procedures for the production of gold nanoparticles for the first time by using an aqueous extract of the Dysosma pleiantha rhizome. The biosynthesized gold nanoparticles were confirmed and characterized by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and scanning electron microscopy equipped with energy dispersive spectroscopy. The results revealed that aqueous extract of D. pleiantha rhizome has potential to reduce chloroauric ions into gold nanoparticles and the synthesized gold nanoparticles were showed spherical in shape with an average of 127nm. Further, we investigated the anti-metastatic activity of biosynthesized gold nanoparticles against human fibrosarcoma cancer cell line HT-1080. The results showed that the biosynthesized gold nanoparticles were non-toxic to cell proliferation and, also it can inhibit the chemo-attractant cell migration of human fibrosarcoma cancer cell line HT-1080 by interfering the actin polymerization pathway. Thus, the usage of gold nanoparticles biosynthesized from D. pleiantha rhizome can be used as a potential candidate in the drug and gene delivery to metastatic cancer.

  6. Pardaxin, a Fish Antimicrobial Peptide, Exhibits Antitumor Activity toward Murine Fibrosarcoma in Vitro and in Vivo

    PubMed Central

    Wu, Shu-Ping; Huang, Tsui-Chin; Lin, Ching-Chun; Hui, Cho-Fat; Lin, Cheng-Hui; Chen, Jyh-Yih

    2012-01-01

    The antitumor activity of pardaxin, a fish antimicrobial peptide, has not been previously examined in in vitro and in vivo systems for treating murine fibrosarcoma. In this study, the antitumor activity of synthetic pardaxin was tested using murine MN-11 tumor cells as the study model. We show that pardaxin inhibits the proliferation of MN-11 cells and reduces colony formation in a soft agar assay. Transmission electron microscopy (TEM) showed that pardaxin altered the membrane structure similar to what a lytic peptide does, and also produced apoptotic features, such as hollow mitochondria, nuclear condensation, and disrupted cell membranes. A qRT-PCR and ELISA showed that pardaxin induced apoptosis, activated caspase-7 and interleukin (IL)-7r, and downregulated caspase-9, ATF 3, SOCS3, STAT3, cathelicidin, p65, and interferon (IFN)-γ suggesting that pardaxin induces apoptosis through the death receptor/nuclear factor (NF)-κB signaling pathway after 14 days of treatment in tumor-bearing mice. An antitumor effect was observed when pardaxin (25 mg/kg; 0.5 mg/day) was used to treat mice for 14 days, which caused significant inhibition of MN-11 cell growth in mice. Overall, these results indicate that pardaxin has the potential to be a novel therapeutic agent to treat fibrosarcomas. PMID:23015777

  7. Paeonol Oxime Inhibits bFGF-Induced Angiogenesis and Reduces VEGF Levels in Fibrosarcoma Cells

    PubMed Central

    Han, Ihn; Jung, Ji Hoon; Lee, Eun-Ok; Zhu, Shudong; Chen, Chang-Yan; Kim, Sung-Hoon

    2010-01-01

    Background We previously reported the anti-angiogenic activity of paeonol isolated from Moutan Cortex. In the present study, we investigated the negative effect of paeonol oxime (PO, a paeonol derivative) on basic fibroblast growth factor (bFGF)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs) (including tumor angiogenesis) and pro-survival activity in HT-1080 fibrosarcoma cell line. Methodology/Principal Findings We showed that PO (IC50  = 17.3 µg/ml) significantly inhibited bFGF-induced cell proliferation, which was achieved with higher concentrations of paeonol (IC50 over 200 µg). The treatment with PO blocked bFGF-stimulated migration and in vitro capillary differentiation (tube formation) in a dose-dependent manner. Furthermore, PO was able to disrupt neovascularization in vivo. Interestingly, PO (25 µg/ml) decreased the cell viability of HT-1080 fibrosarcoma cells but not that of HUVECs. The treatment with PO at 12.5 µg/ml reduced the levels of phosphorylated AKT and VEGF expression (intracellular and extracelluar) in HT-1080 cells. Consistently, immunefluorescence imaging analysis revealed that PO treatment attenuated AKT phosphorylation in HT-1080 cells. Conclusions/Significance Taken together, these results suggest that PO inhibits bFGF-induced angiogenesis in HUVECs and decreased the levels of PI3K, phospho-AKT and VEGF in HT-1080 cells. PMID:20808805

  8. Intestinal congenital/infantile fibrosarcoma: a new clinico-pathological entity?

    PubMed

    Berrebi, Dominique; Fournet, Jean-Christophe; Boman, Françoise; Fabre, Monique; Philippe-Chomette, Pascale; Branchereau, Sophie; Fréneaux, Paul; Bouron-Dal Soglio, Dorothée; Michon, Jean; Peuchmaur, Michel

    2015-04-01

    Congenital/infantile fibrosarcoma (IFS) is a relatively rare form of fibrosarcoma diagnosed at birth or during early years of life and that differs from its adult counterpart because of a more favorable behavior. IFS is also known as cellular congenital mesoblastic nephroma, when it affects the kidney and is often but not always characterized by the ETV6-NTRK3 fusion transcript. We report herein the first series of an exceptional tumor of the small intestine occurring in newborns. The four patients shared a stereotyped clinico-pathological presentation with early and acute onset, intestinal perforation, and an infiltration by a highly cellular spindle cell tumor within the dilated intestinal wall exhibiting pathologic features typical of IFS. Molecular studies for the ETV6-NTRK3 translocation were negative in the three cases tested. Patients were treated by surgical wide resection alone and are alive and well (follow-up: 36 months-25 years). Thus, this new clinico-pathological entity, even with lack of documented evidence of the ETV6-NTRK3 translocation, should be included in the differential diagnosis of congenital bowel perforation or obstruction and may represent an intestinal counterpart of IFS.

  9. TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma.

    PubMed

    Daigeler, Adrien; Brenzel, Christina; Bulut, Daniel; Geisler, Anne; Hilgert, Christoph; Lehnhardt, Marcus; Steinau, Hans U; Flier, Annegret; Steinstraesser, Lars; Klein-Hitpass, Ludger; Mittelkötter, Ulrich; Uhl, Waldemar; Chromik, Ansgar M

    2008-12-12

    Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080). Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed. The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: ARHGDIA, NFKBIA, TNFAIP3; TRD: HSPA1A/B, NFKBIA, GADD45A, SGK, JUN, MAP3K14) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes (HSPA1A/B, NFKBIA, PPP1R15A, GADD45A, AXL, SGK, DUSP1, JUN, IRF1, MYC, BAG5, BIRC3). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone. TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis.

  10. Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway.

    PubMed

    Cui, Yang; Meng, Hongmei; Liu, Weidong; Wang, Huan; Liu, Qingpeng

    2015-04-01

    In recent years, aqueous extract of Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine, has been frequently used in China for complementary cancer therapy. However, the mechanisms underlying its anticancer effects have yet to be elucidated. The present study aimed to evaluate the ability of Huaier extract to inhibit proliferation, promote apoptosis and suppress mobility in the fibrosarcoma HT1080 cell line in vitro. The cells were treated with gradient doses of Huaier extract at concentrations of 0, 4, 8 or 16 mg/ml for 24, 48 or 72 h. The cell viability and motility were measured in vitro using MTT, invasive, migration and scratch assays. The distribution of the cell cycle and the extent of cellular apoptosis were analyzed by flow cytometry. The apoptotic pathways were detected using a mitochondrial membrane potential transition assay and western blotting. The results revealed that the cellular viability decreased significantly with increasing concentrations of Huaier extract. In addition, cell invasiveness and migration were also suppressed significantly. It was demonstrated that Huaier extract induced G2 cell-cycle arrest and cellular apoptosis in a time- and dose-dependent manner. The decreased mitochondrial membrane potential, the downregulation of B-cell lymphoma 2 and pro-caspase-3, and upregulation of Bcl-2-associated X protein, cleaved caspase-9 and caspase-3 suggested that Huaier extract induced the apoptosis of HT1080 cells through the mitochondrial pathway. The results of the present study indicate that Huaier extract is a potential complementary agent for the treatment of fibrosarcoma.

  11. Zoledronic acid significantly enhances radiation‑induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling.

    PubMed

    Koto, Kazutaka; Murata, Hiroaki; Kimura, Shinya; Sawai, Yasushi; Horie, Naoyuki; Matsui, Takaaki; Ryu, Kazuteru; Ashihara, Eishi; Maekawa, Taira; Kubo, Toshikazu; Fushiki, Shinji

    2013-02-01

    Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

  12. Effect of Terminalia catappa on lipid profile in transplanted fibrosarcoma in rats.

    PubMed

    Naitik, Pandya; Prakash, Tigari; Kotresha, Dupadahalli; Rao, Nadendla Rama

    2012-05-01

    To evaluate the effect of an antitumor activity of Terminalia catappa on lipid lowering activity in transplanted fibrosarcoma in Wistar albino rats. Methylcholantherene-induced fibrosarcoma was transplanted in rats. After 30(th) day when tumor became palpable, started the treatment of ethanolic extract of Terminalia catappa by orally (250 and 500 mg/kg) for a period of 20 days. The blood sample was collected on 21(st) day, and the liver and the kidney were also removed for studying the lipid profile in serum and the tissues. The levels of total cholesterol, triglycerides and very low density lipoprotein (VLDL) were markedly elevated and high density lipoprotein (HDL) was markedly decreased in the serum of tumor bearing rats. Significant alterations were also observed in the lipid profile of liver and kidney. These changes were significantly reversed in Terminalia catappa (500 mg/kg) treated animals. The reversal of altered lipid levels to normal values in rats with experimentally induced tumor was showed antitumor activity by Terminalia catappa.

  13. Oncogenic potential of bifunctional bioreductive drugs.

    PubMed

    Hei, T K; Liu, S X; Hall, E J

    1996-07-01

    Potential oncogenicity must be a factor of concern in the design and development of novel bioreductive drugs. In the present studies, the cytotoxicity and oncogenic transforming potential of a series of heterocyclic mono-N-oxides, designed to be used as bioreductive drugs, were examined using the mouse C3H 10T1/2 cell system. Exponential phase cultures of 10T1/2 cells were treated with graded doses of the bioreductive drugs for a 4 h period, either in air or hypoxia, at 37 degrees C. After treatment, cultures were replated for both survival and transformation assays. The fused pyrazine mono-N-oxide RB 90740 and its N-deoxy analogue, RB 92816, demonstrated a dose-dependent cytotoxicity and oncogenic transforming potency under aerobic conditions. Similarly, the indoloquinone E09 and the structurally related mitomycin C demonstrated dose dependence in both toxicity and oncogenic transforming potential. The most cytotoxic aromatic-N-oxides tested, RB 92816, also demonstrated the highest oncogenic transformation incidence. In hypoxia, the bioreductive metabolites of RB 90740 were substantially more cytotoxic and induced a higher oncogenic transformation yield than the drug in air. These data are consistent with the structure-activity relationship for bioreductive drugs in that heterocyclic-N-oxides with reactive side chains such as RB 92816 are cytotoxic and potentially carcinogenic.

  14. bFGF induces changes in hyaluronan synthase and hyaluronidase isoform expression and modulates the migration capacity of fibrosarcoma cells.

    PubMed

    Berdiaki, Aikaterini; Nikitovic, Dragana; Tsatsakis, Aristeidis; Katonis, Pavlos; Karamanos, Nikos K; Tzanakakis, George N

    2009-10-01

    Hyaluronan (HA) a glycosaminoglycan, is capable of transmitting extracellular matrix derived signals to regulate cellular functions. In this study, we investigated whether the changes in HT1080 and B6FS fibrosarcoma cell lines HA metabolism induced by basic fibroblast growth factor (bFGF) are correlated to their migration. Real-time PCR, in vitro wound healing assay, siRNA transfection, enzyme digestions, western blotting and immunofluorescence were utilized. bFGF inhibited the degradation of HA by decreasing hyaluronidase-2 expression in HT1080 cells (p=0.0028), increased HA-synthase-1 and -2 expression as we previously found and enhanced high molecular weight HA deposition in the pericellular matrix. Increased endogenous HA production (p=0.0022) and treatment with exogenous high molecular weight HA (p=0.0268) correlated with a significant decrease of HT1080 cell migration capacity. Transfection with siHAS2 and siHAS1 showed that mainly HAS1 synthesized high molecular weight HA regulates HT1080 cell motility. Induced degradation of the HA content by hyaluronidase treatment and addition of low molecular weight HA, resulted in a significant stimulation of HT1080 cells' motility (p<0.01). In contrast, no effects on B6FS fibrosarcoma cell motility were observed. bFGF regulates, in a cell-specific manner the migration capability of fibrosarcoma cells by modulating their HA metabolism. HA metabolism is suggested to be a potential therapeutic target in fibrosarcoma.

  15. ΔNp73 Facilitates Cell Immortalization and Cooperates with Oncogenic Ras in Cellular Transformation In Vivo

    PubMed Central

    Petrenko, Oleksi; Zaika, Alexander; Moll, Ute M.

    2003-01-01

    TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, ΔNp73, is upregulated in breast and gynecological cancers. We further showed that ΔNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of ΔNp73, this can only be directly shown in primary cells. We report here that ΔNp73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. ΔNp73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, ΔNp73 rescues Ras-induced senescence. Moreover, ΔNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of ΔNp73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of ΔNp73. Taken together, ΔNp73 behaves as an oncogene that targets p53 that might explain why ΔNp73 upregulation may be selected for during tumorigenesis of human cancers. PMID:12897129

  16. Modeling oncogene addiction using RNA interference

    PubMed Central

    Rothenberg, S. Michael; Engelman, Jeffrey A.; Le, Sheila; Riese, David J.; Haber, Daniel A.; Settleman, Jeffrey

    2008-01-01

    The clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. RNAi has been increasingly used to understand such “oncogene addiction” and validate new therapeutic targets. However, RNAi approaches suffer from significant off-target effects that limit their utility. Here, we combine carefully titrated lentiviral-mediated short hairpin RNA knockdown of the epidermal growth factor receptor (EGFR) with heterologous reconstitution by EGFR mutants to rigorously analyze the structural features and signaling activities that determine addiction to the mutationally activated EGFR in human lung cancer cells. EGFR dependence is differentially rescued by distinct EGFR variants and oncogenic mutants, is critically dependent on its heterodimerization partner ErbB-3, and surprisingly, does not require autophosphorylation sites in the cytoplasmic domain. Quantitative “oncogene rescue” analysis allows mechanistic dissection of oncogene addiction, and, when broadly applied, may provide functional validation for potential therapeutic targets identified through large-scale RNAi screens. PMID:18711136

  17. Ameloblastic fibrosarcoma of the mandible: A case report and mini review

    PubMed Central

    HU, YUAN-YUAN; DENG, MO-HONG; YUAN, LING-LING; NIU, YU-MING

    2014-01-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic neoplasm of the jaw. AFS is characteristically composed of a benign odontogenic epithelium and a malignant mesenchymal component. The posterior region of the mandible is the predominantly occupied site. In the present report, a new case of AFS in a 22-year-old male that originated from ameloblastic fibroma was described. Histologically, the tumor showed biphasic components: Benign epithelium and a malignant mesenchymal component. Immunochemical findings revealed that the tumor cells were positive for cluster of differentiation (CD) 34, vimentin, Ki-67 and p53, but negative for smooth muscle actin, S-100, CD68 and desmin. The clinical presentation, radiographic appearances and treatment measures were additionally described and reviewed. PMID:25289041

  18. Ameloblastic fibrosarcoma of the mandible: A case report and mini review.

    PubMed

    Hu, Yuan-Yuan; Deng, Mo-Hong; Yuan, Ling-Ling; Niu, Yu-Ming

    2014-11-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic neoplasm of the jaw. AFS is characteristically composed of a benign odontogenic epithelium and a malignant mesenchymal component. The posterior region of the mandible is the predominantly occupied site. In the present report, a new case of AFS in a 22-year-old male that originated from ameloblastic fibroma was described. Histologically, the tumor showed biphasic components: Benign epithelium and a malignant mesenchymal component. Immunochemical findings revealed that the tumor cells were positive for cluster of differentiation (CD) 34, vimentin, Ki-67 and p53, but negative for smooth muscle actin, S-100, CD68 and desmin. The clinical presentation, radiographic appearances and treatment measures were additionally described and reviewed.

  19. Specific roles of Rac1 and Rac2 in motile functions of HT1080 fibrosarcoma cells.

    PubMed

    Niggli, Verena; Schlicht, Dominique; Affentranger, Sarah

    2009-09-04

    Rho family proteins are constitutively activated in the highly invasive human fibrosarcoma HT1080 cells. We now investigated the specific roles of Rac1 and Rac2 in regulating morphology, F-actin organization, adhesion, migration, and chemotaxis of HT1080 cells. Downregulation of Rac1 using specific siRNA probes resulted in cell rounding, markedly decreased spreading, adhesion, and chemotaxis of HT1080 cells. 2D migration on laminin-coated surfaces in contrast was not markedly affected. Selective Rac2 depletion did not affect cell morphology, cell adhesion, and 2D migration, but significantly reduced chemotaxis. Downregulation of both Rac1 and Rac2 resulted in an even more marked reduction, but not complete abolishment, of chemotaxis indicating distinct as well as overlapping roles of both proteins in chemotaxis. Rac1 thus is selectively required for HT1080 cell spreading and adhesion whereas Rac1 and Rac2 are both required for efficient chemotaxis.

  20. PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells

    SciTech Connect

    Pang, Xiaojuan; Shu, Yuxin; Niu, Zhiyuan; Zheng, Wei; Wu, Haochen; Lu, Yan; Shen, Pingping

    2014-03-10

    Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21{sup Waf1/Cip1} and p27{sup Kip1} descended in PPARγ1{sup S84D} stable HT1080 cell, whereas the expression of p18{sup INK4C} was not changed. Moreover, compared to the PPARγ1{sup S84A}, PPARγ1{sup S84D} up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs. - Highlights: • Phosphorylation attenuates PPARγ1 transcriptional activity. • Phosphorylated PPARγ1 promotes HT1080 cells proliferation. • PPARγ1 phosphorylation regulates cell cycle by mediating expression of cell cycle regulators. • PPARγ1 phosphorylation reduces sensitivity to agonist and anticancer drug. • Our findings establish PPARγ1 phosphorylation as a critical event in HT1080

  1. Pseudolaric acid B induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma l929 cell.

    PubMed

    Yu, Jing hua; Liu, Chun yu; Zheng, Gui bin; Zhang, Li Ying; Yan, Ming hui; Zhang, Wen yan; Meng, Xian ying; Yu, Xiao fang

    2013-01-01

    PAB induced various cancer cell apoptosis, cell cycle arrest and senescence. But in cell line murine fibrosarcoma L929, PAB did not induce apoptosis, but autophagy, therefore it was thought by us as a good model to research the relationship of cell cycle arrest, autophagy and senescence bypass apoptosis. Inhibitory ratio was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Phase contrast microscopy visualized cell morphology. Hoechst 33258 staining for nuclear change, propidium iodode (PI) staining for cell cycle, monodansylcadaverine (MDC) staining for autophagy, and rodanmine 123 staining for mitochondrial membrane potential (MMP) were measured by fluorescence microscopy or flowcytometry. Apoptosis was determined by DNA ladder test. Protein kinase C (PKC) activity was detected by PKC assay kit. SA-β-galactosidase assay was used to detect senescence. Protein expression was examined by western blot. PAB inhibited L929 cell growth in time-and dose-dependent manner. At 12 h, 80 μmol/L PAB induced obvious mitotic arrest; at 24 h, PAB began to induce autophagy; at 36 h, cell-treated with PAB slip into G1 cell cycle; and 3 d PAB induced senescence. In time sequence PAB induced firstly cell cycle arrest, then autophagy, then slippage into G1 phase, lastly senescence. Senescent cells had high level of autophagy, inhibiting autophagy led to apoptosis, and no senescence. PAB activated PKC activity to induce cell cycle arrest, autophagy and senescence, inhibiting PKC activity suppressed cell cycle arrest, autophagy and senescence. PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC.

  2. Tumorigenicity of IL-1α- and IL-1β-Deficient Fibrosarcoma Cells1

    PubMed Central

    Nazarenko, Irina; Marhaba, Rachid; Reich, Eli; Voronov, Elena; Vitacolonna, Mario; Hildebrand, Dagmar; Elter, Elena; Rajasagi, Mohini; Apte, Ron N; Zöller, Margot

    2008-01-01

    Analyzing the growth of fibrosarcoma lines derived from IL-1α-, IL-1β- , or IL-1αβ-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1α and IL-1β exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1α-/-β-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1βcomp lines, IL-1α strengthens anchorage-independent growth, but both IL-1α and IL-1β support drug resistance. Corresponding to the aggressive growth, IL-1βcomp cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated αv/β3 and matrix metalloroteinase expression. Recruitment of myeloid cells requires IL-1β but is regulated by IL-1α, because inflammatory chemokine and cytokine expression is stronger in IL-1α-/-βcomp than in IL-1wt lines. This regulatory effect of tumor-derived IL-1α is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1β. Both sarcoma cell-derived IL-1α and IL-1β promote tumor growth. However, IL-1α exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1β initiates systemic inflammation. PMID:18516292

  3. Gene therapy based on interleukin-12 loaded chitosan nanoparticles in a mouse model of fibrosarcoma

    PubMed Central

    Soofiyani, Saiedeh Razi; Hallaj-Nezhadi, Somayeh; Lotfipour, Farzaneh; Hosseini, Akbar Mohammad; Baradaran, Behzad

    2016-01-01

    Objective(s): Interleukin-12 (IL-12) as a cytokine has been proved to have a critical role in stimulating the immune system and has been used as immunotherapeutic agents in cancer gene therapy. Chitosan as a polymer, with high ability of binding to nucleic acids is a good candidate for gene delivery since it is biodegradable, biocompatible and non-allergenic polysaccharide. The objective of the present study was to investigate the effects of cells transfected with IL-12 loaded chitosan nanoparticles on the regression of fibrosarcoma tumor cells (WEHI-164) in vivo. Materials and Methods: WEHI-164 tumor cells were transfected with IL-12 loaded chitosan nanoparticles and then were injected subcutaneously to inoculate tumor in BALB/c mice. Tumor volumes were determined and subsequently extracted after mice sacrifice. The immunohistochemistry staining was performed for analysis of Ki-67 expression (a tumor proliferation marker) in tumor masses. The expression of IL-12 and IFN-γ were studied using real-time polymerase chain reaction and immunoblotting. Results: The group treated with IL-12 loaded chitosan nanoparticles indicated decreasing of tumor mass[r1] volume (P<0.001). The results of western blotting and real-time PCR showed that the IL-12 expression was increased in the group. Immunohistochemistry staining indicated that the Ki-67expression was reduced in the group treated with IL-12 loaded chitosan nanoparticles. Conclusion: IL-12 gene therapy using chitosan nanoparticles has therapeutic effects on the regression of tumor masses in fibrosarcoma mouse model. PMID:27917281

  4. [Effect and mechanism of LY294002 on growth of fibrosarcoma cell line HT1080].

    PubMed

    Zhou, Hong; Huang, Xiang-Yang; Yang, Ting; Wang, Tao; Xu, Dan; Wen, Fu-Qiang

    2010-01-01

    To investigate the effect and mechanism of LY294002 on growth of fibrosarcoma cell line HT1080. The proliferation inhibitory rate of HT1080 cells treated by LY294002 at doses of 5, 10, 25, 50, 100 micromol/L for 12 and 24 h, respectively, was evaluated using SunBio Am-Blue method. HT1080 cells were divided into two groups, that is, A and B. The A group was control group without treatment. The B group received LY294002 (100 micromol/L) for 24 h. The changes of cell morphology and quantity were observed by phase contrast microscope. The apoptosis rate of HT1080 cells was detected by flow cytometry. And the protein expression of p-Akt and p-mTOR in HT1080 cells were detected by Western Blotting. The proliferation of HT1080 cells was inhibited in time- and dose- dependent manner by LY294002. After the treatment of 100 micromol/L LY294002 for 24 h, the growth of HT1080 cell line was remarkably inhibited by LY294002. The rate of apoptosis increased. And the protein expression of p-Akt (0.23 +/- 0.01) and p-mTOR (0.32 +/- 0.06) in LY294002 group was lower than p-Akt (0.63 +/- 0.02) and p-mTOR (0.71 +/- 0.02) in control group (P<0. 01). LY294002 can inhibit the growth of HT1080 cells through PI3K-mTOR pathway. PI3K-mTOR pathway presents an appealing therapeutic target on fibrosarcoma.

  5. Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway

    PubMed Central

    CUI, YANG; MENG, HONGMEI; LIU, WEIDONG; WANG, HUAN; LIU, QINGPENG

    2015-01-01

    In recent years, aqueous extract of Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine, has been frequently used in China for complementary cancer therapy. However, the mechanisms underlying its anticancer effects have yet to be elucidated. The present study aimed to evaluate the ability of Huaier extract to inhibit proliferation, promote apoptosis and suppress mobility in the fibrosarcoma HT1080 cell line in vitro. The cells were treated with gradient doses of Huaier extract at concentrations of 0, 4, 8 or 16 mg/ml for 24, 48 or 72 h. The cell viability and motility were measured in vitro using MTT, invasive, migration and scratch assays. The distribution of the cell cycle and the extent of cellular apoptosis were analyzed by flow cytometry. The apoptotic pathways were detected using a mitochondrial membrane potential transition assay and western blotting. The results revealed that the cellular viability decreased significantly with increasing concentrations of Huaier extract. In addition, cell invasiveness and migration were also suppressed significantly. It was demonstrated that Huaier extract induced G2 cell-cycle arrest and cellular apoptosis in a time- and dose-dependent manner. The decreased mitochondrial membrane potential, the downregulation of B-cell lymphoma 2 and pro-caspase-3, and upregulation of Bcl-2-associated X protein, cleaved caspase-9 and caspase-3 suggested that Huaier extract induced the apoptosis of HT1080 cells through the mitochondrial pathway. The results of the present study indicate that Huaier extract is a potential complementary agent for the treatment of fibrosarcoma. PMID:25789006

  6. TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

    PubMed Central

    Daigeler, Adrien; Brenzel, Christina; Bulut, Daniel; Geisler, Anne; Hilgert, Christoph; Lehnhardt, Marcus; Steinau, Hans U; Flier, Annegret; Steinstraesser, Lars; Klein-Hitpass, Ludger; Mittelkötter, Ulrich; Uhl, Waldemar; Chromik, Ansgar M

    2008-01-01

    Background Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080). Methods Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed. Results and discussion The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: ARHGDIA, NFKBIA, TNFAIP3; TRD: HSPA1A/B, NFKBIA, GADD45A, SGK, JUN, MAP3K14) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes (HSPA1A/B, NFKBIA, PPP1R15A, GADD45A, AXL, SGK, DUSP1, JUN, IRF1, MYC, BAG5, BIRC3). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone. Conclusion TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis. PMID:19077262

  7. PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells.

    PubMed

    Pang, Xiaojuan; Shu, Yuxin; Niu, Zhiyuan; Zheng, Wei; Wu, Haochen; Lu, Yan; Shen, Pingping

    2014-03-10

    Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21(Waf1/Cip1) and p27(Kip1) descended in PPARγ1(S84D) stable HT1080 cell, whereas the expression of p18(INK4C) was not changed. Moreover, compared to the PPARγ1(S84A), PPARγ1(S84D) up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Regulation of hyaluronan and versican deposition by growth factors in fibrosarcoma cell lines.

    PubMed

    Berdiaki, A; Zafiropoulos, A; Fthenou, E; Katonis, P; Tsatsakis, A; Karamanos, N K; Tzanakakis, G N

    2008-02-01

    Versican, a large chondroitin sulphate proteoglycan and hyaluronan (HA), a non-sulphated glycosaminoglycan are major constituents of the pericellular matrix. In many neoplastic tissues, changes in the expression of versican and HA affect tumour progression. Here, we analyse the synthesis of versican and hyaluronan by fibrosarcoma cells, and document how the latter is affected by PDGF-BB, bFGF and TGFB2, growth factors endogenously produced by these cells. Fibrosarcoma cell lines B6FS and HT1080 were utilised and compared with normal lung fibroblasts (DLF). The major versican isoforms expressed by DLF and B6FS cells were V0 and V1. Treatment of B6FS cells with TGFB2 showed a significant increase of V0 and V1 mRNAs. Versican expression in HT1080 cells was not significantly affected by any of the growth factors. In addition, TGFB2 treatment increased versican protein in DLF cells. HA, showed approximately a 2-fold and a 9-fold higher production in DLF cells compared to B6FS and HT1080 cells, respectively. In HT1080 cells, HA biosynthesis was significantly increased by bFGF, whereas, in B6FS cells it was increased by TGFB2 and PDGF-BB. Furthermore, analysis of HA synthases (HAS) expression indicated that HT1080 expressed similar levels of all three HAS isoforms in the following order: HAS2> HAS3> HAS1. bFGF shifted that balance by increasing the abundance of HAS1. The major HAS isoform expressed by B6FS cells was HAS2. PDGF-BB and TGFB2 showed the most prominent effects by increasing both HAS2 and HAS1 isoforms. In conclusion, these growth factors modulated, through upregulation of specific HAS isoforms, HA synthesis, secretion and net deposition to the pericellular matrix.

  9. Infantile fibrosarcoma successfully treated with chemotherapy, with occurrence of calcifying aponeurotic fibroma and pleomorphic/spindled celled lipoma at the site 12 years later.

    PubMed

    DeComas, Amalia M; Heinrich, Stephen D; Craver, Randall

    2009-06-01

    The treatment of infantile fibrosarcoma has traditionally been wide resection. Chemotherapy has been investigated as an adjuvant and primary treatment in cases in which surgery would cause unacceptable morbidity. Recurrences normally occur within a year of completion of the chemotherapy and display the same histology. We present a child with an infantile fibrosarcoma of the elbow, successfully treated with chemotherapy alone, who developed a calcifying aponeurotic fibroma and a spindle cell/pleomorphic lipoma at the tumor site 12 years later.

  10. Ameloblastic fibrosarcoma of the jaws. A clinicopathologic and DNA analysis of five cases and review of the literature with discussion of its relationship to ameloblastic fibroma.

    PubMed

    Muller, S; Parker, D C; Kapadia, S B; Budnick, S D; Barnes, E L

    1995-04-01

    Ameloblastic fibrosarcoma, the malignant counterpart of the ameloblastic fibroma, is a rare odontogenic tumor characterized by benign epithelium and a malignant fibrous stroma. We have compared nuclear DNA content of five ameloblastic fibrosarcomas and three ameloblastic fibromas by image analysis. The three ameloblastic fibromas were diploid, whereas 1 of 5 ameloblastic fibrosarcomas was aneuploid. There was no correlation with histologic grade and aneuploidy. These five new cases were also added to a review of the literature, bringing the total cases of reported ameloblastic fibrosarcomas to 51. The ameloblastic fibrosarcoma occurs at a later age (mean, 27.5 years) compared with reported ameloblastic fibromas (mean, 14.6 to 22 years), which supports a step-wise malignant transformation. There was histologic documentation that 44% of ameloblastic fibrosarcomas developed in ameloblastic fibromas. In view of this data and of the reported cumulative recurrence rate of 18.3% for ameloblastic fibroma, it is recommended that ameloblastic fibromas be treated with complete surgical excision and long-term follow up rather than simple curettage or enucleation.

  11. Oncogene v-jun modulates DNA replication.

    PubMed

    Wasylyk, C; Schneikert, J; Wasylyk, B

    1990-07-01

    Cell transformation leads to alterations in both transcription and DNA replication. Activation of transcription by the expression of a number of transforming oncogenes is mediated by the transcription factor AP1 (Herrlich & Ponta, 1989; Imler & Wasylyk, 1989). AP1 is a composite transcription factor, consisting of members of the jun and fos gene-families. c-jun and c-fos are progenitors of oncogenes, suggestion that an important transcriptional event in cell transformation is altered activity of AP1, which may arise either indirectly by oncogene expression or directly by structural modification of AP1. We report here that the v-jun oncogene and its progenitor c-jun, as fusion proteins with the lex-A-repressor DNA binding domain, can activate DNA replication from the Polyoma virus (Py) origin of replication, linked to the lex-A operator. The transcription-activation region of v-jun is required for activation of replication. When excess v-jun is expressed in the cell, replication is inhibited or 'squelched'. These results suggest that one consequence of deregulated jun activity could be altered DNA replication and that there are similarities in the way v-jun activates replication and transcription.

  12. Oncogenic mutations of thyroid hormone receptor β

    PubMed Central

    Park, Jeong Won; Zhao, Li; Willingham, Mark; Cheng, Sheue-yann

    2015-01-01

    The C-terminal frame-shift mutant of the thyroid hormone receptor TRβ1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TRβ1 is uniquely dependent on the PV mutated sequence. Using four C-terminal frame-shift mutants—PV, Mkar, Mdbs, and AM—we examined that region in the oncogenic actions of TRβ1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85α regulatory subunit of PI3K similarly in cells. In vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85α with markedly higher avidity. The sustained association of mutants with p85α led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of PV being uniquely dependent on the PV mutated sequence. Rather, these four mutants could favor a C-terminal conformation that interacted with the CSH2 domain of p85α to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TRβ1 could function as an “onco-domain” and TRβ1 is a potential therapeutic target. PMID:25924236

  13. Novel Oncogenes in Breast Cancer Development

    DTIC Science & Technology

    2002-07-01

    determinants that contribute to the development of breast cancer remain unknown We have developed and applied a novel retrovirus-based library ... screening strategy coupled to a biological assay for growth transformation, to identify novel oncogenes in breast cancer development The approach involves the

  14. Viral oncogenes, proto-oncogenes and homoeotic genes related to cell proliferation and differentiation.

    PubMed

    Antohi, S; Antohi-Talle, O

    1987-01-01

    Molecular studies on viral oncogenes and their products have led to the discovery of physiological proto-oncogenes, involved in the control of cell proliferation and gene activation. Other genetic and molecular investigations, initiated in Drosophila melanogaster and continued in different multicellular eukaryotes, have made evident the homoeotic genes, which are directly correlated with cell specialization, in the complex processes of differentiation and morphogenesis. Both gene classes are conserved to a high extent during evolution. They are involved in the eukaryotic mechanisms of differentiation control and proto-oncogenes, in particular, are related to malignant transformation. Some available data suggest a certain extent of relatedness between the gene products of both gene classes. A differentiation trigger model, including retroviral transposition, homoeotic genes and proto-oncogenes is discussed.

  15. Epithelial Dysplasia in Ameloblastic Fibrosarcoma Arising from Recurrent Ameloblastic Fibroma in a 26-Year-Old Iranian Man

    PubMed Central

    Mohsenifar, Zhaleh; Behrad, Samira; Abbas, Fatemeh Mashhadi

    2015-01-01

    Patient: Male, 26 Final Diagnosis: Ameloblastic fibrosarcoma Symptoms: Swelling Medication: — Clinical Procedure: Hemimandibulectomy Specialty: Dentistry Objective: Rare disease Background: Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumor with a mesenchymal component, showing sarcomatous features and epithelial nests resembling ameloblastic fibroma (AF). Case Report: We report a case of AFS showing epithelial dysplasia arising in a recurrent AF in the left mandible after 3 years in a 26-year-old man, which is regarded as an uncommon histopathologic finding in AFS. We also emphasize the comprehensive clinical, radiographic, and histopathologic evaluation, and immunohistochemical staining of this patient. Conclusions: We conclude that it is important to consider malignancy alternations in the epithelial component of AFS, along with that of the mesenchymal component, to provide a proper diagnosis and treatment of recurrent AF. PMID:26289384

  16. The effect of Acemannan Immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas.

    PubMed

    King, G K; Yates, K M; Greenlee, P G; Pierce, K R; Ford, C R; McAnalley, B H; Tizard, I R

    1995-01-01

    Eight dogs and five cats with histopathologically confirmed fibrosarcomas were treated with Acemannan Immunostimulanta in combination with surgery and radiation therapy. These animals had recurring disease that had failed previous treatment, a poor prognosis for survival, or both. Following four to seven weekly acemannan treatments, tumor shrinkage occurred in four (greater than 50%; n = 2) of 12 animals, with tumors accessible to measurement. A notable increase in necrosis and inflammation was observed. Complete surgical excision was performed on all animals between the fourth and seventh week following initiation of acemannan therapy. Radiation therapy was instituted immediately after surgery. Acemannan treatments were continued monthly for one year. Seven of the 13 animals remain alive and tumor-free (range, 440+ to 603+ days) with a median survival time of 372 days. The data suggests that Acemannan Immunostimulant may be an effective adjunct to surgery and radiation therapy in the treatment of canine and feline fibrosarcomas.

  17. Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma

    PubMed Central

    Tannenbaum-Dvir, Sarah; Glade Bender, Julia L.; Church, Alanna J.; Janeway, Katherine A.; Harris, Marian H.; Mansukhani, Mahesh M.; Nagy, Peter L.; Andrews, Stuart J.; Murty, Vundavalli V.; Kadenhe-Chiweshe, Angela; Connolly, Eileen P.; Kung, Andrew L.; Dela Cruz, Filemon S.

    2015-01-01

    Abstract We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma. PMID:27148571

  18. Syndecan-2 is a key regulator of transforming growth factor beta 2/Smad2-mediated adhesion in fibrosarcoma cells.

    PubMed

    Mytilinaiou, Maria; Bano, Artan; Nikitovic, Dragana; Berdiaki, Aikaterini; Voudouri, Kallirroi; Kalogeraki, Alexandra; Karamanos, Nikos K; Tzanakakis, George N

    2013-02-01

    Fibrosarcoma is a rare malignant tumor originating from fibroblasts. Transforming growth factor beta 2 (TGFβ2) has been established to regulate processes correlated to fibrosarcoma tumorigenesis. In this study, we investigated the possible participation of syndecan-2 (SDC-2), a cell membrane heparan sulfate (HS) proteoglycan on these TGFβ2 functions. Our results demonstrate that the inhibition of SDC-2 expression by short interfering RNA (siSDC2) abolished TGFβ2-dependent HT1080 cell adhesion (P ≤ 0.01). In parallel, the downregulation of SDC-2 significantly inhibited TGFβ2-induced Smad2 phosphorylation (P ≤ 0.01). The immunoflourescence signal of TGF receptor III as well as its protein expression was decreased in SDC-2-deficient cells. The enhancement of adhesion molecules integrin β1 (P ≤ 0.01) and focal adhesion kinase expression, induced by TGFβ2 treatment (P ≤ 0.001), was markedly inhibited in SDC-2-defficient cells (P ≤ 0.01). Conclusively, the obtained data suggest that SDC-2 modulates TGFβ2 transcriptional regulation via Smad signaling to facilitate fibrosarcoma cell adhesion. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

  19. Photodynamic therapy with phthalocyanine sensitisation: quantitative studies in a transplantable rat fibrosarcoma.

    PubMed Central

    Tralau, C. J.; MacRobert, A. J.; Coleridge-Smith, P. D.; Barr, H.; Bown, S. G.

    1987-01-01

    Photodynamic therapy (PDT) is a promising approach to the local destruction of malignant tumours, but little work has been done to determine which factors control the extent of tissue necrosis produced. Using a new photosensitiser, a sulphonated aluminium phthalocyanine (AlSPc) and light from an argon ion pumped dye laser at 675 nm, we quantified the effects of interstitial PDT in a transplantable fibrosarcoma in rats. At 100mW laser power, thermal effects were comparable to those of PDT, so subsequent studies were carried out at 50 mW, where thermal effects were minimal. The depth of PDT necrosis increased with the logarithm of the applied energy. Tissue concentration of AlSPc was measured by alkali extraction and at all times after sensitisation, correlated well with the necrosis produced with a given light dose. Peak tumour concentration of AlSPc occurred 24-48 h after sensitisation compared with a peak at 3 h in muscle. The peak ratio tumour:muscle was 2:1 at 24 h. Apart from a different time interval to reach the peak sensitiser concentration, the extent of tumour damage varied with the light and sensitiser parameters in a similar way to that found in normal liver, although the optical penetration depth was greater in the tumour (2.5 mm vs. 1.8 mm). At doses of AlSPc below 1 mg kg-1 the diameter of necrosis increased with the logarithm of the dose of sensitiser, and doubling the dose from 0.25 to 0.5 mg kg-1 increased the depth of necrosis by 50%. However, at higher doses, the changes were smaller and increasing the dose from 2.5 to 5 mg kg-1 only increased the necrosis by 10% for the same light dose. In all dose ranges, a given percentage increase in the tissue concentration of AlSPc gave a much smaller percentage increase in the extent of necrosis for the same light dose, suggesting that selectivity of necrosis between tumour and normal tissue is likely to be much less than the selectivity of retention of the photosensitiser. From these results, the extent

  20. Evaluation of the safety and efficacy of TRAIL and taurolidine use on human fibrosarcoma xenografts in vivo

    PubMed Central

    HARATI, KAMRAN; EMMELMANN, SABINE; BEHR, BJÖRN; GOERTZ, OLE; HIRSCH, TOBIAS; KAPALSCHINSKI, NICOLAI; KOLBENSCHLAG, JONAS; STRICKER, INGO; TANNAPFEL, ANDREA; LEHNHARDT, MARCUS; DAIGELER, ADRIEN

    2016-01-01

    Fibrosarcomas are rare malignant soft tissue tumours that exhibit a poor response to current therapeutic regimens. Previously, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and taurolidine were observed to induce apoptosis synergistically in HT1080 human fibrosarcoma cells in vitro. Consequently, the present study aimed to assess the safety and efficacy of TRAIL in combination with taurolidine on the local growth of fibrosarcoma xenografts in vivo. HT1080 fibrosarcoma cells were inoculated subcutaneously into both flanks of 49 athymic nude mice in order to establish tumour xenografts. TRAIL and taurolidine were applied intraperitoneally at various single and cumulative treatment doses. After 12 days, the experiment was terminated and surviving animals were euthanised. Tumour progression was determined during and following treatment. To assess the potential toxic effects of the two compounds, the organs (lung, liver, kidney and heart) of all animals were examined histologically. The results revealed that combined treatment with TRAIL and taurolidine significantly inhibited the growth of HT1080 xenografts, whereas untreated animals had steadily increasing tumours. The most effective combination was TRAIL at 2 µg per application (cumulative dose, 16 µg) and taurolidine at 30/15 mg per application (cumulative dose, 180 mg), reducing the mean size of implanted xenografts to 10.9 mm2 following treatment (vs. 48.9 mm2 in the control group; P=0.0100). Despite distinct tumour mass reduction, the rate of mortality was significantly increased in animals treated with TRAIL and taurolidine in a taurolidine dose-dependent manner; however, histological examinations of relevant organs revealed no evidence of systemic toxicity (mean survival time, 7.9 days in the treated groups vs. 12 days in the control group; P<0.0010). In summary, whilst the combination of TRAIL and taurolidine synergistically inhibited the growth of fibrosarcoma xenografts in vivo, it was

  1. Function of oncogenes in cancer development: a changing paradigm

    PubMed Central

    Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Cobaleda, Cesar; Sánchez-García, Isidro

    2013-01-01

    Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype–phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions. PMID:23632857

  2. Ras oncogene and inflammation: partners in crime.

    PubMed

    Sparmann, Anke; Bar-Sagi, Dafna

    2005-06-01

    It is well established that Ras oncogenes facilitate neoplastic conversion by stimulating tumor cell growth, survival and motility. However, current studies have indicated that the role of Ras in malignant transformation extends beyond these cell-intrinsic effects to include the establishment of a pro-tumorigenic host environment. We have recently demonstrated that Ras-induced secretion of the chemokine Interleukin-8 (CXCL-8/IL-8) elicits a local inflammatory reaction that is critical for neo-vascularization and sustained tumor growth. Our data identify a novel mechanism by which the Ras oncogene promotes tumor-host interactions that are essential for cancer progression, and suggest that CXCL-8 could serve as a surrogate marker for in-vivo Ras activity.

  3. Oncogenes and tumor-suppressor genes.

    PubMed Central

    Lehman, T A; Reddel, R; Peiifer, A M; Spillare, E; Kaighn, M E; Weston, A; Gerwin, B I; Harris, C C

    1991-01-01

    The functional role of oncogenes in human lung carcinogenesis has been investigated by transfer of activated oncogenes into normal cells or an immortalized bronchial epithelial cell line, BEAS-2B. Transfection of v-Ha-ras, Ki-ras, or the combination of myc and raf into BEAS-2B cells produced tumorigenic cell lines, while transfection of raf or myc alone produced nontumorigenic cell lines. In addition to studying the pathogenic role of oncogenes, we are attempting to define negative growth-regulating genes that have tumor-suppressive effects for human lung carcinomas. Our strategy to identify tumor-suppressor genes involves loss of heterozygosity studies, monochromosome-cell fusion, and cell-cell fusion studies. Loss of heterozygosity studies have revealed consistent allelic DNA sequence deletions on chromosome 17p in squamous cell carcinomas, while large cell carcinomas and adenocarcinomas retained this locus. Mutations in p53, a tumor-suppressor gene located on chromosome 17p, have been observed. Cell-cell hybrid clones produced from fusion of nontumorigenic BEAS-2B cells with tumorigenic HuT292DM cells generally are nontumorigenic. The mechanistic role of the known tumor-suppressor genes Rb-1 and p53 in the development of human lung carcinomas is being investigated in this epithelial cell model of human bronchogenic carcinogenesis. PMID:1685442

  4. Salidroside inhibits migration and invasion of human fibrosarcoma HT1080 cells.

    PubMed

    Sun, Chao; Wang, Zhenhua; Zheng, Qiusheng; Zhang, Hong

    2012-02-15

    Oxidative stress plays an important role in tumorigenesis and metastasis. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant property. Here we investigated the inhibitory effects of salidroside on tumor metastasis in human fibrosarcoma HT1080 cells in vitro. The results indicated that salidroside significantly reduced wound closure areas of HT1080 cells, inhibited HT1080 cells invasion into Matrigel-coated membranes, suppressed matrix metalloproteinases (MMP-2 and MMP-9) activity, and increased tissue inhibitor of metalloproteinase-2 (TIMP-2) expression in a dose-dependent manner in HT1080 cells. Salidroside treatment upregulated the E-cadherin expression, while downregulated the expression of β1-integrin. As an antioxidant, salidroside inhibited the intracellular reactive oxygen species (ROS) formation in a dose-dependent manner. The results also showed that salidroside could inhibit the activation of protein kinase C (PKC) and the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in a dose-dependent manner. In conclusion, these results suggest that salidroside inhibits tumor cells metastasis, which may due to its interfere in the intracellular excess ROS thereby down-regulated the ROS-PKC-ERK1/2 signaling pathway. Copyright © 2011 Elsevier GmbH. All rights reserved.

  5. Ameloblastic Fibrosarcoma of the Mandible: A Case Report and Brief Review of the Literature

    PubMed Central

    Loya-Solis, Abelardo; González-Colunga, Karla Judith; Pérez-Rodríguez, Cynthia M.; Ramírez-Ochoa, Natalie Sofía; Ceceñas-Falcón, Luis; Barboza-Quintana, Oralia

    2015-01-01

    Ameloblastic fibrosarcoma is an uncommon odontogenic tumor composed of a benign epithelial component and a malignant ectomesenchymal component most frequently seen in the third and fourth decades of life. It mainly presents as a painful maxillary or mandibular swelling. Radiographs show a radiolucent mass with ill-defined borders. Radical surgical excision and long-term follow-up are the suggested treatment. We report the case of a 22-year-old female with a 2-month history of an asymptomatic swelling in her left mandible. Examination revealed an exophytic growth measuring 3 × 3 cm extending from the mandibular left first premolar to the second molar. The patient underwent a left hemimandibular resection. Histopathological examination revealed a biphasic tumor composed of inconspicuous islands of benign odontogenic epithelium and an abundant malignant mesenchymal component with marked cellularity, nuclear pleomorphism, hyperchromatism, and moderate mitotic figures with clear margins; one year after the surgical procedure, the patient is clinically and radiologically disease-free. PMID:25861504

  6. Fibrosarcoma of the jaws: two cases of primary tumors with intraosseous growth.

    PubMed

    Angiero, Francesca; Rizzuti, Tommaso; Crippa, Rolando; Stefani, Michele

    2007-01-01

    Fibrosarcoma (FS) is a malignant mesenchymal neoplasm of the fibroblasts that rarely affects the oral cavity. Two cases of primary FS of the jaws with intraosseous growth (2 men, aged 53 and 71 years) are described. Microscopically, in one case the tumor showed an intense proliferation of spindle-shaped cells, varying little in size and shape and arranged in parallel bands, partly crossing each other, with significant mitotic activity and nuclear pleomorphism; the second case was characterized by low cellularity comprising spindle-shaped cells, deposited in a variably fibrous and myxoid stroma. On immunohistochemistry, cells in both cases were strongly immunoreactive for MIB-1 and vimentin, focally positive for CD68, and negative for S-100 protein, pancytokeratin, HMB45, CD34, desmin, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). Based on clinical, histological and immunohistochemical findings, the final diagnosis was FS in the first case, myxofibrosarcoma in the second. Treatment was radical surgery with mandibular reconstruction. After two years, the first patient displayed multiple metastases and died during the third year after the initial diagnosis; the second patient was still alive and doing well five years after treatment. We discuss the differential diagnosis versus other forms of sarcoma, examining the morphological appearance that is frequently very similar, the immunohistochemical expression of MIB-1, vimentin, S-100, CD-34, CD68, EMA, as well as conventional clinicopathological features that may help to distinguish FS from other sarcomas.

  7. A case of interscapular fibrosarcoma in a dwarf rabbit (Oryctolagus cuniculus).

    PubMed

    Petterino, Claudio; Modesto, Paola; Strata, Daniela; Vascellari, Marta; Mutinelli, Franco; Ferrari, Angelo; Ratto, Alessandra

    2009-11-01

    A 1-year-old, intact, male dwarf rabbit (Oryctolagus cuniculus) was vaccinated against myxomatosis and rabbit viral hemorrhagic disease in February 1999, and a localized reaction appeared in the same anatomic site within a few days. No regression was observed after subcutaneous antibiotic treatment. The rabbit was kept under observation, and the swelling apparently disappeared in 3 months. The owner then decided to avoid any further subcutaneous drug administration. The referring veterinarian examined the animal on July 2006 for the sudden appearance of a nodular, 4.5 cm x 3.5 cm x 2.0 cm, subcutaneous mass located over the interscapular space. Fine-needle aspiration was performed, and a population of neoplastic spindle cells, rare pleomorphic multinucleated cells, and rare leukocytes were observed. The mass was surgically removed, fixed in 10% neutral buffered formalin, and routinely processed for histologic, histochemical, and immunohistochemical diagnostic investigation. The neoplastic tissue exhibited fascicles composed of malignant spindle-shaped cells with elongated to oval hyperchromatic nuclei and scant cytoplasm. Occasional multinucleated cells were also observed. The neoplastic cells were immunoreactive for vimentin but did not stain for smooth muscle actin, desmin, myoglobin, and cytokeratins (AE1/AE3). Moreover, the histochemical stain for aluminum was positive. The diagnosis was fibrosarcoma based on morphologic and immunohistochemical results. The histologic features of this neoplasm were remarkably similar to feline injection-site sarcoma.

  8. Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms.

    PubMed

    Baird, Sarah K; Rigopoulos, Angela; Cao, Diana; Allan, Laura; Renner, Christoph; Scott, Fiona E; Scott, Andrew M

    2015-11-01

    Fibroblast activation protein (FAP), an integral membrane serine protease, is found on fibro- and osteo-sarcoma and on myofibroblasts in epithelial carcinoma, but rarely on other adult tissue. FAP has been demonstrated to be an excellent target for tumor imaging in clinical trials, and antibodies and other FAP-targeting drugs are in development. Here we have shown that FAP overexpression increased the growth of HT1080 fibrosarcoma cells in vitro and in vivo, and found that the expression of FAP affects response to chemotherapy. When treated with doxorubicin, expression of FAP increased susceptibility to the drug. In spite of this, FAP-HT1080 cells had fewer markers of classical apoptosis than HT1080 cells and neither necrosis nor necroptosis were enhanced. However, levels of early mitochondrial and lysosomal membrane permeability markers were increased, and autophagy switched from a protective function in HT1080 cells to part of the cell death mechanism with FAP expression. Therefore, FAP may affect how the tumor responds to chemotherapeutic drugs overall, which should be considered in targeted drug development. The overexpression of FAP also alters cell signaling and responses to the environment in this cell line. This includes cell death mechanisms, changing the response of HT1080 cells to doxorubicin from classical apoptosis to an organelle membrane permeability-dependent form of cell death.

  9. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

    PubMed

    Amirkhosravi, M; Francis, J L

    1995-01-01

    Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Type I collagen gel protects murine fibrosarcoma L929 cells from TNFα-induced cell death

    SciTech Connect

    Wang, Hong-Ju; He, Wen-Qi; Chen, Ling; Liu, Wei-Wei; Xu, Qian; Xia, Ming-Yu; Hayashi, Toshihiko; Fujisaki, Hitomi; Hattori, Shunji; Tashiro, Shin-ichi; Onodera, Satoshi; Ikejima, Takashi

    2015-02-20

    Murine fibrosarcoma L929 cells have been used to test efficacy of proinflammatory cytokine TNFα. In the present study, we reported on protective effect of type I collagen gel used as L929 cell culture. L929 cell grew and proliferated well on collagen gel. However, the L929 cells exhibited cobblestone-like morphology which was much different from the spread fusiform shape when cultured on conventional cell dishes as well as the cells tended to aggregate. On conventional cell culture dishes, the cells treated with TNFα became round in shape and eventually died in a necroptotic manner. The cells cultured on collagen gel, however, were completely unaffected. TNFα treatment was reported to induce autophagy in L929 cells on the plastic dish, and therefore we investigated the effect of collagen gel on induction of autophagy. The results indicated that autophagy induced by TNFα treatment was much reduced when the cells were cultured on collagen gel. In conclusion, type I collagen gel protected L929 cell from TNFα-induced cell death. - Highlights: • Collagen gel culture changed the morphology of L929 cells. • L929 cell cultured on collagen gel were resistant to TNFα-induced cell death. • Collagen gel culture inhibited TNFα-induced autophagy in L929 cells.

  11. p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells.

    PubMed

    Choi, Kyu-Sil; Fogg, Darin K; Yoon, Chang-Soon; Waisman, David M

    2003-02-01

    The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue, and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteases at the cell surface. Most cancer cells secrete the urokinase-type plasminogen activator, which converts cell-bound plasminogen to plasmin. Here we address the issue of whether the plasminogen binding protein, p11, plays a significant role in this process. Transfection of human HT1080 fibrosarcoma cells with the human p11 gene in the antisense orientation resulted in a loss of p11 protein from the cell surface and concomitant decreases in cellular plasmin production, ECM degradation, and cellular invasiveness. The transfected cells demonstrated reduced development of lung metastatic foci in SCID mice. In contrast, HT1080 cells transfected with the p11 gene in the sense orientation displayed increased cell surface p11 protein and concomitant increases in cellular plasmin production, as well as enhanced ECM degradation and enhanced cellular invasiveness. The p11 overexpressing cells showed enhanced development of lung metastatic foci. These data establish that changes in the extracellular expression of the plasminogen receptor protein, p11, dramatically affect tumor cell-mediated pericellular proteolysis.

  12. [Effect of calmodulin antagonist EBB on invasion of human fibrosarcoma cell HT1080].

    PubMed

    Pan, Bing; Zhou, Yuan; Qi, Jing; Xiong, Dong-sheng; Liu, Jie-wen; Qi, Shu-ling; Cheng, Yan-hong; Yang, Chun-zheng; Zhu, Hui-fang

    2005-06-01

    To investigate the potential effect of EBB, a calmodulin antagonist, on invasion of human fibrosarcoma cells HT1080. The antitumor effect of EBB was assessed by 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Activities of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by Zymogrophy analysis. The mRNA levels, of MMP-2, MMP-9, and tissue inhibitor of metalloproteinases (TIMP)-1 were evaluated by reverse transcriptionpolymerase chain reaction (RT-PCR). Transwell chamber assay was applied to measure the effect of EBB on the invasion of HT1080 cells. Calmodulin antagonist EBB inhibited the proliferation of HT1080 cells with an IC50 of (8.2 +/- 1.2) microg/ml. EBB down-regulated the activities of MMP-2 and MMP-9, and down-regulated the mRNA levels of MMP-2 and MMP-9, while up-regulated the mRNA levels of TIMP-1. The invasive ability of HT1080 cells was decreased to (31.13 +/- 2.265)%, (59.91 +/- 2.566)%, and (71.58 +/- 0.5960)% after exposure of the cells with 2, 5, and 10 microg/ml EBB, respectively. Treatment with calmodulin antagonist EBB is effective in suppressing tumor invasion. The possible mechanism is the down-regulation of MMPs.

  13. Mechlorethamine-Induced DNA-Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

    PubMed Central

    Michaelson-Richie, Erin D.; Ming, Xun; Codreanu, Simona G.; Loeber, Rachel L.; Liebler, Daniel C.; Campbell, Colin; Tretyakova, Natalia Y.

    2011-01-01

    Antitumor nitrogen mustards, such as bis(2-chloroethyl)methylamine (mechlorethamine), are useful chemotherapeutic agents with a long history of clinical application. The antitumor effects of nitrogen mustards are attributed to their ability to induce DNA-DNA and DNA-protein cross-links (DPCs) that block DNA replication. In the present work, a mass spectrometry based methodology was employed to characterize in vivo DNA-protein cross-linking following treatment of human fibrosarcoma (HT1080) cells with cytotoxic concentrations of mechlorethamine. A combination of mass spectrometry-based proteomics and immunological detection was used to identify 38 nuclear proteins which were covalently cross-linked to chromosomal DNA following treatment with mechlorethamine. Isotope dilution HPLC-ESI+-MS/MS analysis of total proteolytic digests revealed a concentration-dependent formation of N-[2-(S-cysteinyl)ethyl]-N-[2-(guan-7-yl)ethyl]methylamine (Cys-N7G-EMA) conjugates, indicating that mechlorethamine cross-links cysteine thiols within proteins to N-7 positions of guanine in DNA. PMID:21486066

  14. Quercetin suppresses intracellular ROS formation, MMP activation, and cell motility in human fibrosarcoma cells.

    PubMed

    Lee, Dong Eun; Chung, Min-Yu; Lim, Tae Gyu; Huh, Won Bum; Lee, Hyong Joo; Lee, Ki Won

    2013-09-01

    Cell metastasis is a major cause of death from cancer and can arise from excessive levels of oxidative stress. The objective of this study was to investigate whether the natural flavonoid quercetin can inhibit matrix metalloproteinase (MMP)-2 and -9 activities through the attenuation of reactive oxygen species (ROS) formation, an event expected to lead to the inhibition of cell motility. To induce sustained ROS formation, cells were treated with phenazine methosulfate (PMS; 1 μM). Noncytotoxic concentrations of quercetin inhibited PMS-induced increases in cell motility in HT1080 human fibrosarcoma (HT1080) cells. While nearly 100% of cells were observed to migrate after 24 h of PMS treatment, quercetin significantly (P < 0.01) suppressed this effect. We also found that quercetin, up to 10 μg/mL, attenuated PMS-induced MMP-2 activation. We then investigated whether the decreased levels of MMP-2 activation could be attributable to lower levels of ROS formation by quercetin. We found that quercetin treatments significantly attenuated PMS-induced ROS formation (P < 0.01) and resulted in decreased cell motility associated with a reduction in MMP-2 and -9 activitiy in HT1080 cells, even in the absence of PMS treatment. Collectively, these results suggest that quercetin inhibits cell motility via the inhibition of MMP activation in HT1080 cells in the presence and absence of PMS. This is likely to be a result of the suppression of intracellular ROS formation by quercetin. © 2013 Institute of Food Technologists®

  15. Mechlorethamine-induced DNA-protein cross-linking in human fibrosarcoma (HT1080) cells.

    PubMed

    Michaelson-Richie, Erin D; Ming, Xun; Codreanu, Simona G; Loeber, Rachel L; Liebler, Daniel C; Campbell, Colin; Tretyakova, Natalia Y

    2011-06-03

    Antitumor nitrogen mustards, such as bis(2-chloroethyl)methylamine (mechlorethamine), are useful chemotherapeutic agents with a long history of clinical application. The antitumor effects of nitrogen mustards are attributed to their ability to induce DNA-DNA and DNA-protein cross-links (DPCs) that block DNA replication. In the present work, a mass spectrometry-based methodology was employed to characterize in vivo DNA-protein cross-linking following treatment of human fibrosarcoma (HT1080) cells with cytotoxic concentrations of mechlorethamine. A combination of mass spectrometry-based proteomics and immunological detection was used to identify 38 nuclear proteins that were covalently cross-linked to chromosomal DNA following treatment with mechlorethamine. Isotope dilution HPLC-ESI(+)-MS/MS analysis of total proteolytic digests revealed a concentration-dependent formation of N-[2-(S-cysteinyl)ethyl]-N-[2-(guan-7-yl)ethyl]methylamine (Cys-N7G-EMA) conjugates, indicating that mechlorethamine cross-links cysteine thiols within proteins to N-7 positions of guanine in DNA.

  16. Enhanced cellular functions through induction of LPA2 by cisplatin in fibrosarcoma HT1080 cells.

    PubMed

    Takahashi, Kaede; Fukushima, Kaori; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi

    2017-02-15

    Lysophosphatidic acid (LPA) is a simple biophysical lipid which interacts with at least six subtypes of G protein-coupled LPA receptors (LPA1-LPA6). In cancer cells, LPA signaling via LPA receptors is involved in the regulation of malignant properties, such as cell growth, motility, and invasion. The aim of this study was to assess whether LPA receptors regulate cellular functions of fibrosarcoma cells treated with anticancer drug. HT1080 cells were maintained by the stepwise treatment of cisplatin (CDDP) at a range of 0.01 to 1.0 µM for approximately 6 months. The cell motile and invasive activities of long-term CDDP-treated (HT-CDDP) cells were significantly stimulated by LPA treatment, while HT-CDDP cells in the static state showed the low cell motile and invasive activities in comparison with HT1080 cells. Since the expression level of LPAR2 gene was markedly elevated in HT-CDDP cells, LPA2 knockdown cells were generated from HT-CDDP cells. The cell motile and invasive activities of HT-CDDP cells were reduced by LPA2 knockdown. In colony assay, large-sized colonies formed by long-term CDDP treatment were suppressed by LPA2 knockdown. In addition, LPA2 knockdown cells reduced LPA production by autotaxin (ATX), correlating with ATX expression level. These results suggest that LPA signaling via LPA2 may play an important role in the regulation of cellular functions in HT1080 cells treated with CDDP.

  17. Cellular immune responses to methylcholanthrene-induced fibrosarcoma in BALB/c mice

    PubMed Central

    1975-01-01

    Several in vitro parameters of cellular immunity were examined in BALB/c mice with an experimentally induced fibrosarcoma tumor. The results of capillary migration of spleen cells in high tumor cell dose inoculated mice show appearance of cellular immune response in the early stages of the tumor growth. As the tumor progresses, the cellular response declines and rapidly disappears, culminating in stimulation values near the time of the death of these mice. The blastogenic studies also show early cellular recognition of tumor antigen by mouse spleen cells and whole blood (Z24 h). After the 2nd day following tumor injection, no blast transformation is noted. However, the results obtained with a lower inoculating tumor cell dose demonstrate an initial cellular recognition on the 7th day. This response gradually disappears by the 19th day and remains negative up to the time of the death of these mice. This cellular immunity was confirmed by the cytotoxic experiments showing that the primary cells responsible for this cellular reactivity were the immune cells. An interesting finding was the presence of a factor(s) capable of blocking the cytotoxic effect. The nature and mechanism of this blocking factor(s) is now under investigation. PMID:1185107

  18. Local immunotherapy of spontaneous feline fibrosarcomas using recombinant poxviruses expressing interleukin 2 (IL2).

    PubMed

    Jourdier, T-M; Moste, C; Bonnet, M-C; Delisle, F; Tafani, J-P; Devauchelle, P; Tartaglia, J; Moingeon, P

    2003-12-01

    We tested the canarypox virus vector ALVAC and the genetically attenuated vaccinia virus vector NYVAC as vehicles for achieving local immunomodulation in domestic animals bearing spontaneous tumours. Following intratumoral administration of ALVAC-, or NYVAC-luciferase in dogs with melanoma, it was demonstrated that viral recombinants remained localized along the needle track, with no virus detectable in the periphery of the tumour. Given these distribution characteristics and their well-documented safety profile, ALVAC- or NYVAC-based recombinants expressing feline or human IL2, respectively, were administered to domestic cats, in order to prevent the recurrence of spontaneous fibrosarcomas. In the absence of immunotherapy, tumour recurrence was observed in 61% of animals within a 12-month follow-up period after treatment with surgery and iridium-based radiotherapy. In contrast, only 39 and 28% of cats receiving either NYVAC-human IL2 or ALVAC-feline IL2, respectively, exhibited tumour recurrences. Based on such results, and in the context of ongoing clinical studies conducted in humans, we discuss the utilization of ALVAC- or NYVAC-based recombinants as viable therapeutic modalities for local immunotherapy or therapeutic vaccination against cancer, both in humans and companion animals.

  19. Suppression of human fibrosarcoma cell metastasis by Phyllanthus emblica extract in vitro.

    PubMed

    Yahayo, Waraporn; Supabphol, Athikom; Supabphol, Roongtawan

    2013-01-01

    Phyllanthus emblica (PE) is known to exhibit various pharmacological properties. This study aimed to evaluate the antimetastatic potential of a PE aqueous extract. Cytotoxicity to human fibrosarcoma cells, HT1080, was determined by viability assay using the 3-(4,5-dimethylthiazol,2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent. Cell migration and invasion were investigated using chemotaxis chambers containing membranes pre- coated with collagen IV and Matrigel, respectively. Cell attachment onto normal surfaces of cell culture plates was tested to determine the cell-adhesion capability. The molecular mechanism of antimetastatic activity was assessed by measuring the gene expression of matrix metalloproteinases, MMP2, and MMP9, using reverse transcription-polymerase chain reaction (RT-PCR) assay. The mRNA levels of both genes were significantly down-regulated after pretreatment with PE extract for 5 days. Our findings show the antimetastatic function of PE extract in reducing cell proliferation, migration, invasion, and adhesion in both dose- and time-dependent manners, especially growth arrest with low IC50 value. A decrease in the expression of both MMP2 and MMP9 seems to be the cellular mechanism for antimetastasis in this case. There is a high potential to use PE extracts clinically as an optional adjuvant therapeutic drug for therapeutic intervention strategies in cancer therapy or chemoprevention.

  20. Direct reprogramming by oncogenic Ras and Myc.

    PubMed

    Ischenko, Irene; Zhi, Jizu; Moll, Ute M; Nemajerova, Alice; Petrenko, Oleksi

    2013-03-05

    Genetically or epigenetically defined reprogramming is a hallmark of cancer cells. However, a causal association between genome reprogramming and cancer has not yet been conclusively established. In particular, little is known about the mechanisms that underlie metastasis of cancer, and even less is known about the identity of metastasizing cancer cells. In this study, we used a model of conditional expression of oncogenic KrasG12D allele in primary mouse cells to show that reprogramming and dedifferentiation is a fundamental early step in malignant transformation and cancer initiation. Our data indicate that stable expression of activated KrasG12D confers on cells a large degree of phenotypic plasticity that predisposes them to neoplastic transformation and acquisition of stem cell characteristics. We have developed a genetically tractable model system to investigate the origins and evolution of metastatic pancreatic cancer cells. We show that metastatic conversion of KrasG12D-expressing cells that exhibit different degrees of differentiation and malignancy can be reconstructed in cell culture, and that the proto-oncogene c-Myc controls the generation of self-renewing metastatic cancer cells. Collectively, our results support a model wherein non-stem cancer cells have the potential to dedifferentiate and acquire stem cell properties as a direct consequence of oncogene-induced plasticity. Moreover, the disturbance in the normally existing dynamic equilibrium between cancer stem cells and non-stem cancer cells allows the formation of cancer stem cells with high metastatic capacity at any time during cancer progression.

  1. CD133+ subpopulation of the HT1080 human fibrosarcoma cell line exhibits cancer stem-like characteristics.

    PubMed

    Feng, Bao-Hua; Liu, Ai-Guo; Gu, Wen-Guang; Deng, Liang; Cheng, Xian-Gyang; Tong, Tie-Jun; Zhang, Hong-Zhi

    2013-08-01

    The cancer stem cell (CSC) theory holds that a minority population within tumors possesses stem cell properties of self-renewal and multilineage differentiation capacity and provides the initiating cells from which tumors are derived and sustained. However, verifying the existence of these CSCs has been a significant challenge. The CD133 antigen is a pentaspan membrane glycoprotein proposed to be a CSC marker for cancer-initiating subpopulations in the brain, colon and various other tissues. Here, CD133+ cells were obtained and characterized from the HT1080 cell line to determine the utility of this marker for isolating CSCs from human fibrosarcoma cells. In this study, CD133+ cells were separated from HT1080 cells using magnetic beads and characterized for their proliferation rate and resistance to chemotherapeutic drugs, cisplatin and doxorubicin, by MTS assay. Relative expression of tumor-associated genes Sox2, Oct3/4, Nanog, c-Myc, Bmi-1 and ABCG2 was measured by real-time polymerase chain reaction (PCR). Clonal sphere formation and the ability of CD133+ cells to initiate tumors in BALB/c nude mice was also evaluated. We found that CD133+ cells showed a high proliferation rate, increased resistance to chemotherapy drugs and overexpression of tumor-associated genes compared with these features in CD133- cells. Additionally, CD133+ cells were able to form spherical clusters in serum-free medium with high clonogenic efficiency, indicating a significantly greater tumor-initiating potential when compared with CD133- cells. These findings indicate that CD133+ cells identified within the HT1080 human fibrosarcoma cell line possess many CSC properties and may facilitate the development of improved therapies for fibrosarcoma.

  2. Melanoma: oncogenic drivers and the immune system

    PubMed Central

    Karachaliou, Niki; Pilotto, Sara; Teixidó, Cristina; Viteri, Santiago; González-Cao, María; Riso, Aldo; Morales-Espinosa, Daniela; Molina, Miguel Angel; Chaib, Imane; Santarpia, Mariacarmela; Richardet, Eduardo; Bria, Emilio

    2015-01-01

    Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches. PMID:26605311

  3. Satellite DNA sequences flank amplified DHFR domains in marker chromosomes of mouse fibrosarcoma cells.

    PubMed

    Riva, P; Orlando, S; Labella, T; Larizza, L

    1994-01-01

    This study centers on marker chromosomes carrying expanded chromosomal regions which were observed in two independent derivatives of the AA12 murine fibrosarcoma line, the 10(-3) M MTX-res H2 and the 5 x 10(-7) M MTX-res E. Previous characterization of the marker chromosomes of MTX-res variants showed their common derivation from a marker chromosome (m) of the parental line, endowed with two interstitial C-bands. Cytogenetic evidence pointed to one C-band of m as the site involved in the chromosomal rearrangements leading to the HSR/ASR chromosomes. ISH of a 3H-labeled satellite DNA probe allowed satellite sequences flanking the HSR/ASR in the marker chromosomes, where the C-band was no longer visible, to be detected. FISH experiments using biotinylated DHFR and satellite DNA probes showed that the respective target sequences are contiguous in new marker chromosomes. They also allowed inter- and intrachromosomal rearrangements to be seen at DHFR amplicons and satellite sequences. Double-color FISH using digoxygenated satellite DNA and biotinylated pDHFR7 showed that in a marker chromosome from the H2 cell line the two target sequences are not only adjacent, but closer than 3 Mb, as indicated by overlapping of the different fluorescence signals given by the two probes. Another marker chromosome in the E variant was shown to display a mixed ladder structure consisting of a head-to-head tandem of irregularly-sized satellite DNA blocks, with two symmetrical interspersed DHFR clusters.

  4. Cyclic-radiation response of murine fibrosarcoma cells grown as pulmonary nodules

    SciTech Connect

    Grdina, D.J.; Hunter, N.

    1982-10-01

    The radiation age response of murine fibrosarcoma (FSa) cells grown as pulmonary nodules in C/sub 3/Hf/Kam mice was determined. FSa cells were irradiated in vivo either with 10 Gy as 14 day-old lung tumors (i.e., artificial macrometastases) prior to cell separation or with 5 Gy as single cells trapped in the lungs of recipient mice (i.e., artificial micrometastases) following cell separation and synchronization by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine cell-cycle parameters and the relative synchrony of the separated populations, as well as the percent contamination of normal diploid cells in each of the tumor cell populations. Tumor populations containing up to 90% G/sub 1/, 60% S-, and 75% G/sub 2/+M-phase tumor cells were obtained. Cell clonogenicity, determined using a lung colony assay, ranged from 0.7 to 6% for control FSa cells from the various elutriator fractions. The radiation sensitivity of these separated cell populations varied by a factor of 6, regardless of whether the cells were irradiated as artificial micro or macro-metastases. In each experiment, tumor populations most enriched in s-phase cells exhibited the greatest radiation sensitivity. To confirm that these populations were highly enriched in S-phase cells and to demonstrate that they were more radiosensitive than FSa cells in other parts of the cell cycle, the elutriated tumor populations were exposed to either suicide labeling by high specific activity tritiated thymidine or hydroxyurea. The resultant age response curves were qualitatively similar to those obtained following irradiation and reflected the S-phase sensitivity of FSa cells to these agents.

  5. Epigenetic regulation of proMMP-1 expression in the HT1080 human fibrosarcoma cell line.

    PubMed

    Poplineau, Mathilde; Dufer, Jean; Antonicelli, Frank; Trussardi-Regnier, Aurelie

    2011-06-01

    The matrix metalloproteinase (MMP) family members play an important role in various physiological and pathological processes. Although MMP-1 (collagenase-1) has been shown to be involved in tumor invasiveness, the regulation of its expression is still not fully elucidated and could implicate epigenetic mechanisms. The aim of this study was to analyze the effects of the Histone Deacetylase Inhibitor (HDI) trichostatin A (TSA) and the inhibitor of DNA methylation 5-aza-2'-deoxycytidine (5-azadC) on the proMMP-1 expression in the human HT1080 fibrosarcoma cell line. Real-time RT-PCR revealed that 5-azadC or 5-azadC + TSA but not TSA alone, despite global histone H4 hyperacetylation, increased proMMP-1 mRNA levels. This transcription activation was correlated with chromatin decondensation determined by nuclear texture image analysis technique. Western blot analysis of cell culture conditioned media revealed a significant increase in proMMP-1 secretion after 5-azadC or 5-azadC + TSA treatment compared to untreated cells. These results suggested that epigenetic mechanisms could be involved in proMMP-1 gene expression including chromatin supra-organization changes. Indeed, although the proMMP-1 gene promoter does not appear to contain CpG islands, its expression can be induced by the demethylating agent 5-azadC. Further experiments revealed that inhibition of protein neosynthesis by cycloheximide decreased 5-azadC-induced proMMP-1 mRNA, suggesting that epigenetically regulated intermediate molecules could be involved in proMMP-1 expression regulation in these cells.

  6. Systems Biology Strategy Reveals PKCδ is Key for Sensitizing TRAIL-Resistant Human Fibrosarcoma

    PubMed Central

    Hayashi, Kentaro; Tabata, Sho; Piras, Vincent; Tomita, Masaru; Selvarajoo, Kumar

    2015-01-01

    Cancer cells are highly variable and largely resistant to therapeutic intervention. Recently, the use of the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced treatment is gaining momentum due to TRAIL’s ability to specifically target cancers with limited effect on normal cells. Nevertheless, several malignant cancer types still remain non-sensitive to TRAIL. Previously, we developed a dynamic computational model, based on perturbation-response differential equations approach, and predicted protein kinase C (PKC) as the most effective target, with over 95% capacity to kill human fibrosarcoma (HT1080) in TRAIL stimulation (1). Here, to validate the model prediction, which has significant implications for cancer treatment, we conducted experiments on two TRAIL-resistant cancer cell lines (HT1080 and HT29). Using PKC inhibitor bisindolylmaleimide I, we demonstrated that cell viability is significantly impaired with over 95% death of both cancer types, in consistency with our previous model. Next, we measured caspase-3, Poly (ADP-ribose) polymerase (PARP), p38, and JNK activations in HT1080, and confirmed cell death occurs through apoptosis with significant increment in caspase-3 and PARP activations. Finally, to identify a crucial PKC isoform, from 10 known members, we analyzed each isoform mRNA expressions in HT1080 cells and shortlisted the highest 4 for further siRNA knock-down (KD) experiments. From these KDs, PKCδ produced the most cancer cell death in conjunction with TRAIL. Overall, our approach combining model predictions with experimental validation holds promise for systems biology based cancer therapy. PMID:25601862

  7. Anti-metastatic effects of fuzhengfangaitang on human fibrosarcoma cells HT1080.

    PubMed

    Shim, Bum-Sang; Park, Kun-Koo; Choi, Seung-Hoon

    2003-01-01

    Fuzhengfangaitang (FZFAT) is used to inhibit recurrence and metastasis of cancer in the clinic. By applying an in vitro invasion assay model, we examined the antimetastatic effect of FZFAT. In the 3H-thymidine incorporation assay, FZFAT-treated groups showed a decreased DNA synthesis rate compared with the control group (F-value 87.42981, P-value 2.02E-08, F0.05(3,12) 3.4903). Gelatin zymogram assay showed that FZFAT decreased the gelatinolytic activity of matrix metalloproteinases-9 (MMP-9) from human fibrosarcoma cell line (HT-1080), at concentrations of 200 and 400 microg/ml. In the MMPs dot blotting assay, FZFAT inhibited the expression of MMP-1 at concentration of 100 microg/ml, and MMP-9 at concentrations of 200 and 400 microg/ml. Western blots for AP-1 and its signal mediators Erk and JNK showed that expression of Fos and JNK were decreased by the addition of FZFAT at 300 microg/ml, whereas Erk was not. Therefore it was evident that FZFAT regulated the expression of MMP-9 through its transcription factor AP-1 and the signal mediator JNK. We examined whether FZFAT inhibited the invasion of HT-1080 cells through matrigel precoated transwell chambers. The results showed that FZFAT effectively inhibited the invasion of HT-1080 cells as compared with the control phorbol 12-myristate-13-acetate (+PMA) groups (t-value 5.871584, P-value 0.013901, t0.05(2) 2.919987). From our research, part of the mechanism underlying the antimetastatic effect of FZFAT has been elucidated in vitro.

  8. Junctional adhesion molecule-C promotes metastatic potential of HT1080 human fibrosarcoma.

    PubMed

    Fuse, Chiaki; Ishida, Yuuki; Hikita, Tomoya; Asai, Tomohiro; Oku, Naoto

    2007-03-16

    The junctional adhesion molecule (JAM) family is a key molecule in a process called transendothelial migration or diapedesis. Here, we report implications of JAM-C in cancer metastasis. We first determined the mRNA expression of JAMs in 19 kinds of cancer cell lines. JAM-C was expressed in most of tumors having potent metastatic properties. Especially in murine K-1735 melanoma cell lines, the highly metastatic sublines (M2 and X21) strongly expressed JAM-C when compared with the poorly metastatic ones (C-10 and C23). Next, we investigated the role of JAM-C in cancer metastasis by using human JAM-C (hJAM-C) gene-transfected HT1080 fibrosarcoma cells. In comparison with mock-transfected HT1080 cells, these cells showed a significant increase in the adhesion to various extracellular substrates and the invasion across a Matrigel-coated membrane. The knockdown of hJAM-C using small interfering RNA resulted in the suppression of both the adhesion and the invasion of HT1080 cells, suggesting that endogenous hJAM-C might be involved in tumor metastasis. Finally, we studied the role of hJAM-C in an in vivo experimental metastatic model. The results showed that the overexpression of hJAM-C in HT1080 cells significantly decreased the life spans of the tumorbearing mice. In contrast, the knockdown of hJAM-C in HT1080 cells suppressed the weight gain of the lungs with metastatic colonies. We conclude that the expression of JAM-C promotes metastasis by enhancing both the adhesion of cancer cells to extracellular matrices and the subsequent invasion.

  9. Ameloblastic fibrosarcoma of the upper jaw: Report of a rare case with long-term follow-up

    PubMed Central

    Khalili, Maryam; Shakib, Pouyan Amini

    2013-01-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant mixed odontogenic tumor which is usually considered as the malignant counterpart of ameloblastic fibroma. Only mesenchymal component represents sarcomatous alterations and ameloblast-like epithelial nest remains bland in AFS. Here, we report a case of AFS in a 26-year-old man in the maxilla, which was regarded as an uncommon location for this tumor. After 2 years follow up, no evidence of recurrence was noted. We also emphasize on comprehensive clinical, radiographic, and histopathologic evaluation of such patients rather than immunohistochemical staining to make an accurate diagnosis. PMID:23878574

  10. Anaplastic ameloblastic fibrosarcoma arising from recurrent ameloblastic fibroma: restricted molecular abnormalities of certain genes to the malignant transformation.

    PubMed

    Williams, Michelle D; Hanna, Ehab Y; El-Naggar, Adel K

    2007-07-01

    A rare case of anaplastic ameloblastic fibrosarcoma (AS) arising in an ameloblastic fibroma (AF) of the maxilla of a 48-year-old patient 10 years after the primary excision is presented. The recurrent tumor retained focal areas of AF but manifested heterogeneous malignant features ranging from low-grade spindle to highly pleomorphic sarcomas. Biomarker analysis showed alterations of the p53 and c-KIT genes restricted to the sarcomatous component. The biological implications of these findings in the future management of these tumors are discussed.

  11. Ameloblastic fibrosarcoma of the upper jaw: Report of a rare case with long-term follow-up.

    PubMed

    Khalili, Maryam; Shakib, Pouyan Amini

    2013-01-01

    Ameloblastic fibrosarcoma (AFS) is a rare malignant mixed odontogenic tumor which is usually considered as the malignant counterpart of ameloblastic fibroma. Only mesenchymal component represents sarcomatous alterations and ameloblast-like epithelial nest remains bland in AFS. Here, we report a case of AFS in a 26-year-old man in the maxilla, which was regarded as an uncommon location for this tumor. After 2 years follow up, no evidence of recurrence was noted. We also emphasize on comprehensive clinical, radiographic, and histopathologic evaluation of such patients rather than immunohistochemical staining to make an accurate diagnosis.

  12. Ameloblastic Fibrosarcoma of the mandible evolving from a prior Ameloblastic Fibroma after two years: an unusual finding.

    PubMed

    Bertoni, Franco; Del Corso, Giacomo; Bacchini, Patrizia; Marchetti, Claudio; Tarsitano, Achille

    2016-10-01

    Transformation of an ameloblastic fibroma to an ameloblastic fibrosarcoma has been reported rarely in the literature. The present case report describes such evolution in a patient under long-term follow-up. The patient was first treated in 2008, and he developed the malignant counterpart of the disease 2 years later. The patient is currently under careful long-term follow-up and is free of disease. This article describes the clinical and radiographic features, histological characteristics, immunohistochemical findings, and surgical treatment of the tumor. © The Author(s) 2016.

  13. Pro-oncogenic and anti-oncogenic pathways: opportunities and challenges of cancer therapy

    PubMed Central

    Zhang, Jiao; Chen, Yan-Hua; Lu, Qun

    2010-01-01

    Carcinogenesis is the uncontrolled growth of cells gaining the potential to invade and disrupt vital tissue functions. This malignant process includes the occurrence of ‘unwanted’ gene mutations that induce the transformation of normal cells, for example, by overactivation of pro-oncogenic pathways and inactivation of tumor-suppressive or anti-oncogenic pathways. It is now recognized that the number of major signaling pathways that control oncogenesis is not unlimited; therefore, suppressing these pathways can conceivably lead to a cancer cure. However, the clinical application of cancer intervention has not matched up to scientific expectations. Increasing numbers of studies have revealed that many oncogenic-signaling elements show double faces, in which they can promote or suppress cancer pathogenesis depending on tissue type, cancer stage, gene dosage and their interaction with other players in carcinogenesis. This complexity of oncogenic signaling poses challenges to traditional cancer therapy and calls for considerable caution when designing an anticancer drug strategy. We propose future oncology interventions with the concept of integrative cancer therapy. PMID:20373871

  14. Oncogenes and tumor suppressor genes as paradigms in oncogenesis.

    PubMed

    Spandidos, Demetrios A

    2007-09-01

    Cancer is the result of genetic and epigenetic changes that occur mainly in stem (precursor) cells of various cell types. Two main categories of genes are involved in the process of carcinogenesis. Oncogenes are activated proto-oncogenes and tumor suppressor genes are inactivated by mutation in the global sense, that is point mutation, deletion, rearrangement, and duplication. Both types of genes are required for normal cell proliferation and differentiation and aberrant expression leads to abnormal cell proliferation. Ras and p53 genes are the paradigms for oncogenes and tumor suppressor genes, respectively, whereas the oncogenes carried by the human papillomaviruses (HPV) comprise the best example of tumor viruses involvement in human cancer.

  15. Oncogenic activation of NF-kappaB.

    PubMed

    Staudt, Louis M

    2010-06-01

    Recent genetic evidence has established a pathogenetic role for NF-kappaB signaling in cancer. NF-kappaB signaling is engaged transiently when normal B lymphocytes respond to antigens, but lymphomas derived from these cells accumulate genetic lesions that constitutively activate NF-kappaB signaling. Many genetic aberrations in lymphomas alter CARD11, MALT1, or BCL10, which constitute a signaling complex that is intermediate between the B-cell receptor and IkappaB kinase. The activated B-cell-like subtype of diffuse large B-cell lymphoma activates NF-kappaB by a variety of mechanisms including oncogenic mutations in CARD11 and a chronic active form of B-cell receptor signaling. Normal plasma cells activate NF-kappaB in response to ligands in the bone marrow microenvironment, but their malignant counterpart, multiple myeloma, sustains a variety of genetic hits that stabilize the kinase NIK, leading to constitutive activation of the classical and alternative NF-kappaB pathways. Various oncogenic abnormalities in epithelial cancers, including mutant K-ras, engage unconventional IkappaB kinases to activate NF-kappaB. Inhibition of constitutive NF-kappaB signaling in each of these cancer types induces apoptosis, providing a rationale for the development of NF-kappaB pathway inhibitors for the treatment of cancer.

  16. Oncogenic regulation of tumor metabolic reprogramming

    PubMed Central

    Tarrado-Castellarnau, Míriam; de Atauri, Pedro; Cascante, Marta

    2016-01-01

    Development of malignancy is accompanied by a complete metabolic reprogramming closely related to the acquisition of most of cancer hallmarks. In fact, key oncogenic pathways converge to adapt the metabolism of carbohydrates, proteins, lipids and nucleic acids to the dynamic tumor microenvironment, conferring a selective advantage to cancer cells. Therefore, metabolic properties of tumor cells are significantly different from those of non-transformed cells. In addition, tumor metabolic reprogramming is linked to drug resistance in cancer treatment. Accordingly, metabolic adaptations are specific vulnerabilities that can be used in different therapeutic approaches for cancer therapy. In this review, we discuss the dysregulation of the main metabolic pathways that enable cell transformation and its association with oncogenic signaling pathways, focusing on the effects of c-MYC, hypoxia inducible factor 1 (HIF1), phosphoinositide-3-kinase (PI3K), and the mechanistic target of rapamycin (mTOR) on cancer cell metabolism. Elucidating these connections is of crucial importance to identify new targets and develop selective cancer treatments that improve response to therapy and overcome the emerging resistance to chemotherapeutics. PMID:28040803

  17. Oncogenic KRAS signalling in pancreatic cancer.

    PubMed

    Eser, S; Schnieke, A; Schneider, G; Saur, D

    2014-08-26

    Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

  18. The modulation of apoptosis by oncogenic viruses

    PubMed Central

    2013-01-01

    Transforming viruses can change a normal cell into a cancer cell during their normal life cycle. Persistent infections with these viruses have been recognized to cause some types of cancer. These viruses have been implicated in the modulation of various biological processes, such as proliferation, differentiation and apoptosis. The study of infections caused by oncogenic viruses had helped in our understanding of several mechanisms that regulate cell growth, as well as the molecular alterations leading to cancer. Therefore, transforming viruses provide models of study that have enabled the advances in cancer research. Viruses with transforming abilities, include different members of the Human Papillomavirus (HPV) family, Hepatitis C virus (HCV), Human T-cell Leukemia virus (HTLV-1), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV). Apoptosis, or programmed cell death, is a tightly regulated process that plays an important role in development and homeostasis. Additionally, it functions as an antiviral defense mechanism. The deregulation of apoptosis has been implicated in the etiology of diverse diseases, including cancer. Oncogenic viruses employ different mechanisms to inhibit the apoptotic process, allowing the propagation of infected and damaged cells. During this process, some viral proteins are able to evade the immune system, while others can directly interact with the caspases involved in apoptotic signaling. In some instances, viral proteins can also promote apoptosis, which may be necessary for an accurate regulation of the initial stages of infection. PMID:23741982

  19. The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice.

    PubMed

    Chand, Hitendra Singh; Du, Xin; Ma, Duan; Inzunza, Hector David; Kamei, Shintaro; Foster, Donald; Brodie, Steven; Kisiel, Walter

    2004-02-01

    Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin- and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion, and metastasis. To directly assess its role in tumor growth and metastasis in vivo, we stably transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT) and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2 to 3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT or QT cells, whereas only 42% of mice treated with WT cells developed lung metastases. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of each tumor group revealed 3- to 6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene expression analysis revealed that several human genes implicated in oncogenesis, invasion, metastasis, apoptosis, and angiogenesis had significantly altered levels of expression in WT tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in vivo by regulating pericellular extracellular matrix (ECM) remodeling and angiogenesis.

  20. Ambiguous effect of signals transmitted by the vagus nerve on fibrosarcoma incidence and survival of tumor-bearing rats.

    PubMed

    Mikova, Lucia; Horvathova, Lubica; Ondicova, Katarina; Tillinger, Andrej; Vannucci, Luca E; Bizik, Jozef; Gidron, Yori; Mravec, Boris

    2015-04-23

    While the parasympathetic nervous system appears to be involved in the regulation of tumor progression, its exact role is still unclear. Therefore, using a rat BP6-TU2 fibrosarcoma tumor model, we investigated the effect of (1) reduction of vagal activity produced by subdiaphragmatic vagotomy; and (2) enhancement of vagal activity produced by continuous delivery of electric impulses to the cervical part of the vagus nerve on tumor development and survival of tumor-bearing rats. We also evaluated the expression of cholinergic receptors within in vitro cultivated BP6-TU2 cells. Interestingly, we found that both, vagal stimulation and subdiaphragmatic vagotomy slightly reduced tumor incidence. However, survival of tumor-bearing rats was not affected by any of the experimental approaches. Additionally, we detected mRNA expression of the α1, α2, α5, α7, and α10 subunits of nicotinic receptors and the M1, M3, M4, and M5 subtypes of muscarinic receptors within in vitro cultivated BP6-TU2 cells. Our data indicate that the role of the vagus nerve in modulation of fibrosarcoma development is ambiguous and uncertain and requires further investigation.

  1. Immunoexpression of Ki67, proliferative cell nuclear antigen, and Bcl-2 proteins in a case of ameloblastic fibrosarcoma.

    PubMed

    Pontes, Hélder Antônio Rebelo; Pontes, Flávia Sirotheau Corrêa; Silva, Brunno Santos de Freitas; Cury, Sérgio Elias Vieira; Fonseca, Felipe Paiva; Salim, Rodrigo Alves; Pinto Júnior, Décio dos Santos

    2010-12-01

    Ameloblastic fibrosarcoma (AFS), regarded as the malignant counterpart of the benign ameloblastic fibroma, is an extremely rare odontogenic neoplasm with only 68 cases reported in the English literature up to 2009. It is composed of a benign odontogenic epithelium, resembling that of ameloblastoma, and a malignant mesenchymal part exhibiting features of fibrosarcoma. Due to the rarity of the lesion, little is known about its molecular pathogenesis; therefore, in the current study, we sought to evaluate the immunoexpression of Ki67, proliferative cell nuclear antigen, and Bcl-2 proteins in AFS, comparing the results obtained with its benign counterpart, as well as to report a new case of this rare entity affecting a 19-year-old female patient. The results obtained revealed that all the proteins evaluated were overexpressed in the malignant mesenchymal portion of AFS if compared with ameloblastic fibroma, suggesting that nuclear proliferative factors such as Ki67 and proliferative cell nuclear antigen, in association to histopathologic features, may be useful markers for identifying the malignancy and that, despite the lack of molecular analysis in the case reported, Bcl-2 alteration may play a role in AFS pathogenesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. A fish antimicrobial peptide, tilapia hepcidin TH2-3, shows potent antitumor activity against human fibrosarcoma cells.

    PubMed

    Chen, Jyh-Yih; Lin, Wei-Ju; Lin, Tai-Lang

    2009-09-01

    As part of a continuing search for potential anticancer drug candidates from antimicrobial peptides of marine organisms, tilapia (Oreochromis mossambicus) hepcidin TH2-3 was evaluated in several tumor cell lines. The results indicated that TH2-3, a synthetic 20-mer antimicrobial peptide, specifically inhibited human fibrosarcoma cell (HT1080 cell line) proliferation and migration. The way in which TH2-3 inhibited HT1080 cell growth was then studied. TH2-3 inhibited HT1080 cell growth in a concentration-dependent manner according to an MTT analysis, which was confirmed by a soft-agar assay and AO/EtBr staining. Scanning electron microscopy revealed that TH2-3 caused lethal membrane disruption in HT1080 cancer cells, and a wound healing assay supported that TH2-3 decreased the migration of HT1080 cells. In addition, c-Jun mRNA expression was downregulated after treatment with TH2-3 for 48-96 h compared to the untreated group. These findings suggest a mechanism of cytotoxic action of TH2-3 and indicate that TH2-3 may be a promising chemotherapeutic agent against human fibrosarcoma cells.

  3. Boyden chamber-based method for characterizing the distribution of adhesions and cytoskeletal structure in HT1080 fibrosarcoma cells

    PubMed Central

    Tóvári, József; Futosi, Krisztina; Bartal, Alexandra; Tátrai, Enikő; Gacs, Alexandra; Kenessey, István; Paku, Sándor

    2014-01-01

    A 2D model was previously presented that describes the gliding motility of human fibrosarcoma cells. The model was based on the observation that adhesions are present only on the outer rim of the leading lamella of the semicircular cell. The present model describes the organization of adhesions and the cytoskeleton of migrating HT1080 fibrosarcoma and LX2 hepatic stellate cells in three dimensions. The migration assays were performed in a modified Boyden chamber using fibronectin, Matrigel, or collagen I as chemoattractants. The distribution of the adhesions was analyzed by confocal laser scanning microscope, and following decoration with heavy meromyosin, the organization of actin filaments was analyzed by electron microscopy. Double labeling was performed to study the relationship of the actin and vimentin filament network in the moving cells. Vinculin containing adhesions were observed only at the front of the cell in the form of a ring while passing through a filter pore of the Boyden chamber. Actin filaments were present only below the plasma membrane, except the very tip of the leading lamella. Vimentin intermediate filaments were localized around the cell nucleus behind the actin filament-rich lamella. This paper describes a model of the organization of adhesions and the cytoskeleton of migrating cells in the Boyden chamber. The model is based on the observation that adhesions are present only at the leading edge of the cell. The results extend the earlier 2D model of cell locomotion into 3D. PMID:25482525

  4. Boyden chamber-based method for characterizing the distribution of adhesions and cytoskeletal structure in HT1080 fibrosarcoma cells.

    PubMed

    Tóvári, József; Futosi, Krisztina; Bartal, Alexandra; Tátrai, Enikő; Gacs, Alexandra; Kenessey, István; Paku, Sándor

    2014-01-01

    A 2D model was previously presented that describes the gliding motility of human fibrosarcoma cells. The model was based on the observation that adhesions are present only on the outer rim of the leading lamella of the semicircular cell. The present model describes the organization of adhesions and the cytoskeleton of migrating HT1080 fibrosarcoma and LX2 hepatic stellate cells in three dimensions. The migration assays were performed in a modified Boyden chamber using fibronectin, Matrigel, or collagen I as chemoattractants. The distribution of the adhesions was analyzed by confocal laser scanning microscope, and following decoration with heavy meromyosin, the organization of actin filaments was analyzed by electron microscopy. Double labeling was performed to study the relationship of the actin and vimentin filament network in the moving cells. Vinculin containing adhesions were observed only at the front of the cell in the form of a ring while passing through a filter pore of the Boyden chamber. Actin filaments were present only below the plasma membrane, except the very tip of the leading lamella. Vimentin intermediate filaments were localized around the cell nucleus behind the actin filament-rich lamella. This paper describes a model of the organization of adhesions and the cytoskeleton of migrating cells in the Boyden chamber. The model is based on the observation that adhesions are present only at the leading edge of the cell. The results extend the earlier 2D model of cell locomotion into 3D.

  5. Matrix metalloproteinase-9 silencing by RNA interference promotes the adhesive-invasive switch in HT1080 human fibrosarcoma cells.

    PubMed

    Zhu, Xishan; Tai, Weiping; Shi, Wei; Song, Yuguang; Zhang, Hongmei; An, Guangyu

    2012-01-01

    A high level of matrix metalloproteinase-9 (MMP-9) is associated with human tumor invasion and/or metastasis. The HT1080 human fibrosarcoma cell line is highly invasive and metastatic which constitutively express MMP-9. HT1080 cells transfected with a double stranded RNA that targeted the MMP-9 mRNA and the cellular characteristics were examined before and after interference. The inhibition effects of MMP-9 interference on the tumor growth of HT1080 cells in nude mice was also tested by xenograft assay. MMP-9 extinction in HT1080 resulted in the following: (1) inhibited cell mobility; (2) increased cell adhesion, and (3) attenuated tumor cell migration. In addition, MMP-9 knockdown concomitantly resulted in decreased levels of soluble ICAM-1, leading to an adhesion defect and tumor metastasis. Moreover, in vivo assay further demonstrated MMP-9 interference affecting the tumorigenesis of HT1080 cells in mice as follows (1) inhibition of tumor growth; (2) reduced tumor volume, and (3) prolonged survival time. Our observations defined a novel critical role for MMP-9 in the progression of HT1080 fibrosarcoma by changing the inter-cellular adhesion molecular-1 from membrane-anchored state to a soluble one which provides a target for promising tumor therapy in clinics.

  6. Post-radiation fibrosarcoma of the cerebrum associated with a prominent, lace-like, perivascular, desmoplastic change.

    PubMed

    Shintaku, Masayuki; Adachi, Yasushi; Takeuchi, Yasuhide; Yamamoto, Daisuke; Koyama, Junji

    2016-04-01

    An intra-axial tumor measuring about 4 cm was excised from the right temporal lobe of a 35-year-old woman, who had a past history of resection of craniopharyngioma and postoperative radiation 21 years earlier. The tumor involved both the cortex and white matter, but was not attached to the dura mater. It consisted of a dense, interlacing, fascicular proliferation of atypical fibroblastic cells and was associated with an extensive, lace-like, desmoplastic change mainly involving the perivascular region around the tumor and overlying the subarachnoid space. The histopathological features of the desmoplastic change resembled meningioangiomatosis, but no proliferation of meningothelial cells was noted. The patient has been free from recurrence for 12 months since the operation. The association of primary cerebral fibrosarcoma with an extensive, lace-like, perivascular, desmoplastic change has not been documented in the literature. The radiation administered 21 years previously may have played some pathogenetic role in the perivascular desmoplastic change, and a malignant transformation of fibroblasts within the perivascular collagenous tissue is considered the most likely origin of the fibrosarcoma. © 2015 Japanese Society of Neuropathology.

  7. [Oncogenes and the origin of leukemia. Acute avian leukemia viruses].

    PubMed

    Graf, T

    1988-03-01

    Oncogenes have been intimately associated with the genesis of human neoplasms. A particularly useful system to study the mechanism of tumorigenesis is a small group of avian retroviruses that carry two oncogenes. These viruses causes acute leukemias and can transform hematopoietic cells in vitro. The mechanisms by which viral oncogenes affect the growth control and differentiation of their target cells is now understood in fair detail for two of these virus strains. In the avian erythroblastosis virus AEV, the v-erbB oncogene deregulates the growth control of erythroid precursors, while verbA blocks their terminal differentiation into erythrocytes. Based on the findings that v-erbB oncogene corresponds to a mutated growth factor receptor gene and that v-erbA corresponds to a mutated hormone receptor gene, models have been developed that explain the function of these two oncogenes on a molecular basis. The myelomonocytic leukemia virus MH2 acts by a completely different mechanism. In this case, the v-myc oncogene stimulates the proliferation of macrophage-like cells, while the v-mil gene stimulates them to produce their own growth factor, thus leading to autocrine growth. It will be interesting to determine whether the type of mechanisms of oncogene cooperativity elucidated for acute leukemia viruses are also operative during leukemogenesis in humans.

  8. Oncogenic Transformation of Human-Derived Gastric Organoids.

    PubMed

    Bertaux-Skeirik, Nina; Centeno, Jomaris; Gao, Jian; Gabre, Joel; Zavros, Yana

    2016-08-19

    The culture of organoids has represented a significant advancement in the gastrointestinal research field. Previous research studies have described the oncogenic transformation of human intestinal and mouse gastric organoids. Here we detail the protocol for the oncogenic transformation and orthotopic transplantation of human-derived gastric organoids.

  9. Oncogenic pathways implicated in ovarian epithelial cancer.

    PubMed

    Nicosia, Santo V; Bai, Wenlong; Cheng, Jin Q; Coppola, Domenico; Kruk, Patricia A

    2003-08-01

    Characterization of intracellular signaling pathways should lead to a better understanding of ovarian epithelial carcinogenesis and provide an opportunity to interfere with signal transduction targets involved in ovarian tumor cell growth, survival, and progression. Challenges toward such an effort are significant because many of these signals are part of cascades within an intricate and likely redundant intracellular signaling network (Fig.1). For instance, a given signal may activate a dual intracellular pathway (ie, MEK1-MAPK and PI3K/Akt required for fibronectin-dependent activation of matrix metalloproteinase 9). A single pathway also may transduce more than one biologic or oncogenic signal (ie, PI3K signaling in epithelial and endothelial cell growth and sprouting of neovessels). Despite these challenges, evidence for therapeutic targeting of signal transduction pathways is accumulating in human cancer. For instance, the EGF-specific tyrosine kinase inhibitor ZD 1839 (Iressa) may have a beneficial therapeutic effect on ovarian epithelial cancer. Therapy of this cancer may include inhibitors of PI kinase (quercetin), ezrin and PIP kinase (genistein). The G protein-coupled family of receptors, including LPA, also is an attractive target to drugs, although their frequent pleiotropic functions may be at times toxic and lack specificity. Because of the lack of notable toxicity, PI3K/Akt pathway inhibitors such as FTIs are a promising targeted therapy of ovarian epithelial cancer. Increasing insight into the oncogenic pathways involved in ovarian epithelial cancer also is helping clinicians to understand better the phenomenon of chemoresistance in this malignancy. Oncogenic activation of gamma-synuclein promotes cell survival and provides resistance to paclitaxel, but such a resistance is partially overcome by an MEK inhibitor that suppresses ERK activity. Ovarian epithelial cancer is a complex group of neoplasms with an overall poor prognosis. Comprehension of

  10. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

    PubMed

    Northcott, Paul A; Lee, Catherine; Zichner, Thomas; Stütz, Adrian M; Erkek, Serap; Kawauchi, Daisuke; Shih, David J H; Hovestadt, Volker; Zapatka, Marc; Sturm, Dominik; Jones, David T W; Kool, Marcel; Remke, Marc; Cavalli, Florence M G; Zuyderduyn, Scott; Bader, Gary D; VandenBerg, Scott; Esparza, Lourdes Adriana; Ryzhova, Marina; Wang, Wei; Wittmann, Andrea; Stark, Sebastian; Sieber, Laura; Seker-Cin, Huriye; Linke, Linda; Kratochwil, Fabian; Jäger, Natalie; Buchhalter, Ivo; Imbusch, Charles D; Zipprich, Gideon; Raeder, Benjamin; Schmidt, Sabine; Diessl, Nicolle; Wolf, Stephan; Wiemann, Stefan; Brors, Benedikt; Lawerenz, Chris; Eils, Jürgen; Warnatz, Hans-Jörg; Risch, Thomas; Yaspo, Marie-Laure; Weber, Ursula D; Bartholomae, Cynthia C; von Kalle, Christof; Turányi, Eszter; Hauser, Peter; Sanden, Emma; Darabi, Anna; Siesjö, Peter; Sterba, Jaroslav; Zitterbart, Karel; Sumerauer, David; van Sluis, Peter; Versteeg, Rogier; Volckmann, Richard; Koster, Jan; Schuhmann, Martin U; Ebinger, Martin; Grimes, H Leighton; Robinson, Giles W; Gajjar, Amar; Mynarek, Martin; von Hoff, Katja; Rutkowski, Stefan; Pietsch, Torsten; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Kulozik, Andreas E; von Deimling, Andreas; Witt, Olaf; Eils, Roland; Gilbertson, Richard J; Korshunov, Andrey; Taylor, Michael D; Lichter, Peter; Korbel, Jan O; Wechsler-Reya, Robert J; Pfister, Stefan M

    2014-07-24

    Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.

  11. Stimulation and inhibition of 5 ALA induced PplX fluorescence in the diagnosis of fibrosarcoma cultivated on the CAM using glucose versus ethanol as modulating agents.

    PubMed

    Ismail, M Samy

    2008-07-01

    The fluorescence properties of biological tissues have been considered as intrinsic parameters to discriminate diseased from normal conditions. In vivo fluorescence diagnosis of cancer is based on special fluorescent dyes and their properties of tumour selective retention. The experimental in vivo model of the chorioallantoic membrane (CAM) of chicken embryos was used for cultivating a murine tumourous system consisting of the SSK II fibrosarcoma. Proto porphyrine (PplX) synthesis in CAM inoculated tissues as well as in native CAM was induced by 5-ALA. The modulation effects of several biochemicals on the 5-ALA induced PplX production were tested. The fibrosarcoma cells have not revealed autofluorescence with distinctively higher signal intensities than the substrate tissue. Fibrosarcoma cells are clearly distinguished by higher xenofluorescence intensities compared to the CAM tissue in the background. 5-ALA induced xenofluorescence intensity in fibrosarcoma was significantly enhanced by glucose and inhibited by ethanol. It can be concluded that some chemical agents can modulate the intensity of 5-ALA induced xenofluorescence through their modulation the enzymatic cell activity and these can be used for improvement by varying both the diagnostic and the therapeutic effectiveness of the photosensitizers in its application in the photo therapy process.

  12. The Exceptional Oncogenicity of HTLV-1.

    PubMed

    Tagaya, Yutaka; Gallo, Robert C

    2017-01-01

    Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus identified in 1979 by the Gallo group. HTLV-1 causes fatal T-cell leukemia (adult T cell leukemia) and a progressive myelopahy (HTLV-1-associated myelopathy/ tropical spastic paraparesis, HAM/TSP) and other disorders. Since the discovery of HTLV-1, several other microorganisms are demonstrated to cause cancer in humans. In this article, we investigated the oncogenic capacity of HTLV-1, in comparison with those of other oncoviruses and one oncobacterium (Helicobacter pylori, H. Pylori) based on published literature. We conclude here that HTLV-1 is one of the most and may be the most carcinogenic among them and arguably one of the most potent of the known human carcinogens. This fact has not been noted before and is particularly important to justify why we need to study HTLV-1 as an important model of human viral oncogenesis.

  13. Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling

    PubMed Central

    Callahan, Brian P.; Wang, Chunyu

    2015-01-01

    Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog’s biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. PMID:26473928

  14. CDC25 phosphatases as potential human oncogenes.

    PubMed

    Galaktionov, K; Lee, A K; Eckstein, J; Draetta, G; Meckler, J; Loda, M; Beach, D

    1995-09-15

    Cyclin-dependent kinases (CDKs) are activated by CDC25 phosphatases, which remove inhibitory phosphate from tyrosine and threonine residues. In human cells, CDC25 proteins are encoded by a multigene family, consisting of CDC25A, CDC25B, and CDC25C. In rodent cells, human CDC25A or CDC25B but not CDC25C phosphatases cooperate with either Ha-RASG12V or loss of RB1 in oncogenic focus formation. Such transformants were highly aneuploid, grew in soft agar, and formed high-grade tumors in nude mice. Overexpression of CDC25B was detected in 32 percent of human primary breast cancers tested. The CDC25 phosphatases may contribute to the development of human cancer.

  15. K-ras oncogene mutation in pterygium.

    PubMed

    Ozturk, B T; Yıldırım, M S; Zamani, A; Bozkurt, B

    2017-03-01

    PurposePterygium is claimed to be a benign proliferation triggered by prolonged exposure to ultraviolet radiation. The frequency of K-ras oncogene mutation, which is among the initial mutations in tumorigenesis, is evaluated in this study.Patients and methodsIn this prospective randomized clinical, trial pterygium tissues and normal conjunctiva tissue specimens are obtained from the superotemporal quadrant of patients who underwent primary pterygium excision with autograft transplantation. DNA extraction from tissues was performed using the QIAamp DNA FFPE tissue kit. A PCR reaction was performed to amplify sequences containing codons 12, 13, and 61 of the K-ras gene in DNA. These PCR products then underwent the 'pyrosequencing' procedure for mutations at these codons.ResultsPterygium and normal conjunctival tissue samples of 25 patients (10 females, 15 males) were evaluated in the study. The mean age of the patients was 54.54±13.13 years. Genetic analysis revealed no K-ras mutations in normal conjunctival tissues, whereas pterygium tissues of the same cases demonstrated mutation at codon 12 in one case and mutations at codon 61 in seven cases, which was statistically significant (P<0.05). The point missense mutations at codon 61 were glutamine to arginine (Glu61Arg CAA>CGA) in four cases and glutamine to leucine (Glu61Leu CAA>CTA) in three cases.ConclusionThe significantly higher frequency of codon 61 mutation of the ras oncogene in primary and bilateral pterygium specimens compared with normal conjunctiva supports the tumoral origin of pterygium, and thus set the stage for research into a targeted therapy for pterygium with better outcomes than surgical excision.

  16. Glycerophospholipid profile in oncogene-induced senescence.

    PubMed

    Cadenas, Cristina; Vosbeck, Sonja; Hein, Eva-Maria; Hellwig, Birte; Langer, Alice; Hayen, Heiko; Franckenstein, Dennis; Büttner, Bettina; Hammad, Seddik; Marchan, Rosemarie; Hermes, Matthias; Selinski, Silvia; Rahnenführer, Jörg; Peksel, Begüm; Török, Zsolt; Vígh, László; Hengstler, Jan G

    2012-09-01

    Alterations in lipid metabolism and in the lipid composition of cellular membranes are linked to the pathology of numerous diseases including cancer. However, the influence of oncogene expression on cellular lipid profile is currently unknown. In this work we analyzed changes in lipid profiles that are induced in the course of ERBB2-expression mediated premature senescence. As a model system we used MCF-7 breast cancer cells with doxycycline-inducible expression of NeuT, an oncogenic ERBB2 variant. Affymetrix gene array data showed NeuT-induced alterations in the transcription of many enzymes involved in lipid metabolism, several of which (ACSL3, CHPT1, PLD1, LIPG, MGLL, LDL and NPC1) could be confirmed by quantitative realtime PCR. A study of the glycerophospholipid and lyso-glycerophospholipid profiles, obtained by high performance liquid chromatography coupled to Fourier-transform ion cyclotron resonance-mass spectrometry revealed senescence-associated changes in numerous lipid species, including mitochondrial lipids. The most prominent changes were found in PG(34:1), PG(36:1) (increased) and LPE(18:1), PG(40:7) and PI(36:1) (decreased). Statistical analysis revealed a general trend towards shortened phospholipid acyl chains in senescence and a significant trend to more saturated acyl chains in the class of phosphatidylglycerol. Additionally, the cellular cholesterol content was elevated and accumulated in vacuoles in senescent cells. These changes were accompanied by increased membrane fluidity. In mitochondria, loss of membrane potential along with altered intracellular distribution was observed. In conclusion, we present a comprehensive overview of altered cholesterol and glycerophospholipid patterns in senescence, showing that predominantly mitochondrial lipids are affected and lipid species less susceptible to peroxidation are increased.

  17. Activation of ras oncogenes preceding the onset of neoplasia

    SciTech Connect

    Kumar, R.; Barbacid, M. ); Sukumar, S. )

    1990-06-01

    The identification of ras oncogenes in human and animal cancers including precancerous lesions indicates that these genes participate in the early stages of neoplastic development. Yet, these observations do not define the timing of ras oncogene activation in the multistep process of carcinogenesis. To ascertain the timing of ras oncogene activation, an animal model system was devised that involves the induction of mammary carcinomas in rats exposed at birth to the carcinogen nitrosomethylurea. High-resolution restriction fragment length polymorphism analysis of polymerase chain reaction-amplified ras sequences revealed the presence of both H-ras and K-ras oncogenes in normal mammary glands 2 weeks after carcinogen treatment and at least 2 months before the onset of neoplasia. These ras oncogenes can remain latent within the mammary gland until exposure to estrogens, demonstrating that activation of ras oncogenes can precede the onset of neoplasia and suggesting that normal physiological proliferative processes such as estrogen-induced mammary gland development may lead to neoplasia if the targeted cells harbor latent ras oncogenes.

  18. The oncogenic action of ionizing radiation on rat skin

    SciTech Connect

    Burns, F.J.

    1991-01-01

    Progress has occurred in several areas corresponding to the specific aims of the proposal: (1) Progression and multiple events in radiation carcinogenesis of rat skin as a function of LET; (2) cell cycle kinetics of irradiated rat epidermis as determined by double labeling and double emulsion autoradiography; (3) oncogene activation detected by in situ hybridization in radiation-induced rat skin tumors; (4) amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of LET; and (5) transformation of rat skin keratinocytes by ionizing radiation in combination with c-Ki-ras and c-myc oncogenes. 111 refs., 13 figs., 12 tabs.

  19. The Oncogenic Response to MiR-335 Is Associated with Cell Surface Expression of Membrane-Type 1 Matrix Metalloproteinase (MT1-MMP) Activity

    PubMed Central

    Rojas, Fausto; Hernandez, Maria E.; Silva, Milagros; Li, Lihua; Subramanian, Subbaya; Wilson, Michael J.; Liu, Ping

    2015-01-01

    MicroRNA miR-335 has been reported to have both tumor suppressor and oncogenic activities. In order to determine possible tissue and cell type differences in response to miR-335, we examined the effect of miR-335 on cell expression of MT1-MMP, a proteinase commonly expressed in tumors and associated with cell proliferation and migration. miR-335 increased cell surface expression of MT1-MMP in fibrosarcoma HT-1080 and benign prostate BPH-1 cells, but not in prostate LNCaP or breast MCF-7 tumor cells. miR-335 stimulated proliferation and cell migration in a wound healing in vitro assay in HT-1080, BPH-1, and U87 glioblastoma cells, cells which demonstrated significant cell surface expression of MT1-MMP. In contrast, miR-335 did not affect proliferation or migration in cells without a prominent plasma membrane associated MT1-MMP activity. Our data suggest that differences in response to miR-335 by tumor cells may lie in part in the mechanism of regulation of MT1-MMP production. PMID:26204513

  20. The Oncogenic Response to MiR-335 Is Associated with Cell Surface Expression of Membrane-Type 1 Matrix Metalloproteinase (MT1-MMP) Activity.

    PubMed

    Rojas, Fausto; Hernandez, Maria E; Silva, Milagros; Li, Lihua; Subramanian, Subbaya; Wilson, Michael J; Liu, Ping

    2015-01-01

    MicroRNA miR-335 has been reported to have both tumor suppressor and oncogenic activities. In order to determine possible tissue and cell type differences in response to miR-335, we examined the effect of miR-335 on cell expression of MT1-MMP, a proteinase commonly expressed in tumors and associated with cell proliferation and migration. miR-335 increased cell surface expression of MT1-MMP in fibrosarcoma HT-1080 and benign prostate BPH-1 cells, but not in prostate LNCaP or breast MCF-7 tumor cells. miR-335 stimulated proliferation and cell migration in a wound healing in vitro assay in HT-1080, BPH-1, and U87 glioblastoma cells, cells which demonstrated significant cell surface expression of MT1-MMP. In contrast, miR-335 did not affect proliferation or migration in cells without a prominent plasma membrane associated MT1-MMP activity. Our data suggest that differences in response to miR-335 by tumor cells may lie in part in the mechanism of regulation of MT1-MMP production.

  1. MEK1act/tubulin interaction is an important determinant of mitotic stability in cultured HT1080 human fibrosarcoma cells

    PubMed Central

    Cao, Jia-ning; Shafee, Norazizah; Vickery, Larry; Kaluz, Stefan; Ru, Ning; Stanbridge, Eric J.

    2010-01-01

    Activation of the MAPK pathway plays a major role in neoplastic cell transformation. Using a proteomics approach we identified α tubulin and β tubulin as proteins that interact with activated MEK1, a central MAPK regulatory kinase. Confocal analysis revealed spatio-temporal control of MEK1-tubulin co-localization that was most prominent in the mitotic spindle apparatus in variant HT1080 human fibrosarcoma cells. Peptide arrays identified the critical role of positively charged amino acids R108, R113, R160 and K157 on the surface of MEK1 for tubulin interaction. Overexpression of activated MEK1 caused defects in spindle arrangement, chromosome segregation and ploidy. In contrast, chromosome polyploidy was reduced in the presence of an activated MEK1 mutant (R108A, R113A) that disrupted interactions with tubulin. Our findings indicate the importance of signaling by activated MEK1-tubulin in spindle organization and chromosomal instability. PMID:20570892

  2. Inhibition of cellular proliferation and enhancement of hydrogen peroxide production in fibrosarcoma cell line by weak radio frequency magnetic fields.

    PubMed

    Castello, Pablo R; Hill, Iain; Sivo, Frank; Portelli, Lucas; Barnes, Frank; Usselman, Robert; Martino, Carlos F

    2014-12-01

    This study presents experimental data for the effects of weak radio frequency (RF) magnetic fields on hydrogen peroxide (H2O2) production and cellular growth rates of fibrosarcoma HT1080 cells in vitro. Cells were exposed either to 45 µT static magnetic fields (SMFs)-oriented vertical to the plane of growth or to SMFs combined with weak 5 and 10 MHz RF magnetic fields of 10 µTRMS intensity perpendicular to the static field. Cell numbers were reduced up to 30% on Day 2 for the cells exposed to the combination of SMF and a 10 MHz RF magnetic field compared with the SMF control cells. In addition, cells exposed to 10 MHz RF magnetic fields for 8 h increased H2O2 production by 55%. The results demonstrate an overall magnetic field-induced biological effect that shows elevated H2O2 levels with accompanying decrease in cellular growth rates.

  3. Epithelial Dysplasia in Ameloblastic Fibrosarcoma Arising from Recurrent Ameloblastic Fibroma in a 26-Year-Old Iranian Man.

    PubMed

    Mohsenifar, Zhaleh; Behrad, Samira; Abbas, Fatemeh Mashhadi

    2015-08-18

    BACKGROUND Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumor with a mesenchymal component, showing sarcomatous features and epithelial nests resembling ameloblastic fibroma (AF). CASE REPORT We report a case of AFS showing epithelial dysplasia arising in a recurrent AF in the left mandible after 3 years in a 26-year-old man, which is regarded as an uncommon histopathologic finding in AFS. We also emphasize the comprehensive clinical, radiographic, and histopathologic evaluation, and immunohistochemical staining of this patient. CONCLUSIONS We conclude that it is important to consider malignancy alternations in the epithelial component of AFS, along with that of the mesenchymal component, to provide a proper diagnosis and treatment of recurrent AF.

  4. Primary renal sclerosing epithelioid fibrosarcoma: report of 2 cases with EWSR1-CREB3L1 gene fusion.

    PubMed

    Argani, Pedram; Lewin, Jack R; Edmonds, Pamela; Netto, George J; Prieto-Granada, Carlos; Zhang, Lei; Jungbluth, Achim A; Antonescu, Cristina R

    2015-03-01

    We report the first 2 genetically confirmed cases of primary renal sclerosing epithelioid fibrosarcoma (SEF), occurring in a 17-year-old boy and a 61-year-old woman. In both cases, the tumors demonstrated the typical epithelioid clear cell morphology associated with extensive hyalinizing fibrosis, raising the differential diagnosis of solitary fibrous tumor, metanephric stromal tumor, and the sclerosing variant of clear cell sarcoma of the kidney. Both neoplasms demonstrated diffuse immunoreactivity for MUC4, a highly specific marker for SEF, and both demonstrated evidence of rearrangement of both the EWSR1 and CREB3L1 genes, which have recently been shown to be fused in this entity. Both neoplasms presented with metastatic disease. Primary renal SEF represents yet another translocation-associated sarcoma now shown to arise primarily in the kidney.

  5. Cellular cholesterol regulates MT1 MMP dependent activation of MMP 2 via MEK-1 in HT1080 fibrosarcoma cells.

    PubMed

    Atkinson, Susan J; English, Jane L; Holway, Nicholas; Murphy, Gillian

    2004-05-21

    Unstimulated human fibrosarcoma cells (HT1080) constitutively secrete matrix metalloproteinase 2 (MMP 2) as a proenzyme requiring proteolytic cleavage by membrane type-1 MMP (MT1 MMP) for activation. Physiological and pharmacological stimuli induce clustering of MT1 MMP/tissue inhibitor of MMP 2 "receptors", promoting binding and activation of MMP 2. We now report that cholesterol depleted HT1080 cells accumulated MT1 MMP on the cell surface and activated MMP 2. A specific inhibitor of mitogen activated protein kinase kinase 1/2 inhibited both MMP 2 activation and extracellular signal-related kinase phosphorylation induced by cholesterol depletion. Our data indicate that the cholesterol content of unstimulated cells is critical for secretion of MMP 2 as an inactive zymogen and control of pericellular proteolysis.

  6. Sclerosing Epithelioid Fibrosarcoma of the Bone: A Case Report of High Resistance to Chemotherapy and a Survey of the Literature

    PubMed Central

    Grunewald, Thomas G. P.; von Luettichau, Irene; Weirich, Gregor; Wawer, Angela; Behrends, Uta; Prodinger, Peter M.; Jundt, Gernot; Bielack, Stefan S.; Gradinger, Reiner; Burdach, Stefan

    2010-01-01

    Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue sarcoma mostly occurring in extraosseous sites. SEF represents a clinically challenging entity especially because no standardized treatment regimens are available. Intraosseous localization is an additional challenge with respect to the therapeutical approach. We report on a 16-year-old patient with SEF of the right proximal tibia. The patient underwent standardized neoadjuvant chemotherapy analogous to the EURAMOS-1 protocol for the treatment of osteosarcoma followed by tumor resection and endoprosthetic reconstruction. Histopathological analysis of the resected tumor showed >90% vital tumor cells suggesting no response to chemotherapy. Therefore, therapy was reassigned to the CWS 2002 High-Risk protocol for the treatment of soft tissue sarcoma. To date (22 months after diagnosis), there is no evidence of relapse or metastasis. Our data suggest that SEF may be resistant to a chemotherapy regimen containing Cisplatin, Doxorubicin, and Methotrexate, which should be considered in planning treatment for patients with SEF. PMID:20396630

  7. Sensitizers, protectors and oncogenic transformation in vitro

    SciTech Connect

    Miller, R.C.; Osmak, R.; Zimmerman, M.; Hall, E.J.

    1982-03-01

    Systems developed to assay oncogenic transformation in vitro represent a rapid and powerful tool to screen and compare new radiosensitizers in their carcinogenic potential, and to search for compounds that reduce or inhibit carcinogenesis produced by both radiation and sensitizers. An established line of mouse embryo fibroblasts (C3H/10T1/2 cells) has been used to determine the incidence of transformation produced by a variety of 2 and 5 substituted nitroimidazoles; these include metronidazole, desmethylmisonidazle, misonidazole, SR 2508, SR 2555, R0-07-0741, RSU-1047 and RSU-1021. Most of these sensitizers produce a similar level of transformation; for example a three day exposure of aerated cells to a concentration of 1 mM of the drug results in a transformation incidence comparable to 1 Gy of X rays. The notable exception is SR 2508 which produces a five-fold higher incidence of transformation. The potential carcinogenicity of sensitizers must be considered in choosing which of the currently available new drugs is to be used in clinical trials as an alternative to misonidazle. Superoxide dismutase (SOD), a known free radical scavenger, has been shown to reduce the level of transformation produced by radiation and sensitizers. To be effective, SOD must be present for prolonged periods during the fixation and expression period of the transformation process.

  8. SBRT for oligoprogressive oncogene addicted NSCLC.

    PubMed

    Basler, L; Kroeze, S G C; Guckenberger, M

    2017-04-01

    Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development. About 15-47% of patients present with limited oligoprogressive disease (OPD): such patients show only a limited number of metastases with progression in radiological imaging. Radical local treatment to all oligoprogressive lesions is thought to eradicate the de-differentiated clones and restore overall sensitivity of the metastatic disease. Retrospective studies suggest that aggressive local treatment using stereotactic body radiotherapy (SBRT), surgery or others can be used to eradicate TKI-resistant subpopulations enabling prolonged TKI treatment "beyond progression", which may lead to increased PFS and overall survival. This review focuses on the biological background of resistance development, systemic and local treatment options with a focus on SBRT, as well as challenges in defining the state of OPD and current clinical studies in oligoprogressive oncogene addicted NSCLC.

  9. Oncogenic senescence: a multi-functional perspective

    PubMed Central

    van Deursen, Jan M.; Campisi, Judith; Hildesheim, Jeffrey

    2017-01-01

    Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer. Although oncogenic mutations are capable of inducing a beneficial senescence response that prevents the growth of premalignant cells and promotes cancer immune-surveillance, the secretome of senescent cells also includes factors with pro-tumorigenic properties. On June 23rd and 24th, 2016, the Division of Cancer Biology of the National Cancer Institute sponsored a workshop to discuss the complex role of cellular senescence in tumorigenesis with the goal to define the major challenges and opportunities within this important field of cancer research. Additionally, it was noted how the development of novel tools and technologies are required to accelerate research into a mechanistic understanding of senescent cells in carcinogenesis in order to overcome the current limitations in this exciting, yet ill-defined area. PMID:28416761

  10. Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition

    PubMed Central

    Fernandes, Janaina

    2016-01-01

    The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death. PMID:27486347

  11. Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition.

    PubMed

    Fernandes, Janaina

    2016-01-01

    The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death.

  12. Know thy neighbor: stromal cells can contribute oncogenic signals

    NASA Technical Reports Server (NTRS)

    Tlsty, T. D.; Hein, P. W.

    2001-01-01

    Although the stroma within carcinogenic lesions is known to be supportive and responsive to tumors, new data increasingly show that the stroma also has a more active, oncogenic role in tumorigenesis. Stromal cells and their products can transform adjacent tissues in the absence of pre-existing tumor cells by inciting phenotypic and genomic changes in the epithelial cells. The oncogenic action of distinctive stromal components has been demonstrated through a variety of approaches, which provide clues about the cellular pathways involved.

  13. Know thy neighbor: stromal cells can contribute oncogenic signals

    NASA Technical Reports Server (NTRS)

    Tlsty, T. D.; Hein, P. W.

    2001-01-01

    Although the stroma within carcinogenic lesions is known to be supportive and responsive to tumors, new data increasingly show that the stroma also has a more active, oncogenic role in tumorigenesis. Stromal cells and their products can transform adjacent tissues in the absence of pre-existing tumor cells by inciting phenotypic and genomic changes in the epithelial cells. The oncogenic action of distinctive stromal components has been demonstrated through a variety of approaches, which provide clues about the cellular pathways involved.

  14. A database of breast oncogenic specific siRNAs.

    PubMed

    Tyagi, Atul; Semwal, Manoj; Sharma, Ashok

    2017-08-18

    Breast cancer is a serious problem causing the death of women across the world. At present, one of the major challenges is to design drugs to target breast cancer specific gene(s). RNA interference (RNAi) is an important technique for targeted gene silencing that may lead to promising novel therapeutic strategies for breast cancer. Therefore, identification of such molecules having high oncogene specificity is the need of the hour. Here, we have developed a database named as Breast Oncogenic Specific siRNAs (BOSS, http://bioinformatics.cimap.res.in/sharma/boss/ ) on the basis of the current research status on siRNA-mediated repression of oncogenes in different breast cancer cell lines. BOSS is a resource of experimentally validated breast oncogenic siRNAs, collected from research articles and patents published yet. The present database contains information on 865 breast oncogenic siRNA entries. Each entry provides comprehensive information of an siRNA that includes its name, sequence, target gene, type of cells, and inhibition value, etc. Additionally, some useful tools like siRNAMAP and BOSS BLAST were also developed and linked with the database. siRNAMAP can be used for the selection of best siRNA against a target gene while BOSS BLAST tool helps to locate the siRNA sequences in deferent oncogenes.

  15. Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells

    PubMed Central

    Castoria, G; Giovannelli, P; Di Donato, M; Ciociola, A; Hayashi, R; Bernal, F; Appella, E; Auricchio, F; Migliaccio, A

    2014-01-01

    The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions. PMID:25476896

  16. Effect of cellular determination on oncogenic transformation by chemicals and oncogenes.

    PubMed Central

    Harrington, M A; Gonzales, F; Jones, P A

    1988-01-01

    Three developmentally determined myogenic cell lines derived from C3H 10T1/2 C18 (10T1/2) mouse embryo cells treated with 5-azacytidine were compared with the parental 10T1/2 line for their susceptibility to oncogenic transformation by 3-methylcholanthrene or the activated human c-Ha-ras oncogene. Neither the 10T1/2 cells nor the myogenic derivatives grew in soft agar or formed tumors in nude mice. In contrast to 10T1/2 cells, the three myogenic derivatives were not susceptible to transformation by 3-methylcholanthrene, so that cellular determination altered the response of 10T1/2 cells to chemical carcinogen. On the other hand, all cell types were transformed to a tumorigenic phenotype following transfection with the activated c-Ha-ras gene. The transfected myogenic cells expressed both the c-Ha-ras gene and the muscle determination gene MyoD1. In contrast to other reports, the presence of as many as six copies of the c-Ha-ras gene per genome did not prevent the formation of striated muscle cells which expressed immunologically detectable muscle-specific myosin. The expression of the c-Ha-ras gene does not therefore necessarily preclude the expression of the determination gene for myogenesis or prevent end-stage myogenic differentiation. Images PMID:2460742

  17. Assessment of growth potential by MIB-1 immunohistochemistry in ameloblastic fibroma and related lesions of the jaws compared with ameloblastic fibrosarcoma.

    PubMed

    Sano, K; Yoshida, S; Ninomiya, H; Ikeda, H; Ueno, K; Sekine, J; Iwamoto, H; Uehara, M; Inokuchi, T

    1998-02-01

    Specimens from two ameloblastic fibromas (including one recurrent case), two ameloblastic fibro-odontomas, and one ameloblastic fibrosarcoma were subjected to investigation by MIB-1 immunohistochemistry in order to elucidate the growth potential of these tumors. MIB-1 labeling indices in the epithelial component of these tumors ranged from 2.9 to 7.5%, whereas those in the mesenchymal component ranged from 1.5 to 13.5%. Of these, labeling indices in the mesenchymal component of the recurrent ameloblastic fibroma and ameloblastic fibrosarcoma were quite high. These findings suggest that evaluation of growth potential in ameloblastic fibroma and related lesions could be of help in understanding tumor aggressiveness and in selecting appropriate surgical procedures.

  18. Fluorescence-guided surgery of retroperitoneal-implanted human fibrosarcoma in nude mice delays or eliminates tumor recurrence and increases survival compared to bright-light surgery.

    PubMed

    Uehara, Fuminari; Hiroshima, Yukihiko; Miwa, Shinji; Tome, Yasunori; Yano, Shuya; Yamamoto, Mako; Matsumoto, Yasunori; Maehara, Hiroki; Tanaka, Kazuhiro; Bouvet, Michael; Kanaya, Fuminori; Hoffman, Robert M

    2015-01-01

    The aim of this study is to determine if fluorescence-guided surgery (FGS) can eradicate human fibrosarcoma growing in the retroperitoneum of nude mice. One week after retroperitoneal implantation of human HT1080 fibrosarcoma cells, expressing green fluorescent protein (GFP) (HT-1080-GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 22). After BLS, mice were randomized into 2 treatment groups; BLS-only (n = 11) or the combination of BLS + FGS (n = 11). The residual tumors remaining after BLS were resected with FGS using a hand-held portable imaging system under fluorescence navigation. The average residual tumor area after BLS + FGS was significantly smaller than after BLS-only (0.4 ± 0.4 mm(2) and 10.5 ± 2.4 mm(2), respectively; p = 0.006). Five weeks after surgery, the fluorescent-tumor areas of BLS- and BLS + FGS-treated mice were 379 ± 147 mm(2) and 11.7 ± 6.9 mm(2), respectively, indicating that FGS greatly inhibited tumor recurrence compared to BLS. The combination of BLS + FGS significantly decreased fibrosarcoma recurrence compared to BLS-only treated mice (p < 0.001). Mice treated with BLS+FGS had a significantly higher disease-free survival rate than mice treated with BLS-only at five weeks after surgery. These results suggest that combination of BLS + FGS significantly reduced the residual fibrosarcoma volume after BLS and improved disease-free survival.

  19. Role of receptor for hyaluronic acid-mediated motility (RHAMM) in low molecular weight hyaluronan (LMWHA)-mediated fibrosarcoma cell adhesion.

    PubMed

    Kouvidi, Katerina; Berdiaki, Aikaterini; Nikitovic, Dragana; Katonis, Pavlos; Afratis, Nikos; Hascall, Vincent C; Karamanos, Nikos K; Tzanakakis, George N

    2011-11-04

    Hyaluronan (HA) modulates key cancer cell functions through interaction with its CD44 and receptor for hyaluronic acid-mediated motility (RHAMM) receptors. HA was recently found to regulate the migration of fibrosarcoma cells in a manner specifically dependent on its size. Here, we investigated the effect of HA/RHAMM signaling on the ability of HT1080 fibrosarcoma cells to adhere onto fibronectin. Low molecular weight HA (LMWHA) significantly increased (p ≤ 0.01) the adhesion capacity of HT1080 cells, which high molecular weight HA inhibited. The ability of HT1080 RHAMM-deficient cells, but not of CD44-deficient ones, to adhere was significantly decreased (p ≤ 0.001) as compared with control cells. Importantly, the effect of LMWHA on HT1080 cell adhesion was completely attenuated in RHAMM-deficient cells. In contrast, adhesion of RHAMM-deficient cells was not sensitive to high molecular weight HA treatment, which identifies RHAMM as a specific conduit of the LMWHA effect. Western blot and real time-PCR analyses indicated that LMWHA significantly increased RHAMM transcript (p ≤ 0.05) and protein isoform levels (53%, 95 kDa; 37%, 73 kDa) in fibrosarcoma cells. Moreover, Western blot analyses showed that LMWHA in a RHAMM-dependent manner enhanced basal and adhesion-dependent ERK1/2 and focal adhesion kinase (FAK) phosphorylation in HT1080 cells. Utilization of a specific ERK1/2 inhibitor completely inhibited (p ≤ 0.001) LMWHA-dependent adhesion, suggesting that ERK1/2 is a downstream effector of LMWHA/RHAMM signaling. Likewise, the utilization of the specific ERK1 inhibitor resulted in a strong down-regulation of FAK activation in HT1080 cells, which identifies ERK1/2 as a FAK upstream activator. In conclusion, our results suggest that RHAMM/HA interaction regulates fibrosarcoma cell adhesion via the activation of FAK and ERK1/2 signaling pathways.

  20. Role of Receptor for Hyaluronic Acid-mediated Motility (RHAMM) in Low Molecular Weight Hyaluronan (LMWHA)-mediated Fibrosarcoma Cell Adhesion

    PubMed Central

    Kouvidi, Katerina; Berdiaki, Aikaterini; Nikitovic, Dragana; Katonis, Pavlos; Afratis, Nikos; Hascall, Vincent C.; Karamanos, Nikos K.; Tzanakakis, George N.

    2011-01-01

    Hyaluronan (HA) modulates key cancer cell functions through interaction with its CD44 and receptor for hyaluronic acid-mediated motility (RHAMM) receptors. HA was recently found to regulate the migration of fibrosarcoma cells in a manner specifically dependent on its size. Here, we investigated the effect of HA/RHAMM signaling on the ability of HT1080 fibrosarcoma cells to adhere onto fibronectin. Low molecular weight HA (LMWHA) significantly increased (p ≤ 0.01) the adhesion capacity of HT1080 cells, which high molecular weight HA inhibited. The ability of HT1080 RHAMM-deficient cells, but not of CD44-deficient ones, to adhere was significantly decreased (p ≤ 0.001) as compared with control cells. Importantly, the effect of LMWHA on HT1080 cell adhesion was completely attenuated in RHAMM-deficient cells. In contrast, adhesion of RHAMM-deficient cells was not sensitive to high molecular weight HA treatment, which identifies RHAMM as a specific conduit of the LMWHA effect. Western blot and real time-PCR analyses indicated that LMWHA significantly increased RHAMM transcript (p ≤ 0.05) and protein isoform levels (53%, 95 kDa; 37%, 73 kDa) in fibrosarcoma cells. Moreover, Western blot analyses showed that LMWHA in a RHAMM-dependent manner enhanced basal and adhesion-dependent ERK1/2 and focal adhesion kinase (FAK) phosphorylation in HT1080 cells. Utilization of a specific ERK1/2 inhibitor completely inhibited (p ≤ 0.001) LMWHA-dependent adhesion, suggesting that ERK1/2 is a downstream effector of LMWHA/RHAMM signaling. Likewise, the utilization of the specific ERK1 inhibitor resulted in a strong down-regulation of FAK activation in HT1080 cells, which identifies ERK1/2 as a FAK upstream activator. In conclusion, our results suggest that RHAMM/HA interaction regulates fibrosarcoma cell adhesion via the activation of FAK and ERK1/2 signaling pathways. PMID:21914806

  1. Fluorescence-Guided Surgery of Retroperitoneal-Implanted Human Fibrosarcoma in Nude Mice Delays or Eliminates Tumor Recurrence and Increases Survival Compared to Bright-Light Surgery

    PubMed Central

    Uehara, Fuminari; Hiroshima, Yukihiko; Miwa, Shinji; Tome, Yasunori; Yano, Shuya; Yamamoto, Mako; Matsumoto, Yasunori; Maehara, Hiroki; Tanaka, Kazuhiro; Bouvet, Michael; Kanaya, Fuminori; Hoffman, Robert M.

    2015-01-01

    The aim of this study is to determine if fluorescence-guided surgery (FGS) can eradicate human fibrosarcoma growing in the retroperitoneum of nude mice. One week after retroperitoneal implantation of human HT1080 fibrosarcoma cells, expressing green fluorescent protein (GFP) (HT-1080-GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 22). After BLS, mice were randomized into 2 treatment groups; BLS-only (n = 11) or the combination of BLS + FGS (n = 11). The residual tumors remaining after BLS were resected with FGS using a hand-held portable imaging system under fluorescence navigation. The average residual tumor area after BLS + FGS was significantly smaller than after BLS-only (0.4 ± 0.4 mm2 and 10.5 ± 2.4 mm2, respectively; p = 0.006). Five weeks after surgery, the fluorescent-tumor areas of BLS- and BLS + FGS-treated mice were 379 ± 147 mm2 and 11.7 ± 6.9 mm2, respectively, indicating that FGS greatly inhibited tumor recurrence compared to BLS. The combination of BLS + FGS significantly decreased fibrosarcoma recurrence compared to BLS-only treated mice (p < 0.001). Mice treated with BLS+FGS had a significantly higher disease-free survival rate than mice treated with BLS-only at five weeks after surgery. These results suggest that combination of BLS + FGS significantly reduced the residual fibrosarcoma volume after BLS and improved disease-free survival. PMID:25710463

  2. Receptor for hyaluronic acid- mediated motility (RHAMM) regulates HT1080 fibrosarcoma cell proliferation via a β-catenin/c-myc signaling axis.

    PubMed

    Kouvidi, Katerina; Berdiaki, Aikaterini; Tzardi, Maria; Karousou, Evgenia; Passi, Alberto; Nikitovic, Dragana; Tzanakakis, George N

    2016-04-01

    High levels of hyaluronan (HA) synthesis in various cancer tissues, including sarcomas, are correlated with tumorigenesis and malignant transformation. RHAMM (receptor for hyaluronic acid-mediated motility) is overexpressed during tumor development in different malignancies. β-Catenin is a crucial downstream mediator of the Wnt signaling cascade which facilitates carcinogenic events characterized by deregulated cell proliferation. Real-time PCR, in vitro cell proliferation assay, siRNA transfection, flow cytometry, immunoprecipitation, western blotting and immunofluorescence were utilized. The reduction of RHAMM expression was strongly correlated with an inhibition of HT1080 fibrosarcoma cell growth (p≤0.01). LMWHA, in a RHAMM-dependent manner increases cell growth of HT1080 cells (p≤0.01). Both basal and LMWHA dependent growth of HT1080 cells was attenuated by β-catenin deficiency (p≤0.01). β-Catenin cytoplasmatic deposition is positively regulated by RHAMM (p≤0.01). Immunoflourescence and immunoprecipitation suggest that RHAMM/β-catenin form an intracellular complex. Transfection experiments identified c-myc as candidate downstream mediator of RHAMM/β-catenin effects on HT1080 fibrosarcoma cell proliferation. LMWHA/RHAMM downstream signaling regulates fibrosarcoma cell growth in a β-catenin/c-myc dependent manner. The present study suggests that RHAMM is a novel β-catenin intracellular binding partner, protecting β-catenin from degradation and supporting the nuclear translocation of this key cellular mediator, which results in c-myc activation and enhanced fibrosarcoma cell growth. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.

    PubMed

    Moccia, Marialuisa; Liu, Qingsong; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Zhao, Zheng; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Billaud, Marc; Gray, Nathanael S; Carlomagno, Francesca; Santoro, Massimo

    2015-01-01

    Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.

  4. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase

    PubMed Central

    Moccia, Marialuisa; Liu, Qingsong; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Zhao, Zheng; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Billaud, Marc; Gray, Nathanael S.

    2015-01-01

    Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the ‘DFG-out’ inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the ‘gatekeeper’ V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET. PMID:26046350

  5. Protective effects of S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice

    SciTech Connect

    Milas, L.; Hunter, N.; Reid, B.O.; Thames, H.D. Jr.

    1982-05-01

    S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was investigated for its protective effect against radiation-produced damage of jejunum, testis, lung, hair follicles, and a fibrosarcoma of C3Hf/Kam mice. Most of these tissues were radioprotected, and the degree of radioprotection depended on the dose of WR-2721 and the time interval between administration of WR-2721 and radiation treatment. WR-2721 increased resistance of jejunal epithelial cells and spermatogenic cells to single doses of gamma-rays by factors of 1.64 and 1.54, respectively. Protection against hair loss was less pronounced; the dose-modifying factor here was 1.24. The radiation-induced acute damage of the lung expressed by the increased formation of tumor nodules in the lung was not decreased by treatment of animals with WR-2721 before radiation. In contrast, WR-2721 augmented the radiation-induced enhancement of metastasis formation in the lung. WR-2721 protected fibrosarcoma micrometastases in the lung against therapeutic effect of radiation by a factor of 1.238. In contrast, this compound had no effect on the therapy of an 8-mm fibrosarcoma growing in the legs of mice.

  6. Simvastatin, an HMG-CoA reductase inhibitor, reduced the expression of matrix metalloproteinase-9 (Gelatinase B) in osteoblastic cells and HT1080 fibrosarcoma cells.

    PubMed

    Thunyakitpisal, Pasutha D; Chaisuparat, Risa

    2004-04-01

    MMP-9 or Gelatinase B, a member of the matrix metalloproteinase family (MMPs), plays important roles in physiological events such as tissue remodeling and in pathological processes that lead to destructive bone diseases, including osteoarthritis and periodontitis. In addition to its effect on the increase of total bone mass, statin (an HMG-CoA reductase inhibitor) suppresses the expression of MMPs. In this study, we proposed that simvastatin reduces MMP-9 expression in osteoblasts and HT1080 fibrosarcoma cell line. Gelatin zymography, Western blot analysis and reverse transcriptase-PCR were used to investigate the effects of simvastatin on MMP-9 in primary calvaria cells, U2-OS osteosarcoma cells, and HT1080 fibrosarcoma cells. The results from gelatin zymography and Western blot analysis revealed that simvastatin suppressed MMP-9 activity in these cells in concentration- and time-dependent manners. The effective concentrations of simvastatin were 100 - 500 nM, 5 - 15 microM, and 2.5 - 10 microM in primary calvaria, U2-OS, and HT1080 cells, respectively. Collectively, these results suggest that simvastatin is a potent drug for inhibition of MMP-9 expression in osteoblastic cells and HT1080 fibrosarcoma cells.

  7. Latent cellular oncogenes: the paradox dissolves.

    PubMed

    Duesberg, P H

    1987-01-01

    The 20 known transforming onc genes of retroviruses are defined by sequences which are transduced from cellular genes, termed proto-onc genes. Based on these sequences, viral onc genes have been postulated to be transduced cellular cancer genes and proto-onc genes have been postulated to be latent cancer genes that can be activated from within the cell, to cause virus-negative tumours. The hypothesis is popular because it promises direct access to cellular cancer genes. However the existence of latent cancer genes presents a paradox since such genes would be most undesirable for eukaryotes. The hypothesis predicts (i) that viral onc genes and proto-onc genes are isogenic, (ii) that expression of proto-onc genes induces tumours, (iii) that activated proto-onc genes transform diploid cells upon transfection, like viral onc genes, and (iv) it predicts diploid tumours. As yet, none of these predictions is confirmed. Instead: (i) Structural comparisons between viral onc genes, essential retroviral genes, and the proto-onc genes show that all viral onc genes are indeed new genes, rather than transduced cellular cancer genes. They are genetic hybrids put together from truncated viral and truncated proto-onc genes. (ii) Proto-onc genes are frequently expressed in normal cells. (iii) To date, not one activated proto-onc gene has been isolated that transforms diploid cells. (iv) Above all, no diploid tumours with activated proto-onc genes have been found. Moreover the probability of spontaneous transformation in vivo is at least 10(9) times lower than predicted from the mechanisms thought to activate proto-onc genes. Therefore the hypothesis, that proto-onc genes are latent cellular oncogenes, appears to be an over-interpretation of sequence homology to structural and functional homology with viral onc genes. Here is is proposed that only rare truncations and recombinations, that alter the germline configuration of cellular genes, generate viral and possibly cellular cancer

  8. Oncogenes and RNA splicing of human tumor viruses.

    PubMed

    Ajiro, Masahiko; Zheng, Zhi-Ming

    2014-09-01

    Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue-specific manner in virus-induced human carcinogenesis.

  9. Oncogenes and RNA splicing of human tumor viruses

    PubMed Central

    Ajiro, Masahiko; Zheng, Zhi-Ming

    2014-01-01

    Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein–Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue-specific manner in virus-induced human carcinogenesis. PMID:26038756

  10. Multiple oncogene activation in a radiation carcinogenesis model

    SciTech Connect

    Garte, S.J.; Sawey, M.J.; Burns, F.J.; Felber, M.; Ashkenazi-Kimmel, T.

    1987-01-01

    There is evidence from animal systems to suggest that certain oncogenes may be activated by the direct action of the initiating carcinogen. Consistent activation by a point mutation of a single member of the ras oncogene family in different tumors produced by a single agent has been demonstrated. In contrast the c-myc and other oncogenes have been shown to be activated by a process involving chromosomal translocations, enhanced expression, and/or gene amplification. We have examined a panel of 12 late stage rat skin tumors for activation of oncogenes from the ras and myc complementation groups. These tumors were four squamous cell carcinomas, three poorly differentiated carcinomas (clear cell), one each of basal cell carcinoma, sebaceous carcinoma, sarcoma, fibroma, and mixed (largely squamous) histology carcinoma. The positive tumor DNAs were from three poorly differentiated clear cell carcinomas, a sebaceous carcinoma, a squamous cell carcinoma, and a sarcoma. DNA from one of the primary transfectants was positive in a second round of transfection. The transformed phenotype of the transfectants was confirmed by anchorage independent growth and tumorigenicity in nude mice. Southern blot analysis of DNA from primary and secondary transfectants, as well as from nude mouse tumors arising after injection of transfectant cells revealed the presence of rat derived restriction fragments homologous to the K-ras oncogene against the mouse background. Similar experiments using N- and H-ras probes, revealed only the endogenous mouse fragments in transfectant DNA. 11 refs., 1 tab.

  11. Protein kinase Cι: human oncogene, prognostic marker and therapeutic target

    PubMed Central

    Fields, Alan P.; Regala, Roderick P.

    2009-01-01

    The Protein kinase C (PKC) family of serine/threonine kinases has been the subject of intensive study in the field of cancer since their initial discovery as major cellular receptors for the tumor promoting phorbol esters nearly thirty years ago. However, despite these efforts, the search for a direct genetic link between members of the PKC family and human cancer has yielded only circumstantial evidence that any PKC isozyme is a true cancer gene. This situation changed in the past year with the discovery that atypical protein kinase C iota (PKCι) is a bonafide human oncogene. PKCι is required for the transformed growth of human cancer cells and the PKCι gene is the target of tumor-specific gene amplification in multiple forms of human cancer. PKCι participates in multiple aspects of the transformed phenotype of human cancer cells including transformed growth, invasion and survival. Herein, we review pertinent aspects of atypical PKC structure, function and regulation that relate to the role of these enzymes in oncogenesis. We discuss the evidence that PKCι is a human oncogene, review mechanisms controlling PKCι expression in human cancers, and describe the molecular details of PKCι-mediated oncogenic signaling. We conclude with a discussion of how oncogenic PKCι signaling has been successfully targeted to identify a novel, mechanism-based therapeutic drug currently entering clinical trials for treatment of human lung cancer. Throughout, we identify key unanswered questions and exciting future avenues of investigation regarding this important oncogenic molecule. PMID:17570678

  12. Developmental-stage-dependent transcriptional response to leukaemic oncogene expression

    PubMed Central

    Regha, Kakkad; Assi, Salam A.; Tsoulaki, Olga; Gilmour, Jane; Lacaud, Georges; Bonifer, Constanze

    2015-01-01

    Acute myeloid leukaemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression. RUNX1-ETO interferes with both the activating and repressive function of its normal counterpart, RUNX1, at early and late stages of blood cell development. However, the response of the transcriptional network to RUNX1-ETO expression is developmental stage specific, highlighting the molecular mechanisms determining specific target cell expansion after an oncogenic hit. PMID:26018585

  13. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure

    PubMed Central

    Pagliarini, Raymond; Shao, Wenlin; Sellers, William R

    2015-01-01

    A key goal of cancer therapeutics is to selectively target the genetic lesions that initiate and maintain cancer cell proliferation and survival. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to inhibition of single oncogenes, a concept referred to as ‘oncogene addiction’. Herein, we describe the clinical evidence supporting oncogene addiction and discuss common mechanistic themes emerging from the response and acquired resistance to oncogene-targeted therapies. Finally, we suggest several opportunities toward exploiting oncogene addiction to achieve curative cancer therapies. PMID:25680965

  14. Oncogene-mediated transformation of fetal rat colon in vitro.

    PubMed

    Pories, S; Jaros, K; Steele, G; Pauley, A; Summerhayes, I C

    1992-05-01

    Short-term maintenance of fetal rat colonic tissue in vitro has been demonstrated using a collagen matrix organ culture system. The introduction of single (v-myc, v-rasH, v-src) oncogenes or combinations of oncogenes (v-myc/rasH, v-myc/src) into normal colon mucosal elements was established using retroviral vectors, resulting in enhanced proliferation and migration of epithelial cells from the lumen of tissue implants. Expression of a single oncogene in normal colon epithelium did not result in the establishment of cell lines. In contrast, expression of cooperating oncogenic elements resulted in cell lines in greater than 80% of experiments, revealing different morphological characteristics dependent upon the oncogene combination used. Confirmation of the expression of viral transcripts was determined using Northern blot analysis and viral oncoprotein expression using Western blot analysis (p21) and an immunoprecipitation kinase assay (src). Expression of keratin filaments was lost following passaging of cell lines but could be induced by the myc/ras transformants by growth on Rat-1 feeder layers. This induction phenomenon was not observed with myc/src lines, and although these expressed high levels of sucrase isomaltase the epithelial origin of these cells is unclear. Karyotypic analysis performed on three myc/ras-transformed cell lines revealed a normal chromosome complement associated with transformation. In this report we describe a novel in vitro transformation system for normal rat colonic epithelium mediated by the introduction of oncogene elements using different retroviral vector constructs. The potential to generate cell lines representing different stages of neoplastic progression using relevant genetic components presents significant advantages for the study of cellular and molecular interactions underlying colon neoplastic progression.

  15. Avian oncogenic virus differential diagnosis in chickens using oligonucleotide microarray.

    PubMed

    Wang, Lih-Chiann; Huang, Dean; Pu, Chang-En; Wang, Ching-Ho

    2014-12-15

    Avian oncogenic viruses include the avian leukosis virus (ALV), reticuloendotheliosis virus (REV) and Marek's disease virus (MDV). Multiple oncogenic viral infections are frequently seen, with even Marek's disease vaccines reported to be contaminated with ALV and REV. The gross lesions caused by avian oncogenic viruses often overlap, making differentiation diagnosis based on histopathology difficult. The objective of this study is to develop a rapid approach to simultaneously differentiate, subgroup and pathotype the avian oncogenic viruses. The oligonucleotide microarray was employed in this study. Particular DNA sequences were recognized using specific hybridization between the DNA target and probe on the microarray, followed with colorimetric development through enzyme reaction. With 10 designed probes, ALV-A, ALV-E, ALV-J, REV, MDV pathogenic and vaccine strains were clearly discriminated on the microarray with the naked eyes. The detection limit was 27 copy numbers, which was 10-100 times lower than multiplex PCR. Of 102 field samples screened using the oligonucleotide microarray, 32 samples were positive for ALV-E, 17 samples were positive for ALV-J, 6 samples were positive for REV, 4 samples were positive for MDV, 7 samples were positive for both ALV-A and ALV-E, 5 samples were positive for ALV-A, ALV-E and ALV-J, one sample was positive for both ALV-J and MDV, and 3 samples were positive for both REV and MDV. The oligonucleotide microarray, an easy-to-use, high-specificity, high-sensitivity and extendable assay, presents a potent technique for rapid differential diagnosis of avian oncogenic viruses and the detection of multiple avian oncogenic viral infections under field conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review).

    PubMed

    Sinkovics, Joseph G

    2012-02-01

    In some inflammasomes tumor cells are generated. The internal environment of the inflammasome is conducive to the induction of malignant transformation. Epigenetic changes initiate this process. The subverted stromal connective tissue cells act to promote and sustain the process of malignant trans-formation. In its early stages, the premalignant cells depend on paracrine circuitries for the reception of growth factors. The ligands are derived from the connective tissue, and the receptors are expressed on the recipient premalignant cells. The initial events are not a direct attack on the proto-oncogenes, and thus it may be entirely reversible. Epigenetic processes of hypermethylation of the genes at the promoters of tumor suppressor genes (to silence them), and deacetylation of the histones aimed at the promoters of proto-oncogenes (to activate them) are on-going. A large number of short RNA sequences (interfering, micro-, short hairpin, non-coding RNAs) silence tumor suppressor genes, by neutralizing their mRNAs. In a serial sequence oncogenes undergo amplifications, point-mutations, translocations and fusions. In its earliest stage, the process is reversible by demethylation of the silenced suppressor gene promoters (to reactivate them), or re-acetylation of the histones of the oncogene promoters, thus de-activating them. The external administration of histone deacetylase inhibitors usually leads to the restoration of histone acetylation. In time, the uncorrected processes solidify into constitutive and irreversible gene mutations. Some of the pathogens inducing inflammations with consquential malignant transformation contain oncogenic gene sequences (papilloma viruses, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, hepatitis B and C viruses, Merkel cell polyoma virus, Helicobacter pylori, enterotoxigenic Bacteroides fragilis). These induced malignancies may be multifocal. Other pathogens are devoid of any known oncogenic genomic sequences

  17. In vivo evolution of c-rel oncogenic potential.

    PubMed

    Hrdlicková, R; Nehyba, J; Humphries, E H

    1994-04-01

    The c-rel proto-oncogene belongs to the NF-kappa B/rel and I kappa B gene families, which regulate several inducible processes, including self-defense/repair and embryogenesis. Transduction of the c-rel transcription factor by the avian retrovirus resulted in the formation of a highly oncogenic virus, reticuloendotheliosis virus strain T (REV-T), that encodes the oncogene v-rel. To examine the oncogenic potential of c-rel, we inserted it into a REV-T-based retroviral vector, rescued virus [REV-C(CSV)], and infected 1-day-old chicks. All birds developed tumors, and all cell lines established from REV-C-induced tumors expressed c-rel proteins that lacked C-terminal sequences. These proteins, responsible for both in vivo and in vitro cell proliferation, were apparently selected for their oncogenic potential. In order to examine the cooperation of C-terminal deletions with other oncogenic alterations in vivo, point mutations present in the N-terminal and middle regions of v-rel were analyzed by a similar protocol. The data obtained support four conclusions. (i) c-rel proteins bearing any of three single-amino-acid mutations present in the N-terminal portion of v-rel were sufficiently oncogenic to induce tumor development in the absence of additional mutations. (ii) Combining a mutation from the N-terminal region of v-rel with a deletion of the C-terminal sequences of c-rel increases the oncogenicity of the protein in an additive manner. (iii) Mutations present in the middle of v-rel cooperated synergistically with C-terminal deletions to produce highly transforming viruses. (iv) Deletion of c-rel produced a variety of transforming rel proteins with sizes that extended from 42 to 65 kDa. The most frequently isolated rel deletion was 62 kDa in size. To examine the basis for the selection of different rel mutants, their ability to induce immunoregulatory surface receptors was analyzed. The data revealed a correlation between the induction capacity of these mutants and

  18. Hydrophilic extract from Posidonia oceanica inhibits activity and expression of gelatinases and prevents HT1080 human fibrosarcoma cell line invasion

    PubMed Central

    Barletta, Emanuela; Ramazzotti, Matteo; Fratianni, Florinda; Pessani, Daniela; Degl'Innocenti, Donatella

    2015-01-01

    Posidonia oceanica (L.) Delile is an endemic Mediterranean sea-grass distributed in the infralittoral zones, where it forms meadows playing a recognized ecological role in the coastal marine habitat. Although its use as a traditional herbal remedy is poorly documented, recent literature reports interesting pharmacological activities as antidiabetic, antioxidant and vasoprotective. Differently from previous literature, this study presents a hydrophilic extraction method that recovers metabolites that may be tested in biological buffers. We showed for the first time in the highly invasive HT1080 human fibrosarcoma cell line that our hydrophilic extract from P. oceanica was able to strongly decrease gene and protein expression of gelatinases MMP-2 and MMP-9 and to directly inhibit in a dose-dependent manner gelatinolytic activity in vitro. Moreover, we have revealed that our extract strongly inhibited HT1080 cell migration and invasion. Biochemical analysis of the hydrophilic extract showed that catechins were the major constituents with minor contribution of gallic acid, ferulic acid and chlorogenic plus a fraction of uncharacterized phenols. However, if each individual compound was tested independently, none by itself was able to induce a direct inhibition of gelatinases as strong as that observed in total extract, opening up new routes to the identification of novel compounds. These results indicate that our hydrophilic extract from P. oceanica might be a source of new pharmacological natural products for treatment or prevention of several diseases related to an altered MMP-2 and MMP-9 expression. PMID:26176658

  19. Involvement of gangliosides in the suppression of the immune response: an explanation for the progression of UV-induced fibrosarcomas

    SciTech Connect

    Frey, J.L.

    1987-01-01

    Ultraviolet-irradiation-induced fibrosarcoma cells with either progressor or regressor properties were studied for structural differences in their glycosphingolipid (GSL) content and composition. UV-progressor tumor cells contained a ganglioside, G/sub Dla/, which the UV-regressor cells lacked. This ganglioside was found in the serum of tumor bearing animals and was shed from the UV-progressor tumor cells. In our analysis of the role gangliosides might play in the tumor progression, we found that both spent medium and crude ganglioside preparations from progressor UV-tumor cells inhibited the mitogenic proliferation of normal lymphocytes. In vitro analysis with purified preparations of G/sub Dla/ showed that this ganglioside had immunosuppressive properties in mitogen-stimulated cultures. The kinetics of the inhibition response showed that maximal inhibition occurred if G/sub Dla/ was present at the prereplicative stage of lymphocyte proliferation. If lymphocytes are precultured with G/sub Dla/, exogenous ganglioside could be removed without loss of the inhibitory activity on lymphocyte proliferation. These results suggest that the presence of the ganglioside, G/sub Dla/, on the cell surface of progressor tumors could alter an immune response

  20. Influence of total parenteral nutrition on tumor growth and polyamine biosynthesis of fibrosarcoma-bearing rats after induced cachexia.

    PubMed

    Grossie, V B; Ota, D M; Ajani, J A; Chang, T H; Patenia, D; Nishioka, K

    1988-01-01

    The effect of a protein-free diet (PF) or a restricted intake of chow (RI) and subsequent host repletion with total parenteral nutrition (PF-TPN, RI-TPN) on tumor growth and polyamine metabolism of fibrosarcoma-bearing rats was examined. Host weight was significantly reduced by PF and RI. Tumor growth was reduced in malnourished rats with the PF regimen resulting in the greatest decrease. Rats receiving TPN after 14 days of the RI or PF regimens had higher host weight and plasma albumin levels than malnourished rats. Tumor growth during TPN was evaluated as the percent increase and compared with that of the respective malnourished rats. The percent increase for RI-TPN rats was significantly greater although a trend toward an increase was also evident for PF-TPN rats. Tumor ornithine decarboxylase (ODC) activity and putrescine levels were increased for PF rats and decreased for RI rats while tumor ODC activity was consistently increased by TPN. Tumor growth, ODC activity, and putrescine levels were simultaneously increased only for those rats fed the RI regimen prior to TPN. These results show a disparity in tumor ODC activity, putrescine levels, and tumor growth in malnourished rats. The results of this study suggest that the nutritional origin of cachexia influences the response of the tumor to TPN and emphasizes the importance of considering the methods to induce malnutrition in designing therapuetic regimens.

  1. Growth-related variations in the glycosaminoglycan synthesis of ultraviolet light-induced murine cutaneous fibrosarcoma cells

    SciTech Connect

    Piepkorn, M.; Carney, H.; Linker, A.

    1985-08-01

    Glycosaminoglycan synthesis was studied in cell populations of ultraviolet light-induced murine cutaneous fibrosarcoma cells under conditions of varying growth rates in vitro. After labeling with the precursors, /sup 3/H-glucosamine and /sup 35/SO/sub 4/, sulfated glycosaminoglycans recoverable by direct proteolysis of the culture monolayers increased approximately 5-fold on a per cell basis from sparsely populated, exponential cell cultures (greater than 85% of cells in S, G2, or M phases) to stationary cultures inhibited by high cell density (greater than 50% of cells in G1). Within this cell surface-associated material, the relative ratio of heparan sulfate to the chondroitin sulfates was approximately 60/40% under conditions of exponential growth; in the growth-arrested cultures, the reverse ratio was found. The substratum attached material, obtained from the flask surface after ethyl glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA)-mediated detachment of the monolayers, contained relatively more hyaluronic acid, heparan sulfate, and chondroitin sulfates in the most actively proliferating cultures compared with the growth-inhibited cell populations. Furthermore, heparan sulfate and the chondroitin sulfates, which were enriched in the substratum material and in the cell pellet of exponential cultures, showed a relative shift to the cell surface-associated compartment (releasable by mild trypsinization after EGTA-mediated cell detachment) and to the compartment loosely associated with the pericellular matrix (i.e., released into the supernatant during detachment of the monolayers in the presence of EGTA).

  2. 1,2,3,4-Diepoxybutane-Induced DNA-Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

    PubMed Central

    Gherezghiher, Teshome B.; Ming, Xun; Villalta, Peter; Campbell, Colin; Tretyakova, Natalia Y.

    2013-01-01

    1,2,3,4-diepoxybutane (DEB) is the key carcinogenic metabolite of 1,3-butadiene (BD), an important industrial and environmental chemical present in urban air and in cigarette smoke. DEB is a genotoxic bis-electrophile capable of cross-linking cellular biomolecules to form DNA-DNA and DNA-protein cross-links (DPCs). In the present work, mass spectrometry-based proteomics was employed to characterize DEB-mediated DNA-protein cross-linking in human fibrosarcoma (HT1080) cells. Over 150 proteins including histones, high mobility group proteins, transcription factors, splicing factors, and tubulins were found among those covalently cross-linked to chromosomal DNA in the presence of DEB. A large portion of the cross-linked proteins are known factors involved in DNA binding, transcriptional regulation, cell signaling, DNA repair, and DNA damage response. HPLC-ESI+-MS/MS analysis of total proteolytic digests revealed the presence of 1-(S-cysteinyl)-4-(guan-7-yl)-2,3-butanediol conjugates, confirming that DEB forms DPCs between cysteine thiols within proteins and the N-7 guanine positions within DNA. However, relatively high concentrations of DEB were required to achieve significant DPC formation, indicating that it is a poor cross-linking agent as compared to antitumor nitrogen mustards and platinum compounds. PMID:23506368

  3. 1,2,3,4-Diepoxybutane-induced DNA-protein cross-linking in human fibrosarcoma (HT1080) cells.

    PubMed

    Gherezghiher, Teshome B; Ming, Xun; Villalta, Peter W; Campbell, Colin; Tretyakova, Natalia Y

    2013-05-03

    1,2,3,4-Diepoxybutane (DEB) is the key carcinogenic metabolite of 1,3-butadiene (BD), an important industrial and environmental chemical present in urban air and in cigarette smoke. DEB is a genotoxic bis-electrophile capable of cross-linking cellular biomolecules to form DNA-DNA and DNA-protein cross-links (DPCs). In the present work, mass spectrometry-based proteomics was employed to characterize DEB-mediated DNA-protein cross-linking in human fibrosarcoma (HT1080) cells. Over 150 proteins including histones, high mobility group proteins, transcription factors, splicing factors, and tubulins were found among those covalently cross-linked to chromosomal DNA in the presence of DEB. A large portion of the cross-linked proteins are known factors involved in DNA binding, transcriptional regulation, cell signaling, DNA repair, and DNA damage response. HPLC-ESI(+)-MS/MS analysis of total proteolytic digests revealed the presence of 1-(S-cysteinyl)-4-(guan-7-yl)-2,3-butanediol conjugates, confirming that DEB forms DPCs between cysteine thiols within proteins and the N-7 guanine positions within DNA. However, relatively high concentrations of DEB were required to achieve significant DPC formation, indicating that it is a poor cross-linking agent as compared to antitumor nitrogen mustards and platinum compounds.

  4. Tetraspanin CD9 Promotes the Invasive Phenotype of Human Fibrosarcoma Cells via Upregulation of Matrix Metalloproteinase-9

    PubMed Central

    Herr, Michael J.; Kotha, Jayaprakash; Hagedorn, Nikolaus; Smith, Blake; Jennings, Lisa K.

    2013-01-01

    Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080) to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression. PMID:23840773

  5. In vitro decreases of the fibrinolytic potential of cultured human fibrosarcoma cell line, HT1080, by Nigella sativa oil.

    PubMed

    Awad, E M

    2005-01-01

    It is generally accepted that the fibrinolytic potential of tumor cells is related to their malignant phenotype. In the present study, Nigella sativa oil (NSO) was studied to evaluate its effect on the fibrinolytic potential of the fibosarcoma cell line HT1080 to elucidate whether this oil might have an antitumor activity through its modulation of the fibrinolytic potential of such cells. NSO produced a concentration-dependent inhibition of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor type 1 (PAI-1). When subconfluent HT1080 cells were conditioned with oil, a concentration (0.0-200 microg oil/ml)-dependent decrease in t-PA, u-PA and PAI-1 antigen was observed. There was also a concentration-dependent decrease (from 0.0 to 112.5 microg oil/ml) in the confluent cultures. The results showed that blackseed oil decreases the fibrinolytic potential of the human fibrosarcoma cell line (HT1080) in vitro, implying that inhibition of local tumor invasion and metastasis may be one such mechanism.

  6. Hypoxia enhances metastatic efficiency in HT1080 fibrosarcoma cells by increasing cell survival in lungs, not cell adhesion and invasion.

    PubMed

    Zhang, Li; Hill, Richard P

    2007-08-15

    This study examined possible mechanisms for hypoxia-increased metastasis in a green fluorescent protein-labeled human fibrosarcoma cell line (HT1080). The efficiency of the lung arrest of tumor cells, which can be dependent on the adhesive potential of the tumor cells, was assessed by measuring the level of integrin alpha3beta1 protein and by adhesion assays, whereas the extravasation potential was examined by an invasion assay. These properties were not changed by exposure to hypoxia, indicating that lung arrest and extravasation are unlikely to play a major role in the effect of hypoxia on metastasis in this model. The main effect of hypoxic exposure was found to be increased survival after lung arrest as determined by clonogenic assay of tumor cells recovered from mouse lungs after i.v. injection. Concomitantly, apoptosis was identified as responsible for the death of lung-arrested cells, suggesting the involvement of an altered apoptotic response following hypoxic exposure of these cells. Consistent with this finding, we found that the effect of hypoxia on both increased metastasis and survival of arrested cells was inhibited by treatment with farnesylthiosalicylic acid. However, this effect was not due to down-regulation of hypoxia-inducible factor-1alpha, a mechanism of action of this drug reported by previous studies. Further detailed studies of the mechanisms of action of the drug are needed.

  7. Dietary gallic acid and anthocyanin cytotoxicity on human fibrosarcoma HT1080 cells. A study on the mode of action.

    PubMed

    Filipiak, Kamila; Hidalgo, Maria; Silvan, Jose Manuel; Fabre, Benjamin; Carbajo, Rodrigo J; Pineda-Lucena, Antonio; Ramos, Ana; de Pascual-Teresa, Beatriz; de Pascual-Teresa, Sonia

    2014-02-01

    Gallic acid and anthocyanins are abundant plant food bioactives present in many fruits and vegetables, being especially important in the composition of berries. Gallic acid has been shown to possess cytotoxic properties in several cancer cell lines and to inhibit carcinogenesis in animal models. However, its mechanism of action is not yet fully understood. The aim of this study was to elucidate whether the observed inhibitory activity of gallic acid against gelatinases corresponds to its cytotoxic activity in HT1080 cells and to determine if anthocyanins could exhibit a similar behavior. Gallic acid and delphinidin-3-glucoside have shown selective cytotoxicity towards HT1080 cells. Further analysis by a migration and invasion assay showed anti-invasive activities of gallic acid, delphinidin and pelargonidin-3-glucosides. Zymographic analysis demonstrated the inhibitory activity of gallic acid at the level of secreted and activated gelatinases. Moreover, gallic acid inhibited MMP-2 and MMP-9 proteolytic activity with very similar potency. NMR and molecular modelling experiments confirmed the interaction of gallic acid with MMP-2, and suggested that it takes place within the catalytic center. In this work we give some new experimental data supporting the role of these compounds in the inhibition of metalloproteases as the mechanism for their cytotoxic activity against fibrosarcoma.

  8. Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9.

    PubMed

    Herr, Michael J; Kotha, Jayaprakash; Hagedorn, Nikolaus; Smith, Blake; Jennings, Lisa K

    2013-01-01

    Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080) to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression.

  9. Hydrophilic extract from Posidonia oceanica inhibits activity and expression of gelatinases and prevents HT1080 human fibrosarcoma cell line invasion.

    PubMed

    Barletta, Emanuela; Ramazzotti, Matteo; Fratianni, Florinda; Pessani, Daniela; Degl'Innocenti, Donatella

    2015-01-01

    Posidonia oceanica (L.) Delile is an endemic Mediterranean sea-grass distributed in the infralittoral zones, where it forms meadows playing a recognized ecological role in the coastal marine habitat. Although its use as a traditional herbal remedy is poorly documented, recent literature reports interesting pharmacological activities as antidiabetic, antioxidant and vasoprotective. Differently from previous literature, this study presents a hydrophilic extraction method that recovers metabolites that may be tested in biological buffers. We showed for the first time in the highly invasive HT1080 human fibrosarcoma cell line that our hydrophilic extract from P. oceanica was able to strongly decrease gene and protein expression of gelatinases MMP-2 and MMP-9 and to directly inhibit in a dose-dependent manner gelatinolytic activity in vitro. Moreover, we have revealed that our extract strongly inhibited HT1080 cell migration and invasion. Biochemical analysis of the hydrophilic extract showed that catechins were the major constituents with minor contribution of gallic acid, ferulic acid and chlorogenic plus a fraction of uncharacterized phenols. However, if each individual compound was tested independently, none by itself was able to induce a direct inhibition of gelatinases as strong as that observed in total extract, opening up new routes to the identification of novel compounds. These results indicate that our hydrophilic extract from P. oceanica might be a source of new pharmacological natural products for treatment or prevention of several diseases related to an altered MMP-2 and MMP-9 expression.

  10. Receptor-dependent antiproliferative effects of corticosteroids in radiation-induced fibrosarcomas and implications for sequential therapy

    SciTech Connect

    Braunschweiger, P.G.; Ting, H.L.; Schiffer, L.M.

    1982-05-01

    Competitive binding studies with (/sup 3/H)dexamethasone and Scatchard analysis demonstrated a single class of high-affinity, low-capacity glucocorticoid receptor sites in 105,000 x g cytosols from radiation-induced fibrosarcomas. In vivo, both dexamethasone (DEX) and methylprednisolone treatments resulted in dose-dependent inhibition of tumor growth and cell proliferation. Changes in the sensitivity of the clonogenic cell population to 3 mM hydroxyurea were used to assess changes in the clonogenic cell proliferation during and after treatments with DEX or methylprednisolone. Neither methylprednisolone nor DEX given every 12 hr for three doses resulted in significant cell kill in the clonogenic fraction. However, changes in the hydroxyurea sensitivity of the clonogenic population after cessation of DEX treatments indicated G1 cell cycle progression delay with transient enrichment of S-phase clonogenic cells 24 to 48 hr after cessation of DEX treatments. The duration of the DEX-induced progression delay and the timing of maximal S-phase cellularity after DEX was directly correlated with the level of glucocorticoid receptors in the treated tumors. Using regrowth delay to assess the efficacy of kinetically directed sequential chemotherapy, the effectiveness of vincristine, given after DEX, was highly sequence dependent, with the most effective treatment interval being coincident with maximal S-phase clonogenic fraction. Other studies indicated that the effectiveness of cyclophosphamide could also be increased by time sequencing after DEX.

  11. A novel branched TAT(47-57) peptide for selective Ni(2+) introduction into the human fibrosarcoma cell nucleus.

    PubMed

    Szyrwiel, Łukasz; Shimura, Mari; Shirataki, Junko; Matsuyama, Satoshi; Matsunaga, Akihiro; Setner, Bartosz; Szczukowski, Łukasz; Szewczuk, Zbigniew; Yamauchi, Kazuto; Malinka, Wiesław; Chavatte, Laurent; Łobinski, Ryszard

    2015-07-01

    A TAT47-57 peptide was modified on the N-terminus by elongation with a 2,3-diaminopropionic acid residue and then by coupling of two histidine residues on its N-atoms. This branched peptide could bind to Ni under physiological conditions as a 1 : 1 complex. We demonstrated that the complex was quantitatively taken up by human fibrosarcoma cells, in contrast to Ni(2+) ions. Ni localization (especially at the nuclei) was confirmed by imaging using both scanning X-ray fluorescence microscopy and Newport Green fluorescence. A competitive assay with Newport Green showed that the latter displaced the peptide ligand from the Ni-complex. Ni(2+) delivered as a complex with the designed peptide induced substantially more DNA damage than when introduced as a free ion. The availability of such a construct opens up the way to investigate the importance of the nucleus as a target for the cytotoxicity, genotoxicity or carcinogenicity of Ni(2+).

  12. Mouse Elk oncogene maps to chromosome X and a novel Elk oncogene (Elk3) maps to chromosome 10

    SciTech Connect

    Tamai, Yoshitaka; Taketo, Makoto; Nozaki, Masami

    1995-03-20

    The Elk protein is a member of the Ets family found in both vertebrates and invertebrates. Human ELK1 encoded by ELK1 binds alone or together with serum response factor to DNA and regulates gene expression in a variety of biological processes. Using a panel of interspecific backcross mice, we have mapped the Elk oncogene (Elk) and a novel type Elk oncogene (Elk3), closely related to ELK1. Elk maps to Chr X, and Elk3 maps to the proximal region of Chr 10. 18 refs., 1 fig., 1 tab.

  13. The mystery of oncogenic KRAS: Lessons from studying its wild-type counter part.

    PubMed

    Chang, Yuan-I; Damnernsawad, Alisa; Kong, Guangyao; You, Xiaona; Wang, Demin; Zhang, Jing

    2016-07-22

    Using conditional knock-in mouse models, we and others have shown that despite the very high sequence identity between Nras and Kras proteins, oncogenic Kras displays a much stronger leukemogenic activity than oncogenic Nras in vivo. In this manuscript, we will summarize our recent work of characterizing wild-type Kras function in adult hematopoiesis and in oncogenic Kras-induced leukemogenesis. We attribute the strong leukemogenic activity of oncogenic Kras to 2 unique aspects of Kras signaling. First, Kras is required in mediating cell type- and cytokine-specific ERK1/2 signaling. Second, oncogenic Kras, but not oncogenic Nras, induces hyperactivation of wild-type Ras, which significantly enhances Ras signaling in vivo. We will also discuss a possible mechanism that mediates oncogenic Kras-evoked hyperactivation of wild-type Ras and a potential approach to down-regulate oncogenic Kras signaling.

  14. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

    PubMed Central

    Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

    2016-01-01

    Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

  15. c-Abl antagonizes the YAP oncogenic function

    PubMed Central

    Keshet, R; Adler, J; Ricardo Lax, I; Shanzer, M; Porat, Z; Reuven, N; Shaul, Y

    2015-01-01

    YES-associated protein (YAP) is a central transcription coactivator that functions as an oncogene in a number of experimental systems. However, under DNA damage, YAP activates pro-apoptotic genes in conjunction with p73. This program switching is mediated by c-Abl (Abelson murine leukemia viral oncogene) via phosphorylation of YAP at the Y357 residue (pY357). YAP as an oncogene coactivates the TEAD (transcriptional enhancer activator domain) family transcription factors. Here we asked whether c-Abl regulates the YAP–TEAD functional module. We found that DNA damage, through c-Abl activation, specifically depressed YAP–TEAD-induced transcription. Remarkably, c-Abl counteracts YAP-induced transformation by interfering with the YAP–TEAD transcriptional program. c-Abl induced TEAD1 phosphorylation, but the YAP–TEAD complex remained unaffected. In contrast, TEAD coactivation was compromised by phosphomimetic YAP Y357E mutation but not Y357F, as demonstrated at the level of reporter genes and endogenous TEAD target genes. Furthermore, YAP Y357E also severely compromised the role of YAP in cell transformation, migration, anchorage-independent growth, and epithelial-to-mesenchymal transition (EMT) in human mammary MCF10A cells. These results suggest that YAP pY357 lost TEAD transcription activation function. Our results demonstrate that YAP pY357 inactivates YAP oncogenic function and establish a role for YAP Y357 phosphorylation in cell-fate decision. PMID:25361080

  16. c-Abl antagonizes the YAP oncogenic function.

    PubMed

    Keshet, R; Adler, J; Ricardo Lax, I; Shanzer, M; Porat, Z; Reuven, N; Shaul, Y

    2015-06-01

    YES-associated protein (YAP) is a central transcription coactivator that functions as an oncogene in a number of experimental systems. However, under DNA damage, YAP activates pro-apoptotic genes in conjunction with p73. This program switching is mediated by c-Abl (Abelson murine leukemia viral oncogene) via phosphorylation of YAP at the Y357 residue (pY357). YAP as an oncogene coactivates the TEAD (transcriptional enhancer activator domain) family transcription factors. Here we asked whether c-Abl regulates the YAP-TEAD functional module. We found that DNA damage, through c-Abl activation, specifically depressed YAP-TEAD-induced transcription. Remarkably, c-Abl counteracts YAP-induced transformation by interfering with the YAP-TEAD transcriptional program. c-Abl induced TEAD1 phosphorylation, but the YAP-TEAD complex remained unaffected. In contrast, TEAD coactivation was compromised by phosphomimetic YAP Y357E mutation but not Y357F, as demonstrated at the level of reporter genes and endogenous TEAD target genes. Furthermore, YAP Y357E also severely compromised the role of YAP in cell transformation, migration, anchorage-independent growth, and epithelial-to-mesenchymal transition (EMT) in human mammary MCF10A cells. These results suggest that YAP pY357 lost TEAD transcription activation function. Our results demonstrate that YAP pY357 inactivates YAP oncogenic function and establish a role for YAP Y357 phosphorylation in cell-fate decision.

  17. Targeting Oncogenic Mutant p53 for Cancer Therapy.

    PubMed

    Parrales, Alejandro; Iwakuma, Tomoo

    2015-01-01

    Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently have oncogenic gain-of-function activities and exacerbate malignant properties of cancer cells, such as metastasis and drug resistance. Increasing evidence reveals that stabilization of mutant p53 in tumors is crucial for its oncogenic activities, while depletion of mutant p53 attenuates malignant properties of cancer cells. Thus, mutant p53 is an attractive druggable target for cancer therapy. Different approaches have been taken to develop small-molecule compounds that specifically target mutant p53. These include compounds that restore wild-type conformation and transcriptional activity of mutant p53, induce depletion of mutant p53, inhibit downstream pathways of oncogenic mutant p53, and induce synthetic lethality to mutant p53. In this review article, we comprehensively discuss the current strategies targeting oncogenic mutant p53 in cancers, with special focus on compounds that restore wild-type p53 transcriptional activity of mutant p53 and those reducing mutant p53 levels.

  18. Role of ets Oncogenes in the Progression of Breast Cancer

    DTIC Science & Technology

    1998-10-01

    Mazabraud A. (1988). Cancer Kato J, Matsuoka M, Polyak K, Massague J and Sherr CJ. Genet. Cytogenet., 32, 229-238. (1994). Cell, 79, 487-496. Vairo G...Francisco LV , Roach JC, Argonza R, D, Weber BL and EI-Deiryh WS. (1998). Oncogene, 16, King MC and Ostrander EA. (1996). Human Mol. Genet., 1713-1721. 5

  19. Oncogenic cancer/testis antigens: prime candidates for immunotherapy.

    PubMed

    Gjerstorff, Morten F; Andersen, Mads H; Ditzel, Henrik J

    2015-06-30

    Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.

  20. Folate levels modulate oncogene-induced replication stress and tumorigenicity

    PubMed Central

    Lamm, Noa; Maoz, Karin; Bester, Assaf C; Im, Michael M; Shewach, Donna S; Karni, Rotem; Kerem, Batsheva

    2015-01-01

    Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development. PMID:26197802

  1. The Oncogenic Hazard from Chronic Inhalation of Hydrazine,

    DTIC Science & Technology

    1980-01-01

    kidneys, thyroids, adrenals; and liver hemosiderosis, kidney mineralization, general degeneration of the adrenals; and senile atrophy ...nasal polyps. Small numbers of villous nasal polyps, muco-epidermoid papillomas, and squamous cell papillomas were also noted. The incidence of these...unexposed controls that are usually associated with aging such as amyloidosis and senile atrophy of the testes. Analysis of the oncogenic changes and other

  2. Activation of oncogenes by radon progeny and x-rays

    SciTech Connect

    Ling, C.C.

    1990-01-01

    The overall goal of this proposal is to study the carcinogenic effect of both high and low LET radiation at the molecular level, utilizing techniques developed in molecular biology, cancer cell biology and radiation biology. The underlying assumption is that malignant transformation of normal cells is a multistep process requiring two or more molecular events in the genomic DNA. These events are most likely the activation of proto-oncogenes, or the inactivation of tumor suppressor genes. We hypothesize that radiation may induce such events in one or more steps of the multistep process. We will use in vitro models of transformation that reproduce the stepwise progression of normal cells towards the transformed phenotype and ask whether radiation can provide the necessary activating function at discrete steps along this path. Our strategy involves transfecting into normal primary cells a variety of cloned oncogenes that are known to supply only some of the functions necessary for full transformation. These partially transformed'' cells will be the targets for irradiation by x-rays and alpha particles. The results will provide the basis for assessing the ability of ionizing radiation to activate oncogenic functions that complement'' the oncogene already present in the transfected ells and produce the fully transformed phenotype. 121 refs.

  3. Protein Kinase Cι Expression and Oncogenic Signaling Mechanisms in Cancer

    PubMed Central

    Murray, Nicole R.; Kalari, Krishna R.; Fields, Alan P.

    2010-01-01

    Accumulating evidence demonstrates that PKCι is an oncogene and prognostic marker that is frequently targeted for genetic alteration in many major forms of human cancer. Functional data demonstrate that PKCι is required for the transformed phenotype of NSCLC, pancreatic, ovarian, prostate, colon and brain cancer cells. Future studies will be required to determine whether PKCι is also an oncogene in the many other cancer types that also overexpress PKCι. Studies of PKCι using genetically defined models of tumorigenesis have revealed a critical role for PKCι in multiple stages of tumorigenesis, including tumor initiation, progression and metastasis. Recent studies in a genetic model of lung adenocarcinoma suggest a role for PKCι in transformation of lung cancer stem cells. These studies have important implications for the therapeutic use of aurothiomalate (ATM), a highly selective PKCι signaling inhibitor currently undergoing clinical evaluation. Significant progress has been made in determining the molecular mechanisms by which PKCι drives the transformed phenotype, particularly the central role played by the oncogenic PKCι-Par6 complex in transformed growth and invasion, and of several PKCι-dependent survival pathways in chemo-resistance. Future studies will be required to determine the composition and dynamics of the PKCι-Par6 complex, and the mechanisms by which oncogenic signaling through this complex is regulated. Likewise, a better understanding of the critical downstream effectors of PKCι in various human tumor types holds promise for identifying novel prognostic and surrogate markers of oncogenic PKCι activity that may be clinically useful in ongoing clinical trials of ATM. PMID:20945390

  4. Combination treatment with arsenic trioxide and irradiation enhances cell-killing effects in human fibrosarcoma cells in vitro and in vivo through induction of both autophagy and apoptosis.

    PubMed

    Chiu, Hui-Wen; Lin, Jing-Hua; Chen, Yi-An; Ho, Sheng-Yow; Wang, Ying-Jan

    2010-04-01

    The traditional treatments for fibrosarcoma have limited efficacy. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Accumulating evidence indicates that programmed cell death (PCD) is closely related to anticancer therapy. Many studies have shown that tumor cells treated with anticancer drugs experience the induction of type I PCD, apoptosis, and type II PCD, autophagy. In the present study, we investigated the anticancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) in human fibrosarcoma cells in vitro and in xenograft tumors in SCID mice in vivo. We found that IR increased the population of HT1080 cells in the G2/M phase in a time-dependent manner within 9 h. IR treatment combined with ATO at this time point induced a significantly prolonged G2/M arrest and consequently enhanced cell death. Furthermore, damage of mitochondria membrane potential could be involved in the underlying mechanisms. The enhanced cytotoxic effect of combined treatment occurred due to the increased induction of more autophagy and apoptosis through the inhibition of Akt and the activation of ERK1/2 signaling pathways in HT1080 cells. The combined treatment of HT1080 cells pretreated with Z-VAD or 3-MA resulted in a significant reduction in AO-positive cells, apoptotic cells and cytotoxicity. In in vivo studies, the combination of IR and ATO significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. The data suggest that a combination of IR and ATO could be a new potential therapeutic strategy for the treatment of fibrosarcoma.

  5. Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells.

    PubMed

    Funasaka, Tatsuyoshi; Hu, Huankai; Yanagawa, Takashi; Hogan, Victor; Raz, Avraham

    2007-05-01

    Phosphoglucose isomerase (PGI) is one of the glycolytic enzymes and is a multifunctional enzyme that functions in glucose metabolism inside the cell while acting as a cytokine outside the cell, with properties that include autocrine motility factor (AMF) regulating tumor cell motility. Although there are many studies indicating that PGI/AMF has been implicated in progression of metastasis, no direct studies of the significance of exogenous PGI/AMF on tumor progression have been reported. Here, we report on the mesenchymal-to-epithelial transition (MET), which is the reverse phenomenon of the epithelial-to-mesenchymal transition that is associated with loss of cell polarity, loss of epithelia markers, and enhancement of cell motility essential for tumor cell invasion and metastasis. Mesenchymal human fibrosarcoma HT1080 cells, which have naturally high levels of endogenous and exogenous PGI/AMF, were stably transfected with PGI/AMF small interfering RNA (siRNA). The siRNA targeting human PGI/AMF down-regulated the endogenous PGI/AMF expression and completely extinguished the secretion of PGI/AMF in a human fibrosarcoma HT1080, whereas the control siRNA showed no effects. The PGI/AMF siRNA caused cells to change shape dramatically and inhibited cell motility and invasion markedly. Suppression of PGI/AMF led to a contact-dependent inhibition of cell growth. Those PGI/AMF siRNA-transfected cells showed epithelial phenotype. Furthermore, tumor cells with PGI/AMF deficiency lost their abilities to form tumor mass. This study identifies that MET in HT1080 human lung fibrosarcoma cells was initiated by down-regulation of the housekeeping gene product/cytokine PGI/AMF, and the results depicted here suggest a novel therapeutic target/modality for mesenchymal cancers.

  6. Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro.

    PubMed

    Hayashi, Masanobu; Nishiya, Hide; Chiba, Toshiaki; Endoh, Daiji; Kon, Yasuhiro; Okui, Toyo

    2007-02-01

    Anti-copper treatments have been investigated to determine whether they suppress angiogenesis and tumor development since Cu is widely accepted as being required for angiogenesis. We examined the effects of treatment with trientine, a copper-chelating agent, on tumor development in a murine xenograft model using fibrosarcoma-derived transplantable QRsp-11 cells and C57BL/6 mice and induction of apoptosis in tumor cells and endothelial cells in vivo and in vitro. The tumor volumes increased more slowly in trientine-treated mice than in untreated mice. Tumor volumes in the treated mice were significantly smaller than those in the untreated mice at 24 days postinoculation (d.p.i.) of tumor cells. A cluster of pyknotic tumor cells and morphological abnormalities in capillary endothelial cells were observed in the tumors of trientine-treated mice but not in the tumors of untreated mice. The proportions of apoptotic and necrotic cells in the tumors of treated mice were approximately 3.5-fold higher than those in the tumors of untreated mice at 14 d.p.i. When the cells were treated with trientine in vitro, mouse endothelial cells and bovine primary endothelial cells showed an approximately 10-fold higher sensitivity to trientine than QRsp-11 cells in terms of D37. However, the proportion of apoptotic cells in endothelial cells was significantly lower than that in QRsp-11 cells after treatment with trientine. These results show that apoptosis was induced in tumor cells by treatment with trientine in vivo and in vitro.

  7. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

    PubMed Central

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D.; Shetake, Neena; Balla, Murali M. S.; Kumar, Amit; Ray, Pritha; Ghosh, Anu

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  8. Characterization of defectiveness in endogenous antigen presentation of novel murine cells established from methylcholanthrene-induced fibrosarcomas.

    PubMed Central

    Kuroda, K; Yamashina, K; Kitatani, N; Kagishima, A; Hamaoka, T; Hosaka, Y

    1995-01-01

    Three cell lines (4A1, 4C2 and 6D1 cells) derived from fibrosarcoma induced by the inoculation of 3-methylcholanthrene into C3H/HeN (H-2k) mice were examined for their ability to present antigens to CD8+ cytotoxic T lymphocytes (CTL). 6D1 and 4C2 cells were deficient in presenting endogenously synthesized influenza virus antigens to CTL, but they were able to present antigens when they were sensitized with a synthetic epitope peptide. The expression of the H-2 Kk gene in 4C2 and 6D1 cells was much reduced and was detectable only with Northern blot hybridization. The expression of two transporter genes (TAP1 and TAP2), examined by Northern hybridization, was also reduced in both cells, and negligible particularly in 4C2 cells. Interferon-gamma (IFN-gamma) treatment of these cells induced expression of Kk, TAP1 and TAP2 genes and rescued the defect of class I-restricted antigen presentation in 4C2 and 6D1 cells. Even after this treatment, however, antigen-presentation capability of 4C2 cells was still much lower than that of normal 4A1 cells. This finding suggests that 4C2 cells might have an additional defective gene(s), whose products are involved in the processing of class I-restricted antigen, besides the Kk and TAP genes, and this may explain the difficulty of 4C2 cells to induce tumour-specific immunity, as described previously. To our knowledge, the 4C2 cell is the first tumour cell postulated to have more than three defective genes involved in class I-restricted antigen presentation. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:7890298

  9. Depth of necrosis induced by photodynamic therapy with sulfonated aluminum phthalocyanine in S180 fibrosarcoma of mice

    NASA Astrophysics Data System (ADS)

    Yu, Hong-Yu; Dong, Rong-Chun; Chen, Ji-Yao; Cai, Huai-Xin

    1993-03-01

    In view of explaining the results that AlSPC-PDT was more effective than HPD-PDT in destroying S180 fibrosarcoma (diameter: 0.5 - 0.8 cm; thickness: 0.4 - 0.7 cm) transplanted in white mice, the depth of necrosis of S180 sarcoma in mice in AlSPC-PDT was studied, compared with it in HPD-PDT. Two kinds of HPD were chosen as the control photosensitizers of AlSPC: Photofrin I (PI), and Photosensitizing drug-007 (PSD-007). The experimental tumors in mice were chosen with longitudinal diameters in the range of 0.8 - 1.0 cm and thickness in the range of 0.7 - 1.0 cm. A photosensitizer dose of 10 mg/kg was given (iv) for PI-PDT, PSD-007-PDT, and AlSPC-PDT. The dose of exposure light (600 - 750 nm) was 180 J/cm2. The experimental mice were killed 48 h after PDT to get the tumor necrotic depth. The depth was 0.55 +/- 0.14 cm (0.30 - 0.85 cm) in the AlSPC-PDT group, 0.35 +/- 0.12 cm (0.20 - 0.55 cm) in the PI-PDT group, and 0.36 +/- 0.11 cm (0.20 - 0.50 cm) in the PSD-007-PDT group. These differences may be due to the differences of the dyes' light absorbance spectra. AlSPC's main absorbance peak is at 675 nm and HPD's is around 400 nm with a smaller peak at 630 nm. The penetration of 675 nm light through biologic tissue is deeper than that of 400 nm light and 630 nm light.

  10. A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits antitumor metastasis in human fibrosarcoma HT-1080 cells.

    PubMed

    Miyata, Yoshiki; Sato, Takashi; Imada, Keisuke; Dobashi, Akira; Yano, Masamichi; Ito, Akira

    2008-02-01

    The activation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) is well known to be associated with tumor invasion and metastasis. We previously reported that a polymethoxyflavonoid, nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), derived from Citrus depressa (Hayata), inhibits the phosphorylation of MEK and thereby suppresses matrix metalloproteinase (MMP) expression in a tumor-metastasis stimulator, 12-O-tetradecanoyl phorbol 13-acetate (TPA)-stimulated human fibrosarcoma HT-1080 cells [Mol. Cancer Ther. 3 (2004) 839-847]. In the present study, we investigated whether or not nobiletin might directly influence MEK activity to exhibit the antitumor metastatic activity in vitro. MEK kinase assay using myelin basic protein (MBP) revealed that TPA-augmented MEK activity in HT-1080 cells and that the augmented MEK activity was diminished by nobiletin treatment. In addition, the decrease in MEK activity caused by nobiletin was found to inhibit the phosphorylation of extracellular regulated kinases (ERK), a downstream signaling factor for MEK. Furthermore, when an immunoprecipitated active MEK was incubated with nobiletin under cell-free conditions, nobiletin was found to inhibit the MEK-mediated MBP phosphorylation. In contrast, other citrus polymethoxyflavonoids such as 3-hydroxy-5,6,7,8,3',4'-hexamethoxyflavone (natsudaidain) and 3,5,6,7,8,3',4'-heptamethoxyflavone, did not directly inhibit MEK activity. Moreover, natsudaidain and 3,5,6,7,8,3',4'-heptamethoxyflavone exhibited no or less inhibitory effect than nobiletin on the proMMP-9/progelatinase B production in HT-1080 cells. Therefore, these results provide novel evidence that nobiletin directly inhibits MEK activity and decreases the sequential phosphorylation of ERK, exhibiting the antitumor metastatic activity by suppressing MMP expression in HT-1080 cells.

  11. Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

    PubMed Central

    Guo, Yi; Xie, Jun; Rubin, Elyssa; Tang, Ya-Xiong; Lin, Fritz; Zi, Xiaolin; Hoang, Bang H.

    2010-01-01

    Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 ( fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control–transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS. PMID:18451162

  12. Fibroblast activation protein increases metastatic potential of fibrosarcoma line HT1080 through upregulation of integrin-mediated signaling pathways.

    PubMed

    Baird, Sarah K; Allan, Laura; Renner, Christoph; Scott, Fiona E; Scott, Andrew M

    2015-06-01

    The serine protease fibroblast activation protein (FAP) is selectively expressed on tumour-associated fibroblasts in most human epithelial tumours, as well as on some mesenchymal tumours such as sarcoma. High FAP expression is most often associated with poor outcome and increased metastasis. Here, we compare the in vitro metastatic potential of HT1080 fibrosarcoma cells with and without FAP expression in order to elucidate the mechanism by which FAP may influence metastasis. In the presence of FAP, cells were more adhesive to extracellular matrix proteins and migrated and invaded through Matrigel to a greater degree. The anti-FAP antibody ESC11, which caused internalization of FAP, decreased adhesion and migration, but only when cells expressed FAP. It was also found that blocking activity of integrins β1 and αvβ3 reduced both cell adhesion and migration and this effect was much more marked in FAP-expressing HT1080 cells than mock-transfected HT1080 cells. The expression or activation of intracellular proteins that form part of the downstream signaling of integrins, including integrin-linked kinase, Rac1 and focal adhesion kinase, was also upregulated when FAP was expressed, suggesting that FAP not only upregulates metastatic-like cell behaviours through interaction with integrins, but also influences the intracellular signaling of integrins. This was confirmed using both PI3 kinase and Src kinase inhibitors, which decreased adhesion and migration in FAP-expressing cells, but did not affect mock-transfected HT1080 cells. FAP is therefore a useful target for anti-cancer therapy, as not only is its expression tumour-selective, but its downregulation has the potential to reduce incidence of metastasis.

  13. Impact of carbamylation and glycation of collagen type I on migration of HT1080 human fibrosarcoma cells.

    PubMed

    Said, Georges; Guilbert, Marie; Millerot-Serrurot, Emilie; Van Gulick, Laurence; Terryn, Christine; Garnotel, Roselyne; Jeannesson, Pierre

    2012-06-01

    Collagen type I is an abundant component of the extracellular matrix and due to its longevity, constitutes a prominent target of non-enzymatic post-translational in vivo modifications such as carbamylation and glycation. These protein modifications involved in aging, renal diseases and diabetes, are linked to elevated cancer risk. In this in vitro study, we investigated the impact of carbamylated and glycated collagen type I on the migratory behavior of the highly invasive HT1080 human fibrosarcoma cells. The proliferation of HT1080 on modified collagens did not differ from that on native form. The glycated collagen delayed the cell adhesion time whereas the carbamylated one had no effect. The migration ability of HT1080 was studied by quantifying single cell speed using videomicroscopy. Glycation strongly inhibited mean cell speed by 47% whereas carbamylation moderately affected it by 12%. In addition, the influence of these collagen modifications on actin and vinculin organization was studied. On the glycated collagen, 63% of cells revealed a dramatic loss of actin stress fibers vs. 28% on the carbamylated one. In these cells, disorganized F-actin was accompanied with a disturbance of vinculin and both proteins were localized at the rim of the cells. Concerning the focal adhesion kinase (FAK) expression, glycated collagen only induced a significant inhibition. Whereas, both collagen modifications provoked a differential inhibition of FAK phosphorylation state by 25% for carbamylation and 60% for glycation. In conclusion, our data suggest that, in vivo, collagen glycation and carbamylation may affect tumor cell metastasis. This suggestion is supported by clinical studies reporting less aggressive tumors in diabetic or uremic patients. Consequently, the impact of such post-translational modifications has to be taken into account in order to better understand the link between aging, diabetes or uremia and cancer progression.

  14. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.

    PubMed

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D; Shetake, Neena; Balla, Murali M S; Kumar, Amit; Ray, Pritha; Ghosh, Anu; Pandey, B N

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  15. The use of Gene Ontology terms and KEGG pathways for analysis and prediction of oncogenes.

    PubMed

    Xing, Zhihao; Chu, Chen; Chen, Lei; Kong, Xiangyin

    2016-11-01

    Oncogenes are a type of genes that have the potential to cause cancer. Most normal cells undergo programmed cell death, namely apoptosis, but activated oncogenes can help cells avoid apoptosis and survive. Thus, studying oncogenes is helpful for obtaining a good understanding of the formation and development of various types of cancers. In this study, we proposed a computational method, called OPM, for investigating oncogenes from the view of Gene Ontology (GO) and biological pathways. All investigated genes, including validated oncogenes retrieved from some public databases and other genes that have not been reported to be oncogenes thus far, were encoded into numeric vectors according to the enrichment theory of GO terms and KEGG pathways. Some popular feature selection methods, minimum redundancy maximum relevance and incremental feature selection, and an advanced machine learning algorithm, random forest, were adopted to analyze the numeric vectors to extract key GO terms and KEGG pathways. Along with the oncogenes, GO terms and KEGG pathways were discussed in terms of their relevance in this study. Some important GO terms and KEGG pathways were extracted using feature selection methods and were confirmed to be highly related to oncogenes. Additionally, the importance of these terms and pathways in predicting oncogenes was further demonstrated by finding new putative oncogenes based on them. This study investigated oncogenes based on GO terms and KEGG pathways. Some important GO terms and KEGG pathways were confirmed to be highly related to oncogenes. We hope that these GO terms and KEGG pathways can provide new insight for the study of oncogenes, particularly for building more effective prediction models to identify novel oncogenes. The program is available upon request. We hope that the new findings listed in this study may provide a new insight for the investigation of oncogenes. This article is part of a Special Issue entitled "System Genetics" Guest Editor

  16. Generation and characterization of a recombinant Moloney murine leukemia virus containing the v-myc oncogene of avian MC29 virus: in vitro transformation and in vivo pathogenesis.

    PubMed Central

    Brightman, B K; Pattengale, P K; Fan, H

    1986-01-01

    A new retrovirus consisting of the v-myc oncogene sequences of avian MC29 virus inserted into the genome of Moloney murine leukemia virus (M-MuLV) was generated. This was accomplished by constructing a recombinant DNA clone containing the desired organization, introducing the recombinant DNA into mouse NIH 3T3 cells, and superinfecting the cells with replication-competent M-MuLV. The construction was designed so that an M-MuLV gag-myc fusion protein would be produced. The resulting virus, M-MuLV(myc), morphologically transformed uninfected NIH 3T3 cells. Stocks of M-MuLV(myc)-M-MuLV were infected into secondary mouse embryo cultures. M-MuLV(myc) induced striking growth and proliferation of hematopoietic cells. These cells were of the myeloid lineage by morphology, phagocytic properties, and surface staining with Mac-1 and Mac-2 monoclonal antibodies. They resembled mature macrophages, although they displayed minor properties of immaturity. The myeloid cells were transformed in comparison with uninfected myeloid cells since they were less adherent and had unlimited proliferative capacity and reduced growth factor requirements. The transformed myeloid cells with proliferative potential were actually myeloid progenitors which apparently underwent terminal differentiation to macrophages. It was possible to derive a permanent line of factor-independent macrophages from M-MuLV(myc)-transformed myeloid cells. M-MuLV(myc) also immortalized and morphologically transformed mouse embryo fibroblasts. These in vitro properties closely resembled the biological activity of MC29 virus in avian cells and suggested that the nature of the v-myc oncogene was an important determinant in transformation specificity. Neonatal NIH Swiss mice inoculated intraperitoneally with M-MuLV(myc)-M-MuLV only developed lymphoblastic lymphoma characteristic of the M-MuLV helper alone, and no acute fibrosarcomas or myeloid tumors resulted. In light of the strong myeloid transformation observed in vitro

  17. Regulation of oncogene-induced cell cycle exit and senescence by chromatin modifiers.

    PubMed

    David, Gregory

    2012-09-01

    Oncogene activation leads to dramatic changes in numerous biological pathways controlling cellular division, and results in the initiation of a transcriptional program that promotes transformation. Conversely, it also triggers an irreversible cell cycle exit called cellular senescence, which allows the organism to counteract the potentially detrimental uncontrolled proliferation of damaged cells. Therefore, a tight transcriptional control is required at the onset of oncogenic signal, coordinating both positive and negative regulation of gene expression. Not surprisingly, numerous chromatin modifiers contribute to the cellular response to oncogenic stress. While these chromatin modifiers were initially thought of as mere mediators of the cellular response to oncogenic stress, recent studies have uncovered a direct and specific regulation of chromatin modifiers by oncogenic signals. We review here the diverse functions of chromatin modifiers in the cellular response to oncogenic stress, and discuss the implications of these findings on the regulation of cell cycle progression and proliferation by activated oncogenes.

  18. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences

    PubMed Central

    Balaj, Leonora; Lessard, Ryan; Dai, Lixin; Cho, Yoon-Jae; Pomeroy, Scott L.; Breakefield, Xandra O.; Skog, Johan

    2011-01-01

    Tumour cells release an abundance of microvesicles containing a selected set of proteins and RNAs. Here, we show that tumour microvesicles also carry DNA, which reflects the genetic status of the tumour, including amplification of the oncogene c-Myc. We also find amplified c-Myc in serum microvesicles from tumour-bearing mice. Further, we find remarkably high levels of retrotransposon RNA transcripts, especially for some human endogenous retroviruses, such as LINE-1 and Alu retrotransposon elements, in tumour microvesicles and these transposable elements could be transferred to normal cells. These findings expand the nucleic acid content of tumour microvesicles to include: elevated levels of specific coding and non-coding RNA and DNA, mutated and amplified oncogene sequences and transposable elements. Thus, tumour microvesicles contain a repertoire of genetic information available for horizontal gene transfer and potential use as blood biomarkers for cancer. PMID:21285958

  19. Malignant transformation of diploid human fibroblasts by transfection of oncogenes

    SciTech Connect

    McCormick, J.J.

    1992-01-01

    This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

  20. The ETS family of oncogenic transcription factors in solid tumours.

    PubMed

    Sizemore, Gina M; Pitarresi, Jason R; Balakrishnan, Subhasree; Ostrowski, Michael C

    2017-06-01

    Findings over the past decade have identified aberrant activation of the ETS transcription factor family throughout all stages of tumorigenesis. Specifically in solid tumours, gene rearrangement and amplification, feed-forward growth factor signalling loops, formation of gain-of-function co-regulatory complexes and novel cis-acting mutations in ETS target gene promoters can result in increased ETS activity. In turn, pro-oncogenic ETS signalling enhances tumorigenesis through a broad mechanistic toolbox that includes lineage specification and self-renewal, DNA damage and genome instability, epigenetics and metabolism. This Review discusses these different mechanisms of ETS activation and subsequent oncogenic implications, as well as the clinical utility of ETS factors.

  1. SUMOylated IRF-1 shows oncogenic potential by mimicking IRF-2

    SciTech Connect

    Park, Sun-Mi; Chae, Myounghee; Kim, Bo-Kyoung; Seo, Taegun; Jang, Ik-Soon; Choi, Jong-Soon; Kim, Il-Chul; Lee, Je-Ho; Park, Junsoo

    2010-01-01

    Interferon regulatory factor-1 (IRF-1) is an interferon-induced transcriptional activator that suppresses tumors by impeding cell proliferation. Recently, we demonstrated that the level of SUMOylated IRF-1 is elevated in tumor cells, and that SUMOylation of IRF-1 attenuates its tumor-suppressive function. Here we report that SUMOylated IRF-1 mimics IRF-2, an antagonistic repressor, and shows oncogenic potential. To demonstrate the role of SUMOylated IRF-1 in tumorigenesis, we used SUMO-IRF-1 recombinant protein. Stable expression of SUMO-IRF-1 in NIH3T3 cells resulted in focus formation and anchorage-independent growth in soft agar. Inoculation of SUMO-IRF-1-transfected cells into athymic nude mice resulted in tumor formation and infiltration of adipose tissues. Finally, we demonstrated that SUMO-IRF-1 transforms NIH3T3 cells in a dose-dependent manner suggesting that SUMOylated IRF-1 may act as an oncogenic protein in tumor cells.

  2. Small genomic insertions form enhancers that misregulate oncogenes

    PubMed Central

    Abraham, Brian J.; Hnisz, Denes; Weintraub, Abraham S.; Kwiatkowski, Nicholas; Li, Charles H.; Li, Zhaodong; Weichert-Leahey, Nina; Rahman, Sunniyat; Liu, Yu; Etchin, Julia; Li, Benshang; Shen, Shuhong; Lee, Tong Ihn; Zhang, Jinghui; Look, A. Thomas; Mansour, Marc R.; Young, Richard A.

    2017-01-01

    The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers. PMID:28181482

  3. Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer.

    PubMed

    Chuang, Hsiao-Ching; Huang, Po-Hsien; Kulp, Samuel K; Chen, Ching-Shih

    2017-03-01

    The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.

  4. The oncogenic action of ionizing radiation on rat skin

    SciTech Connect

    Burns, F.J.; Garte, S.J.

    1990-01-01

    An extensive experiment involving approximately 400 rats exposed to the neon ion beam at the Bevalac in Berkeley, CA and to electrons is nearing completion. Progress is described in three areas corresponding to the specific aims of the proposal: (1) carcinogenesis and DNA strand breaks in rat skin following exposure by the neon ions or electrons; (2) oncogene activation in radiation-induced rat skin cancers; (3) DNA strand breaks in the epidermis as a function of radiation penetration. 59 refs., 4 tabs.

  5. Serum antibodies to some oncogenic viruses in the child.

    PubMed

    Arnaudova, V; Nastac, E; Predescu, E

    1978-01-01

    The presence of complement fixing antibodies to four viruses with oncogenic potential for animals was studied in children (including neonates and infants). Antibodies to herpes, adenovirus and avian "gs" sarcoma-leukosis antigens were detected, but there were no antibodies to SV-40. Positivity percentages varied with age and with the antigen used. Possible explanations of the appearance of these antibodies in the child are provided.

  6. The Oncogenic Palmitoyl-Protein Network in Prostate Cancer

    DTIC Science & Technology

    2011-03-31

    fatty acid palmitate , or a closely related fatty acid , is affixed to proteins). Studies from our laboratory and others indicate that these lipid...an enzyme, fatty acid synthase (FASN), as a biochemically relevant protein in PCa. FASN has been described as a "metabolic oncogene," which operates...by an unknown mechanism to promote tumor growth. We know that FASN is the source of a class of lipids called long-chain fatty acids . Most of the long

  7. Mutations in the RET proto-oncogene in sporadic pheochromocytomas

    SciTech Connect

    Thibodeau, S.N.; Lindor, N.M.; Honchel, R.

    1994-09-01

    Mutations in the RET proto-oncogene have recently been demonstrated in kindreds with Multiple Endocrine Neoplasia (MEN) types 2A and 2B. Both of these autosomal dominant disorders are characterized by the development of neoplasia in cell lines of neural crest origin, such as medullary throid carcinomas and pheochromocytomas. Individuals with MEN 2B have, in addition, ganglioneuromas of the lips, tongue and colon, a marfanoid habitus, and corneal nerve thickening. Approximately 90% of patients with MEN 2A have a germline mutation in exons 10 or 11, while 95% of patients with MEN 2B have a T{yields}C transition in codon 918 of exon 16. In this study, pheochromocytomas from 29 individuals who had no clinical evidence of MEN 2A or 2B (sporadic) were examined for the presence of either germline or somatic mutations in exons 10, 11, and 16 of the RET proto-oncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in one of the three exons. One tumor had a G{yields}A transition in codon 609 (exon 10), another had a 6 bp deletion encompassing codons 632 & 633 (exon 11), and the final tumor had a T{yields}C transition in codon 918 (exon 16). These mutations were not found in the corresponding normal DNA from these individuals, indicating that the mutation were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET proto-oncogene, our data suggests that: (1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN 2A or 2B; and (2) somatic mutations in the RET proto-oncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.

  8. Oncogenic effects of evolutionarily conserved noncoding RNA ECONEXIN on gliomagenesis.

    PubMed

    Deguchi, S; Katsushima, K; Hatanaka, A; Shinjo, K; Ohka, F; Wakabayashi, T; Zong, H; Natsume, A; Kondo, Y

    2017-04-03

    Accumulating studies have demonstrated the importance of long noncoding RNAs (lncRNAs) during oncogenic transformation. However, because most lncRNAs are currently uncharacterized, the identification of novel oncogenic lncRNAs is difficult. Given that intergenic lncRNA have substantially less sequence conservation patterns than protein-coding genes across species, evolutionary conserved intergenic lncRNAs are likely to be functional. The current study identified a novel intergenic lncRNA, LINC00461 (ECONEXIN) using a combined approach consisting of searching lncRNAs by evolutionary conservation and validating their expression in a glioma mouse model. ECONEXIN was the most highly conserved intergenic lncRNA containing 83.0% homology with the mouse ortholog (C130071C03Rik) for a region over 2500 bp in length within its exon 3. Expressions of ECONEXIN and C130071C03Rik were significantly upregulated in both human and mouse glioma tissues. Moreover, the expression of C130071C03Rik was upregulated even in precancerous conditions and markedly increased during glioma progression. Functional analysis of ECONEXIN in glioma cell lines, U87 and U251, showed it was dominantly located in the cytoplasm and interacted with miR-411-5p via two binding sites within ECONEXIN. Inhibition of ECONEXIN upregulated miR-411-5p together with the downregulation of its target, Topoisomerase 2 alpha (TOP2A), in glioma cell lines, resulting in decreased cell proliferation. Our data demonstrated that ECONEXIN is a potential oncogene that regulates TOP2A by sponging miR-411-5p in glioma. In addition, our investigative approaches to identify conserved lncRNA and their molecular characterization by validation in mouse tumor models may be useful to functionally annotate novel lncRNAs, especially cancer-associated lncRNAs.Oncogene advance online publication, 3 April 2017; doi:10.1038/onc.2017.88.

  9. Oncogenes induce the cancer-associated fibroblast phenotype

    PubMed Central

    Lisanti, Michael P; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica

    2013-01-01

    Metabolic coupling, between mitochondria in cancer cells and catabolism in stromal fibroblasts, promotes tumor growth, recurrence, metastasis, and predicts anticancer drug resistance. Catabolic fibroblasts donate the necessary fuels (such as L-lactate, ketones, glutamine, other amino acids, and fatty acids) to anabolic cancer cells, to metabolize via their TCA cycle and oxidative phosphorylation (OXPHOS). This provides a simple mechanism by which metabolic energy and biomass are transferred from the host microenvironment to cancer cells. Recently, we showed that catabolic metabolism and “glycolytic reprogramming” in the tumor microenvironment are orchestrated by oncogene activation and inflammation, which originates in epithelial cancer cells. Oncogenes drive the onset of the cancer-associated fibroblast phenotype in adjacent normal fibroblasts via paracrine oxidative stress. This oncogene-induced transition to malignancy is “mirrored” by a loss of caveolin-1 (Cav-1) and an increase in MCT4 in adjacent stromal fibroblasts, functionally reflecting catabolic metabolism in the tumor microenvironment. Virtually identical findings were obtained using BRCA1-deficient breast and ovarian cancer cells. Thus, oncogene activation (RAS, NFkB, TGF-β) and/or tumor suppressor loss (BRCA1) have similar functional effects on adjacent stromal fibroblasts, initiating “metabolic symbiosis” and the cancer-associated fibroblast phenotype. New therapeutic strategies that metabolically uncouple oxidative cancer cells from their glycolytic stroma or modulate oxidative stress could be used to target this lethal subtype of cancers. Targeting “fibroblast addiction” in primary and metastatic tumor cells may expose a critical Achilles’ heel, leading to disease regression in both sporadic and familial cancers. PMID:23860382

  10. Genome-Wide Chromosomal Targets of Oncogenic Transcription Factors

    DTIC Science & Technology

    2005-04-01

    cancer. Cancer involves, at least in part, aberrant programs of gene expression often mediated by oncogenic transcription factors activating downstream...networks that underlie complex gene expression programs that are activated in cancer. Indeed, transcription factors have been proposed as targets of...some of the limitations of ChIP-chip analysis and can be applied to transcription factors important in breast cancer such as c-myc and ER ( estrogen

  11. CRAF R391W is a melanoma driver oncogene

    PubMed Central

    Atefi, Mohammad; Titz, Bjoern; Tsoi, Jennifer; Avramis, Earl; Le, Allison; Ng, Charles; Lomova, Anastasia; Lassen, Amanda; Friedman, Michael; Chmielowski, Bartosz; Ribas, Antoni; Graeber, Thomas G.

    2016-01-01

    Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas. PMID:27273450

  12. KRAS insertion mutations are oncogenic and exhibit distinct functional properties

    PubMed Central

    White, Yasmine; Bagchi, Aditi; Van Ziffle, Jessica; Inguva, Anagha; Bollag, Gideon; Zhang, Chao; Carias, Heidi; Dickens, David; Loh, Mignon; Shannon, Kevin; Firestone, Ari J.

    2016-01-01

    Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-RasG60_A66dup and K-RasE62_A66dup proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications. PMID:26854029

  13. RNAi screens in mice identify physiological regulators of oncogenic growth

    PubMed Central

    Beronja, Slobodan; Janki, Peter; Heller, Evan; Lien, Wen-Hui; Keyes, Brice; Oshimori, Naoki; Fuchs, Elaine

    2013-01-01

    Summary Tissue growth is the multifaceted outcome of a cell’s intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here, we tackle this problem by carrying out the first genome-wide RNAi-mediated screens in mice. Focusing on skin development and oncogenic (HrasG12V-induced) hyperplasia, our screens uncover novel as well as anticipated regulators of embryonic epidermal growth. Among top oncogenic screen hits are Mllt6 and the Wnt effector β-catenin; they maintain HrasG12V-dependent hyperproliferation. We also expose β-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we document physiological relevance to mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies. PMID:23945586

  14. PRG3 induces Ras-dependent oncogenic cooperation in gliomas

    PubMed Central

    Yakubov, Eduard; Chen, Daishi; Broggini, Thomas; Sehm, Tina; Majernik, Gökce Hatipoglu; Hock, Stefan W.; Schwarz, Marc; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.

    2016-01-01

    Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas. PMID:27058420

  15. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture

    PubMed Central

    Li, Xingnan; Nadauld, Lincoln; Ootani, Akifumi; Corney, David C.; Pai, Reetesh K.; Gevaert, Olivier; Cantrell, Michael A.; Rack, Paul G.; Neal, James T.; Chan, Carol W-M.; Yeung, Trevor; Gong, Xue; Yuan, Jenny; Wilhelmy, Julie; Robine, Sylvie; Attardi, Laura D.; Plevritis, Sylvia K.; Hung, Kenneth E.; Chen, Chang-Zheng; Ji, Hanlee P.; Kuo, Calvin J.

    2014-01-01

    The application of primary organoid cultures containing epithelial and mesenchymal elements to cancer modeling holds promise for combining the accurate multilineage differentiation and physiology of in vivo systems with the facile in vitro manipulation of transformed cell lines. Here, a single air-liquid interface culture method was used without modification to engineer oncogenic mutations into primary epithelial/mesenchymal organoids from mouse colon, stomach and pancreas. Pancreatic and gastric organoids exhibited dysplasia upon KrasG12D expression and/or p53 loss, and readily generated adenocarcinoma upon in vivo transplantation. In contrast, primary colon organoids required combinatorial Apc, p53, KrasG12D and Smad4 mutations for progressive transformation to invasive adenocarcinoma-like histology in vitro and tumorigenicity in vivo, recapitulating multi-hit models of colorectal cancer (CRC), and versus more promiscuous transformation of small intestinal organoids. Colon organoid culture functionally validated the microRNA miR-483 as a dominant driver oncogene at the Insulin-like growth factor-2 (IGF2) 11p15.5 CRC amplicon, inducing dysplasia in vitro and tumorigenicity in vivo. These studies demonstrate the general utility of a highly tractable primary organoid system for cancer modeling and driver oncogene validation in diverse gastrointestinal tissues. PMID:24859528

  16. Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

    PubMed Central

    Wang, Hua; Lafdil, Fouad; Wang, Lei; Park, Ogyi; Yin, Shi; Niu, Junyang; Miller, Andrew M.; Sun, Zhaoli; Gao, Bin

    2011-01-01

    Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl4)–induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injury-driven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth. PMID:21684247

  17. Phosphoglycerate dehydrogenase: potential therapeutic target and putative metabolic oncogene.

    PubMed

    Zogg, Cheryl K

    2014-01-01

    Exemplified by cancer cells' preference for glycolysis, for example, the Warburg effect, altered metabolism in tumorigenesis has emerged as an important aspect of cancer in the past 10-20 years. Whether due to changes in regulatory tumor suppressors/oncogenes or by acting as metabolic oncogenes themselves, enzymes involved in the complex network of metabolic pathways are being studied to understand their role and assess their utility as therapeutic targets. Conversion of glycolytic intermediate 3-phosphoglycerate into phosphohydroxypyruvate by the enzyme phosphoglycerate dehydrogenase (PHGDH)-a rate-limiting step in the conversion of 3-phosphoglycerate to serine-represents one such mechanism. Forgotten since classic animal studies in the 1980s, the role of PHGDH as a potential therapeutic target and putative metabolic oncogene has recently reemerged following publication of two prominent papers near-simultaneously in 2011. Since that time, numerous studies and a host of metabolic explanations have been put forward in an attempt to understand the results observed. In this paper, I review the historic progression of our understanding of the role of PHGDH in cancer from the early work by Snell through its reemergence and rise to prominence, culminating in an assessment of subsequent work and what it means for the future of PHGDH.

  18. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes.

    PubMed

    Choudhary, Chunaram; Olsen, Jesper V; Brandts, Christian; Cox, Jürgen; Reddy, Pavankumar N G; Böhmer, Frank D; Gerke, Volker; Schmidt-Arras, Dirk-E; Berdel, Wolfgang E; Müller-Tidow, Carsten; Mann, Matthias; Serve, Hubert

    2009-10-23

    Inappropriate activation of oncogenic kinases at intracellular locations is frequently observed in human cancers, but its effects on global signaling are incompletely understood. Here, we show that the oncogenic mutant of Flt3 (Flt3-ITD), when localized at the endoplasmic reticulum (ER), aberrantly activates STAT5 and upregulates its targets, Pim-1/2, but fails to activate PI3K and MAPK signaling. Conversely, membrane targeting of Flt3-ITD strongly activates the MAPK and PI3K pathways, with diminished phosphorylation of STAT5. Global phosphoproteomics quantified 12,186 phosphorylation sites, confirmed compartment-dependent activation of these pathways and discovered many additional components of Flt3-ITD signaling. The differential activation of Akt and Pim kinases by ER-retained Flt3-ITD helped to identify their putative targets. Surprisingly, we find spatial regulation of tyrosine phosphorylation patterns of the receptor itself. Thus, intracellular activation of RTKs by oncogenic mutations in the biosynthetic route may exploit cellular architecture to initiate aberrant signaling cascades, thus evading negative regulation.

  19. PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development.

    PubMed

    Bu, Yiwen; Diehl, J Alan

    2016-10-01

    Unfolded protein responses (UPR), consisting of three major transducers PERK, IRE1, and ATF6, occur in the midst of a variety of intracellular and extracellular challenges that perturb protein folding in the endoplasmic reticulum (ER). ER stress occurs and is thought to be a contributing factor to a number of human diseases, including cancer, neurodegenerative disorders, and various metabolic syndromes. In the context of neoplastic growth, oncogenic stress resulting from dysregulation of oncogenes such as c-Myc, Braf(V600E) , and HRAS(G12V) trigger the UPR as an adaptive strategy for cancer cell survival. PERK is an ER resident type I protein kinase harboring both pro-apoptotic and pro-survival capabilities. PERK, as a coordinator through its downstream substrates, reprograms cancer gene expression to facilitate survival in response to oncogenes and microenvironmental challenges, such as hypoxia, angiogenesis, and metastasis. Herein, we discuss how PERK kinase engages in tumor initiation, transformation, adaption microenvironmental stress, chemoresistance and potential opportunities, and potential opportunities for PERK targeted therapy. J. Cell. Physiol. 231: 2088-2096, 2016. © 2016 Wiley Periodicals, Inc.

  20. Activation of oncogenes by radon progeny and x-rays

    SciTech Connect

    Ling, C.C.

    1990-01-01

    The overall goal of this proposal is to study the carcinogenic effect of both high and low LET radiation at the molecular level, utilizing techniques developed in molecular biology, cancer cell biology and radiation biology. The underlying assumption is that malignant transformation of normal cells is a multistep process requiring two or more molecular events in the genomic DNA. We hypothesize that radiation may induce such events in one or more steps of the multistep process. We will use in vitro models of transformation that reproduce the stepwise progression of normal cells toward the transformed phenotype and ask whether radiation can provide the necessary activating function at discrete steps along this path. Our strategy involves transfecting into normal primary cells a variety of cloned oncogenes that are known to supply only some of the functions necessary for full transformation. These partially transformed'' cells will be the targets for irradiation by x-rays and alpha particles. The results will provide the basis for assessing the ability of ionizing radiation to activate oncogenic functions that complement'' the oncogene already present in the transfected cells and produce the fully transformed phenotype. Progress is described. 121 refs.

  1. Combined effects of treatment with trientine, a copper-chelating agent, and x-irradiation on tumor growth in transplantation model of a murine fibrosarcoma.

    PubMed

    Hayashi, Masanobu; Hirai, Ryou; Ishihara, Yuusuke; Horiguchi, Noboru; Endoh, Daiji; Okui, Toyo

    2007-10-01

    Combined effects of treatment with trientine, a copper-chelating agent, and X-irradiation on development of fibrosarcoma using a murine transplantation model in vivo and on cellular survival in vitro were examined. Copper contents in the tumors and serum of trientine-treated mice were significantly lower than those of untreated mice. The tumor volumes of mouse fibrosarcoma QRsp-11 cells increased more slowly in the trientine-treated and the X-irradiated mice than in the control mice from 10 to 24 days postinoculation. The extent of inhibition of tumor growth by X-irradiation at 3 Gy was similar to that obtained by treatment with trientine. A combination of trientine and X-irradiation at 3 Gy showed inhibitory effects on tumor growth similar to those obtained by X-irradiation at 6 Gy. The results showed that trientine and X-irradiation interacted additively in inhibition of tumor growth. When QRsp-11 cells and mouse and bovine endothelial cells were treated with trientine after X-irradiation, the surviving fractions of the cells with combined treatments were essentially consistent with the products of the surviving fractions of trientine-treated cells and those of X-irradiated cells. When the cells were pretreated with trientine and X-irradiated, the surviving fractions of the pretreated cells were lower than those of cells without treatment.

  2. Derivation of feline vaccine-associated fibrosarcoma cell line and its growth on chick embryo chorioallantoic membrane - a new in vivo model for veterinary oncological studies.

    PubMed

    Zabielska, K; Lechowski, R; Król, M; Pawłowski, K M; Motyl, T; Dolka, I; Zbikowski, A

    2012-12-01

    Feline vaccine associated fibrosarcomas are the second most common skin tumor in cats. Methods of treatment are: surgery, chemotherapy and radiotherapy. Nevertheless, the usage of cytostatics in feline vaccine associated sarcoma therapy is limited due to their adverse side effects, high toxicity and low biodistribution after i.v. injection. Therefore, much research on new therapeutic drugs is being conducted. In human medicine, the chick embryo chorioallantoic membrane (CAM) model is used as a cheap and easy to perform assay to assess new drug effectiveness in cancer treatment. Various human cell lines have different tumors growth on CAM. In veterinary medicine such model has not been described yet. In the present article derivation of feline vaccine associated fibrosarcoma cell line and its growth on CAM is described. The cell line and the tumor grown were confirmed by histopathological and immunohistochemical examination. As far as we believe, this is the first attempt to create such model, which may be used for further in vivo studies in veterinary oncology.

  3. Inhibitory effects of caffeic acid phenethyl ester on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells.

    PubMed

    Hwang, Hye Jin; Park, Hyen Joo; Chung, Hwa-Jin; Min, Hye-Young; Park, Eun-Jung; Hong, Ji-Young; Lee, Sang Kook

    2006-05-01

    Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine. Recent study also revealed that CAPE has several biological activities including antioxidation, anti-inflammation and inhibition of tumor growth. The present study investigated the effect of CAPE on tumor invasion and metastasis by determining the regulation of matrix metalloproteinases (MMPs). Matrix metalloproteinases, which are zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix (ECM) as well as nonmatrix substrates. On this line, we examined the influence of CAPE on the gene expression of MMPs (MMP-2, MMP-9, MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases in MMP and TIMP-2 mRNA levels were observed in CAPE-treated HT1080 human fibrosarcoma cells as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Gelatin zymography analysis also exhibited a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with CAPE compared to controls. In addition, CAPE inhibited the activated MMP-2 activity as well as invasion, motility, cell migration and colony formation of tumor cells. These data therefore provide direct evidence for the role of CAPE as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of malignant cells.

  4. Resveratrol induces MMP-9 and cell migration via the p38 kinase and PI-3K pathways in HT1080 human fibrosarcoma cells.

    PubMed

    Gweon, Eun Jeong; Kim, Song Ja

    2013-02-01

    Trans-3,4',5-trihydroxystilbene (resveratrol) is a grape polyphenol present in various plants, food products, red wine and grapes. Resveratrol has anti-inflammatory, anticarcinogenic, anti-oxidant and anti-aging properties. Matrix metalloproteinases (MMPs) are key enzymes involved in the degradation of the extracellular matrix, and their expression may be regulated in cancer metastasis. In the present study, we aimed to evaluate the effect of resveratrol on MMPs and cell migration, and to understand the mechanism of action in HT1080 human fibrosarcoma cells. We found that resveratrol inhibited HT1080 cell viability at various concentrations as detected by the MTT assay and FACS analysis. However, resveratrol dramatically increased the activation and expression of MMP-9 in a dose- and time-dependent manner, as determined by gelatin zymography assay and western blot analysis. We also discovered that resveratrol enhanced the migratory ability of HT1080 cells, as determined by the wound healing assay, and decreased the phosphorylation of p38 kinase. Moreover, the Akt kinase was inhibited by resveratrol in the HT1080 cells. The inhibition of p38 and Akt kinases with SB203580 and LY294002 further increased resveratrol-induced MMP-9 as well as cell migration in the HT1080 cells. Our results suggest that resveratrol regulates MMP-9 and migratory abilities through the p38 kinase and PI-3K pathways in HT1080 human fibrosarcoma cells.

  5. Rottlerin induces autophagy and apoptotic cell death through a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells: the protective role of autophagy in apoptosis.

    PubMed

    Song, Kyoung-Sub; Kim, Jong-Seok; Yun, Eun-Jin; Kim, Young-Rae; Seo, Kang-Sik; Park, Ji-Hoon; Jung, Yeon-Joo; Park, Jong-Il; Kweon, Gi-Ryang; Yoon, Wan-Hee; Lim, Kyu; Hwang, Byung-Doo

    2008-07-01

    Rottlerin is widely used as a protein kinase C-delta inhibitor. Recently, several reports have shown the possible apoptosis-inducing effect of rottlerin in some cancer cell lines. Here we report that rottlerin induces not only apoptosis but also autophagy via a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells. Rottlerin treatment induced a dose- and time-dependent inhibition of cell growth, and cytoplasmic vacuolations were markedly shown. These vacuoles were identified as acidic autolysosomes by electron microscopy, acidic vesicular organelle (AVO) staining and transfection of green fluorescent protein-LC3. The LC3-II protein level also increased after treatment with rottlerin. Prolonged exposure to rottlerin eventually caused apoptosis via loss of mitochondrial membrane potential and translocation of AIF from mitochondria to the nucleus. However, the activities of caspase-3, -8 and -9 were not changed, and PARP did not show signs of cleavage. Interestingly, the pretreatment of cells with a specific inhibitor of autophagy (3-methyladenine) accelerated rottlerin-induced apoptosis as revealed by an analysis of the subdiploid fraction and TUNEL assay. Nevertheless, the knockdown of PKC-delta by RNA interference neither affected cell growth nor acidic vacuole formation. Similarly, rottlerin-induced cell death was not prevented by PKC-delta overexpression. Taken together, these findings suggest that rottlerin induces early autophagy and late apoptosis in a PKC-delta-independent manner, and the rottlerin-induced early autophagy may act as a survival mechanism against late apoptosis in HT1080 human fibrosarcoma cells.

  6. In vivo activation of NK cells induces inhibition of lung colonization of H-2 positive and H-2 negative fibrosarcoma tumor clones.

    PubMed

    Algarra, I; Pérez, M; Gaforio, J J; Gasca, F; Garrido, F

    1994-01-01

    The role of different tilorone analogs in the abrogation of the metastatic spread of H-2 positive and H-2 negative tumor clones was studied. Pre-treatment of BALB/c mice with RMI 10,874DA compound completely abolished lung colonization of an H-2 negative (GR9.B9) MCA-induced fibrosarcoma clone in an experimental metastasis assay. This effect was also evident when clones were treated with other tilorone analogs (R11,567DA or R11,513DA). Other H-2 positive and H-2 negative chemically induced fibrosarcoma clones were also tested. The effect was not due to direct toxicity of the tilorone analog on tumor cells, but instead was dependent on NK cells; this was suggested by the finding that treatment of mice with anti-asialo GM1 abrogated the effect of the tilorone analog (RMI 10,874DA compound). Interestingly, the inhibition of lung colonization after intravenous injection was again observed regardless of the H-2 phenotype of the tumor clones, and H-2+ and H-2- clones were similarly inhibited. In vitro assays of NK sensitivity of tumor clones showed that lysis varied depending on the H-2 phenotype of tumor clones, indicating an absence of correlation between in vivo and in vitro results.

  7. Pancreatitis promotes oncogenic Kras(G12D)-induced pancreatic transformation through activation of Nupr1.

    PubMed

    Grasso, Daniel; Garcia, Maria Noé; Hamidi, Tewfik; Cano, Carla; Calvo, Ezequiel; Lomberk, Gwen; Urrutia, Raul; Iovanna, Juan L

    2014-01-01

    During the initiation stage of pancreatic adenocarcinoma induced by oncogenic Kras, pancreatic cells are exposed to both a protumoral effect and an opposing tumor suppressive process known as oncogene-induced senescence. Pancreatitis disrupts this balance in favor of the transforming effect of oncogenes by lowering the tumor suppressive threshold of oncogene-induced senescence through expression of the stress protein Nupr1.

  8. Piroxicam, indomethacin and aspirin action on a murine fibrosarcoma. Effects on tumour-associated and peritoneal macrophages.

    PubMed Central

    Valdéz, J C; Perdigón, G

    1991-01-01

    Growth of a methylcholanthrene-induced fibrosarcoma in BALB/c mice was accompanied by an increase in the activation state of tumour-associated macrophages (TAM), as measured by their FcIgG receptor expression, phagocytic index and beta-glucuronidase levels. All of these parameters were markedly higher in TAM than in peritoneal macrophages (PM) derived from the same animal. On the other hand, PM from tumour-bearing mice showed lower activation parameters than PM from normal animals. We also studied the effect on tumour development of three inhibitors of prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached different volumes by the end of the treatment, was delayed to a similar extent by the three anti-inflammatory non-steroidal drugs (NSAID). With respect to TAM, the treatment did not induce any significant change in their activation state, though both piroxicam and indomethacin increased slightly the TAM number. In contrast, NSAID administration was followed by a remarkable increase in the activation parameters of PM when compared with PM from tumour-bearing mice receiving no treatment. Indeed, these parameters were in some cases higher than those of PM from normal mice. The leukocytosis (60,000/microliters) with neutrophilia (80%) induced by tumour growth on peripheral blood leukocytes (PBL) was reversed by the treatment to values close to normal, in parallel with the reduction of tumour size. A drop in haematocrit was also noted which was most probably a consequence of tumour growth rather than of the treatment. This study reveals that the three NSAID tested have a remarkable antitumour activity, which

  9. Can plant oncogenes inhibit programmed cell death? The rolB oncogene reduces apoptosis-like symptoms in transformed plant cells.

    PubMed

    Gorpenchenko, Tatiana Y; Aminin, Dmitry L; Vereshchagina, Yuliya V; Shkryl, Yuri N; Veremeichik, Galina N; Tchernoded, Galina K; Bulgakov, Victor P

    2012-09-01

    The rolB oncogene was previously identified as an important player in ROS metabolism in transformed plant cells. Numerous reports indicate a crucial role for animal oncogenes in apoptotic cell death. Whether plant oncogenes such as rolB can induce programmed cell death (PCD) in transformed plant cells is of particular importance. In this investigation, we used a single-cell assay based on confocal microscopy and fluorescent dyes capable of discriminating between apoptotic and necrotic cells. Our results indicate that the expression of rolB in plant cells was sufficient to decrease the proportion of apoptotic cells in steady-state conditions and diminish the rate of apoptotic cells during induced PCD. These data suggest that plant oncogenes, like animal oncogenes, may be involved in the processes mediating PCD.

  10. Risk assessment of oncogenic potency of pesticide residues in fruits and vegetables.

    PubMed

    Keikotlhaile, B M; Spanoghe, P; Steurbaut, W

    2011-01-01

    Pesticides are used in agriculture to improve food security by assuring good harvest, however, they can have harmful effects in human beings and animals. One of the harmful effects of pesticides is their carcinogenicity. Exposure to oncogenic compounds may result in cancer to the exposed animal or person. In this paper, exposure assessment of oncogenic potency of pesticides was performed from raw and processed fruits and vegetables. The oncogenic risk was calculated by multiplying the estimated daily intake (EDI) of the pesticide residue with the oncogenic potency factor (Q*) of the concerned pesticide. The total potential oncogenic risk was calculated to be 2.76 x 10(-3) before processing and 8.97 x 10(-4) after processing. The risk was higher than the EPA acceptable limit of 1 x10(-6). Despite the calculated levels exceeding the EPA acceptable limit, food processing activities reduced the dietary oncogenic risk to an average 33.8%.

  11. EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth.

    PubMed

    Chabu, Chiswili; Li, Da-Ming; Xu, Tian

    2017-03-10

    Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog.

  12. EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth

    PubMed Central

    Chabu, Chiswili; Li, Da-Ming; Xu, Tian

    2017-01-01

    Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog. PMID:28281543

  13. ENL links histone acetylation to oncogenic gene expression in AML

    PubMed Central

    Wan, Liling; Wen, Hong; Li, Yuanyuan; Lyu, Jie; Xi, Yuanxin; Hoshii, Takayuki; Joseph, Julia; Wang, Xiaolu; Loh, Yong-Hwee E.; Erb, Michael A.; Souza, Amanda L.; Bradner, James E.; Shen, Li; Li, Wei; Li, Haitao; Allis, C. David; Armstrong, Scott A.; Shi, Xiaobing

    2017-01-01

    Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs1. Recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of BET bromodomain inhibitors2, 3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in acute myeloid leukaemia (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and ChIP-seq analyses revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment to ENL target genes, leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin may be a promising epigenetic therapy alone or in combination with BET inhibitors for AML. PMID:28241141

  14. Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate

    PubMed Central

    Zimmerman, M. Bridget; Mahajan, Vinit B.; Bassuk, Alexander G.

    2016-01-01

    Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0x10-8). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism. PMID:26934580

  15. Comprehensive Characterization of Oncogenic Drivers in Asian Lung Adenocarcinoma.

    PubMed

    Li, Shiyong; Choi, Yoon-La; Gong, Zhuolin; Liu, Xiao; Lira, Maruja; Kan, Zhengyan; Oh, Ensel; Wang, Jian; Ting, Jason C; Ye, Xiangsheng; Reinhart, Christoph; Liu, Xiaoqiao; Pei, Yunfei; Zhou, Wei; Chen, Ronghua; Fu, Shijun; Jin, Gang; Jiang, Awei; Fernandez, Julio; Hardwick, James; Kang, Min Woong; I, Hoseok; Zheng, Hancheng; Kim, Jhingook; Mao, Mao

    2016-12-01

    The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in Asians might be distinct from those in LUAD in whites. We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers. Mutations in EGFR, KRAS, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), and BRAF; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene (ALK), ROS1, and ret proto-oncogene (RET); and Met Proto-Oncogene Tyrosine Kinase (MET) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians. In addition, we identified a novel mutational signature of XNX (the mutated base N in the middle flanked by two identical bases at the 5' and 3' positions) that was overrepresented in LUAD tumors in nonsmokers and negatively correlated with the overall mutational frequency. In this cohort, approximately 85% of individuals have known driver mutations (EGFR 59.4%, KRAS 7.4%, ALK 7.4%, ERBB2 2.6%, ROS1 2.2%, RET 2.2%, MET 1.8%, BRAF 1.1%, and NRAS 0.4%). Seventy percent of smokers and 90% of nonsmokers had defined oncogenic drivers matching the U.S. Food and Drug Administration-approved targeted therapies. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  16. Oncogenic NRAS Primes Primary Acute Myeloid Leukemia Cells for Differentiation

    PubMed Central

    Millahn, Axel; Stiewe, Thorsten; Krause, Michael; Stabla, Kathleen; Ross, Petra; Huynh, Minh; Illmer, Thomas; Mernberger, Marco; Barckhausen, Christina; Neubauer, Andreas

    2015-01-01

    RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies. PMID:25901794

  17. Enhancing Anti-Tumor Efficacy of Doxorubicin by Non-Covalent Conjugation to Gold Nanoparticles – In Vitro Studies on Feline Fibrosarcoma Cell Lines

    PubMed Central

    Wójcik, Michał; Lewandowski, Wiktor; Król, Magdalena; Pawłowski, Karol; Mieczkowski, Józef; Lechowski, Roman; Zabielska, Katarzyna

    2015-01-01

    Background Feline injection-site sarcomas are malignant skin tumors of mesenchymal origin, the treatment of which is a challenge for veterinary practitioners. Methods of treatment include radical surgery, radiotherapy and chemotherapy. The most commonly used cytostatic drugs are cyclophosphamide, doxorubicin and vincristine. However, the use of cytostatics as adjunctive treatment is limited due to their adverse side-effects, low biodistribution after intravenous administration and multidrug resistance. Colloid gold nanoparticles are promising drug delivery systems to overcome multidrug resistance, which is a main cause of ineffective chemotherapy treatment. The use of colloid gold nanoparticles as building blocks for drug delivery systems is preferred due to ease of surface functionalization with various molecules, chemical stability and their low toxicity. Methods Stability and structure of the glutathione-stabilized gold nanoparticles non-covalently modified with doxorubicin (Au-GSH-Dox) was confirmed using XPS, TEM, FT-IR, SAXRD and SAXS analyses. MTT assay, Annexin V and Propidium Iodide Apoptosis assay and Rhodamine 123 and Verapamil assay were performed on 4 feline fibrosarcoma cell lines (FFS1WAW, FFS1, FFS3, FFS5). Statistical analyses were performed using Graph Pad Prism 5.0 (USA). Results A novel approach, glutathione-stabilized gold nanoparticles (4.3 +/- 1.1 nm in diameter) non-covalently modified with doxorubicin (Au-GSH-Dox) was designed and synthesized. A higher cytotoxic effect (p<0.01) of Au-GSH-Dox than that of free doxorubicin has been observed in 3 (FFS1, FFS3, FFS1WAW) out of 4 feline fibrosarcoma cell lines. The effect has been correlated to the activity of glycoprotein P (main efflux pump responsible for multidrug resistance). Conclusions The results indicate that Au-GSH-Dox may be a potent new therapeutic agent to increase the efficacy of the drug by overcoming the resistance to doxorubicin in feline fibrosarcoma cell lines. Moreover, as

  18. Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma.

    PubMed

    Santiago, Teresa; Clay, Michael R; Allen, Sariah J; Orr, Brent A

    2017-06-01

    Primitive myxoid mesenchymal tumor of infancy is a rare sarcoma that preferentially affects infants. It can be locally aggressive and rarely metastasizes, but the long-term outcome of children with this tumor is mostly unknown. Histologically, it is characterized by primitive cells with abundant myxoid stroma. Internal tandem duplication of B-cell CLL/lymphoma 6 (BCL6)-interacting co-repressor (BCOR) exon 15 has recently been described in clear cell sarcoma of kidney, central nervous system high-grade neuroepithelial tumor with BCOR alteration, and primitive myxoid mesenchymal tumor of infancy. Herein, we report five cases of primitive myxoid mesenchymal tumor of infancy: three girls and two boys with mean age of 6.5 months. The tumors were located in the paraspinal region (n=3), back (n=1), or foot (n=1) and ranged in size from 2.5 to 10.2 cm. BCOR internal tandem duplication was confirmed by PCR and sequencing in all five cases. The minimally duplicated region consisted of nine residues, which is shorter than was previously reported in other BCOR-associated tumors. To assess the clinical value and specificity of the BCOR internal tandem duplication, a group of 11 ETV6-rearranged congenital infantile fibrosarcomas were evaluated and no BCOR internal tandem duplication was identified in any case. Though not detected in congenital infantile fibrosarcomas, BCOR and BCL6 immunoreactivity was present in >90% of the nuclei of tumor cells in each of the five primitive myxoid mesenchymal tumor of infancy. The presence of BCOR internal tandem duplication in all five primitive myxoid mesenchymal tumors of infancy provides evidence that it is a recurrent somatic abnormality and substantiates the concept that this tumor is a unique sarcoma of infancy. Our findings indicate that identification of BCOR internal tandem duplication and/or nuclear immunoreactivity for BCOR or BCL6 can aid in the diagnosis of primitive myxoid mesenchymal tumor of infancy and help to differentiate

  19. Fibrosarcoma-like lipomatous neoplasm: a reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other liposarcomas.

    PubMed

    Deyrup, Andrea T; Chibon, Frederic; Guillou, Louis; Lagarde, Pauline; Coindre, Jean-Michel; Weiss, Sharon W

    2013-09-01

    The term "spindle cell liposarcoma" has been applied to liposarcomas (LPSs) composed predominantly or exclusively of spindled cells. These tumors have been considered variants of well-differentiated LPS (WDL), myxoid LPS, and spindle cell lipoma, suggesting that this is a heterogenous group of lesions. Using strict morphologic criteria and molecular and immunohistochemical analyses, we have identified a homogenous group of spindle cell lipomatous tumors, histologically and genetically distinct from other forms of LPS, which we have called "fibrosarcoma-like lipomatous neoplasm." Cases classified as "spindle cell LPS" or "low-grade LPS with spindle cell features" were reviewed. Final selection criteria included: (1) an exclusive low-grade spindle cell component resembling fibrosarcoma; (2) a mixture of bland fibroblastic cells resembling the preadipocyte and early-adipocyte stage of embryonic fat; and (3) molecular-genetic analysis that excluded other forms of lipomatous tumors. Of the initial 25 cases identified, comparative genomic hybridization (CGH) was uninformative in 2 cases; 5 were reclassified as WDL on the basis of molecular data (MDM2 amplification) and 6 as spindle cell lipoma (CGH profiles with a few gains and losses including a constant loss of chromosome 13 and frequent losses of chromosomes 16 and 6). The 12 remaining cases showed flat CGH profiles; of these cases, 11 were negative for DDIT3 gene rearrangements, and 1 result was uninterpretable. Patients ranged in age from 15 to 82 years (mean 50 y); male patients were affected slightly more often (7:5). Tumors arose in the deep (6) and superficial (3) soft tissue of the groin (4), buttock (3), thigh (2), flank (1), shoulder (1), and paratesticular tissue (1) and ranged in size from 2 to 20 cm (mean 7.5 cm). Clinical follow-up in 11 patients (9 mo to 20 y; mean 68 mo) showed no recurrences or metastases. As defined above, "fibrosarcoma-like lipomatous neoplasm" is a unique lipomatous tumor that

  20. Histone Code Modulation by Oncogenic PWWP-Domain Protein in Breast Cancers

    DTIC Science & Technology

    2011-06-01

    amplicon for identifying candidate oncogenes in breast cancer. We identified Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) as a candidate...amplicon for identifying candidate oncogenes in breast cancer (4). We identified Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) as a candidate...oncogenes that are drugable targets for cancer therapy in the near future? Pharmacol Ther 2007; 115: 419-34. 16. Kim JK, Esteve PO, Jacobsen SE

  1. Oncogenic PTEN functions and models in T-cell malignancies.

    PubMed

    Tesio, M; Trinquand, A; Macintyre, E; Asnafi, V

    2016-07-28

    PTEN is a protein phosphatase that is crucial to prevent the malignant transformation of T-cells. Although a numerous mechanisms regulate its expression and function, they are often altered in T-cell acute lymphoblastic leukaemias and T-cell lymphomas. As such, PTEN inactivation frequently occurs in these malignancies, where it can be associated with chemotherapy resistance and poor prognosis. Different Pten knockout models recapitulated the development of T-cell leukaemia/lymphoma, demonstrating that PTEN loss is at the center of a complex oncogenic network that sustains and drives tumorigenesis via the activation of multiple signalling pathways. These aspects and their therapeutic implications are discussed in this review.

  2. ERBB oncogene proteins as targets for monoclonal antibodies.

    PubMed

    Polanovski, O L; Lebedenko, E N; Deyev, S M

    2012-03-01

    General properties of the family of tyrosine kinase ERBB receptors are considered in connection with their role in the generation of cascades of signal transduction in normal and tumor cells. Causes of acquisition of oncogene features by genes encoding these receptors and their role in tumorigenesis are analyzed. Anti-ERBB monoclonal antibodies approved for therapy are described in detail, and mechanisms of their antitumor activity and development of resistance to them are reviewed. The existing and the most promising strategies for creating and using monoclonal antibodies and their derivatives for therapy of cancer are discussed.

  3. Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy.

    PubMed

    Pak, Ekaterina; Segal, Rosalind A

    2016-08-22

    The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights into regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies.

  4. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy

    PubMed Central

    Pak, Ekaterina; Segal, Rosalind A.

    2016-01-01

    Summary The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly-regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights on regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies. PMID:27554855

  5. Detecting and Targeting Oncogenic Myc in Breast Cancer

    DTIC Science & Technology

    2006-06-01

    Proteomics, Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, Canada M5G 2M9. Phone: 416- 946 -2276; Fax: 416- 946 -2840; E...rights reserved. doi:10.1016/j.ejca.2005.08.017 * Corresponding author. Tel.: +1 416 946 2276; fax: +1 416 946 2840. E-mail address: lpenn...etic cells [133], mammary gland [134], liver [135], skin [135,136] and pancreatic islets [137] have demonstrated that induction of oncogenic Myc leads

  6. Role of ets Oncogenes in the Progression of Breast Cancer

    DTIC Science & Technology

    1997-10-01

    4 Introduction 5-9 Body 9-17 Conclusion 17-18 Figures 19-31 References 32-36 Veena N. Rao, Ph.D. INTRODUCTION Majority of the ets-oncogene superfamily...threshold by BRCA 1/elk-I gene therapy may have the potential to prevent the progression of these malignancies. BODY Task 1 COMPLETED PREVIOUSLY Task 2...weights of ýý 175, 125 and BRCAI protein using several BRCA1 specific anti- 110 kD (Figure 2a). All these results suggest BRCA1 bodies in normal, breast

  7. Galangin and kaempferol suppress phorbol-12-myristate-13-acetate-induced matrix metalloproteinase-9 expression in human fibrosarcoma HT-1080 cells.

    PubMed

    Choi, Yu Jung; Lee, Young Hun; Lee, Seung-Taek

    2015-01-01

    Matrix metalloproteinase (MMP)-9 degrades type IV collagen in the basement membrane and plays crucial roles in several pathological implications, including tumorigenesis and inflammation. In this study, we analyzed the effect of flavonols on MMP-9 expression in phorbol-12-myristate-13-acetate (PMA)-induced human fibrosarcoma HT-1080 cells. Galangin and kaempferol efficiently decreased MMP-9 secretion, whereas fisetin only weakly decreased its secretion. Galangin and kaempferol did not affect cell viability at concentrations up to 30 μM. Luciferase reporter assays showed that galangin and kaempferol decrease transcription of MMP-9 mRNA. Moreover, galangin and kaempferol strongly reduce IκBα phosphorylation and significantly decrease JNK phosphorylation. These results indicate that galangin and kaempferol suppress PMA-induced MMP-9 expression by blocking activation of NF-κB and AP-1. Therefore, these flavonols could be used as chemopreventive agents to lower the risk of diseases involving MMP-9.

  8. Differential roles of Rho-kinase and myosin light chain kinase in regulating shape, adhesion, and migration of HT1080 fibrosarcoma cells.

    PubMed

    Niggli, Verena; Schmid, Manuela; Nievergelt, Alexandra

    2006-05-05

    We present evidence for differential roles of Rho-kinase and myosin light chain kinase (MLCK) in regulating shape, adhesion, migration, and chemotaxis of human fibrosarcoma HT1080 cells on laminin-coated surfaces. Pharmacological inhibition of Rho-kinase by Y-27632 or inhibition of MLCK by W-7 or ML-7 resulted in significant attenuation of constitutive myosin light chain phosphorylation. Rho-kinase inhibition resulted in sickle-shaped cells featuring long, thin F-actin-rich protrusions. These cells adhered more strongly to laminin and migrated faster. Inhibition of MLCK in contrast resulted in spherical cells and marked impairment of adhesion and migration. Inhibition of myosin II activation with blebbistatin resulted in a morphology similar to that induced by Y-27632 and enhanced migration and adhesion. Cells treated first with blebbistatin and then with ML-7 also rounded up, suggesting that effects of MLCK inhibition on HT1080 cell shape and motility are independent of inhibition of myosin activity.

  9. Collagen-binding domains of gelatinase A and thrombospondin-derived peptides impede endocytic clearance of active gelatinase A and promote HT1080 fibrosarcoma cell invasion.

    PubMed

    Robinet, Arnaud; Emonard, Hervé; Banyai, Laszlo; Laronze, Jean-Yves; Patthy, Lazlo; Hornebeck, William; Bellon, Georges

    2008-02-13

    Gelatinase A (matrix metalloproteinase-2, MMP-2) binds to several proteins through its collagen-binding domains (CBDs). Surface plasmon resonance analysis revealed a strong interaction between CBD123 and thrombospondin-1 (TSP-1), with a K(D) value of 2x10(-9) M. CBD123, as well as individual domains, behave as competitive inhibitors of the TSP-1-directed endocytic clearance of active MMP-2, but not of its latent form, by HT1080 fibrosarcoma cells. Enhanced level of active MMP-2 in conditioned medium was associated to increased matrigel invasion. Similarly, GGWSHWSPWSS and GGWSHW peptides, as tryptophan-rich peptides within properdin-repeat motifs (TSRs) of TSP-1, promoted MMP-2 accumulation and cell invasiveness. Our data document the importance of TSP-1 in promoting MMP-2-mediated cancer cell invasion through interaction between CBDs of the enzyme and TSRs motifs of TSP-1.

  10. Inhibitory effect of the carnosine-gallic acid synthetic peptide on MMP-2 and MMP-9 in human fibrosarcoma HT1080 cells.

    PubMed

    Kim, Sung-Rae; Eom, Tae-Kil; Byun, Hee-Guk

    2014-09-01

    Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade extracellular matrix components and play important roles in a variety of biological and pathological processes such as malignant tumor metastasis and invasion. In this study, we constructed carnosine-gallic acid peptide (CGP) to identify a better MMP inhibitor than carnosine. The inhibitory effects of CGP on MMP-2 and MMP-9 were investigated in the human fibrosarcoma (HT1080) cell line. As a result, CGP significantly decreased MMP-2 and MMP-9 expression levels without a cytotoxic effect. Moreover, CGP may inhibit migration and invasion in HT1080 cells through the urokinase plasminogen activator (uPA)-uPA receptor signaling pathways to inhibit MMP-2 and MMP-9. Based on these results, it appears that CGP may play an important role in preventing and treating several MMP-2 and MMP-9-mediated health problems such as metastasis. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

  11. Reverse engineering a hierarchical regulatory network downstream of oncogenic KRAS

    PubMed Central

    Stelniec-Klotz, Iwona; Legewie, Stefan; Tchernitsa, Oleg; Witzel, Franziska; Klinger, Bertram; Sers, Christine; Herzel, Hanspeter; Blüthgen, Nils; Schäfer, Reinhold

    2012-01-01

    RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here, we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT–PCR and western blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions, we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype. PMID:22864383

  12. Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

    PubMed Central

    Shukla, Ruchi; Upton, Kyle R.; Muñoz-Lopez, Martin; Gerhardt, Daniel J.; Fisher, Malcolm E.; Nguyen, Thu; Brennan, Paul M.; Baillie, J. Kenneth; Collino, Agnese; Ghisletti, Serena; Sinha, Shruti; Iannelli, Fabio; Radaelli, Enrico; Dos Santos, Alexandre; Rapoud, Delphine; Guettier, Catherine; Samuel, Didier; Natoli, Gioacchino; Carninci, Piero; Ciccarelli, Francesca D.; Garcia-Perez, Jose Luis; Faivre, Jamila; Faulkner, Geoffrey J.

    2013-01-01

    Summary LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC. PMID:23540693

  13. Oncogenicity of the developmental transcription factor Sox9

    PubMed Central

    Matheu, Ander; Collado, Manuel; Wise, Clare; Manterola, Lorea; Cekaite, Lina; Tye, Angela J.; Canamero, Marta; Bujanda, Luis; Schedl, Andreas; Cheah, Kathryn S.E.; Skotheim, Rolf I.; Lothe, Ragnhild A.; de Munain, Adolfo López; Briscoe, James; Serrano, Manuel; Lovell-Badge, Robin

    2012-01-01

    SOX9, a high mobility group (HMG) box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence and collaborate with other oncogenes in neoplastic transformation. In primary MEFs and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whilst its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb protein Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly in colorectal cancer. PMID:22246670

  14. Association of oncogenic and nononcogenic human papillomavirus with HIV incidence

    PubMed Central

    Auvert, Bertran; Lissouba, Pascale; Cutler, Ewalde; Zarca, Kevin; Puren, Adrian; Taljaard, Dirk

    2010-01-01

    Objective Little is known about the interaction between HPV and HIV. This study aimed to explore the association of oncogenic (HR) and non oncogenic (LR) human papillomavirus (HPV) with HIV incidence. Methods We used urethral swabs collected at the last follow-up visit of a male circumcision trial conducted in Orange Farm (South Africa). Swabs analyses and HPV genotyping were performed by polymerase chain reaction. We estimated HIV adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) using survival analysis. Background characteristics, male circumcision status, sexual behavior, HPV status and other sexually transmitted infections were used as covariates. Results The prevalence of HR and LR HPV was 14.0% (95%CI: 12.4 to 15.7) and 17.3% (95%CI: 15.6 to 19.2), respectively. When controlling for HR-HPV status, LR-HPV status was not associated with HIV incidence (aIRR = 1.13, 95%CI: 0.40 to 3.16; P = 0.82). When controlling for all covariates, HIV incidence increased significantly with HR-HPV positivity (aIRR=3.76, 95%CI: 1.83 to 7.73, P < 0.001) and with the number of HR-HPV genotypes (adjusted-P linear trend = 0.0074). Conclusions Several explanations could account for our findings. One is that HR-HPV facilitates HIV acquisition. The association of HPV with HIV acquisition requires further investigations. PMID:19779357

  15. CCAT1: an oncogenic long noncoding RNA in human cancers.

    PubMed

    Guo, Xiaoqiang; Hua, Yuming

    2017-04-01

    Long noncoding RNAs (lncRNAs) are a new class of noncoding RNAs that participate in a variety of biological processes such as cell proliferation, cell cycle, differentiation and apoptosis, mainly by regulation of gene expression at various levels, including chromatin, splicing, transcriptional and post-transcriptional levels. CCAT1 is a recently identified oncogenic lncRNA, which has been reported to be consistently upregulated in multiple cancer tissues and closely correlated with initiation and progression of cancers. The aim of this paper is to provide an overview of various roles of CCAT1 in human cancers. We searched studies in electronic databases. Studies have shown the high expression pattern and oncogenic role of CCAT1 in different types of cancer, and aberrant expression of CCAT1 is involved in several processes correlated with carcinogenesis such as cell proliferation, apoptosis, migration and invasion by regulating different target genes and pathways. LncRNA CCAT1 promises to be a novel diagnostic biomarker, therapeutic target, as well as prognostic biomarker in human cancers.

  16. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.

    PubMed

    Turner, Kristen M; Deshpande, Viraj; Beyter, Doruk; Koga, Tomoyuki; Rusert, Jessica; Lee, Catherine; Li, Bin; Arden, Karen; Ren, Bing; Nathanson, David A; Kornblum, Harley I; Taylor, Michael D; Kaushal, Sharmeela; Cavenee, Webster K; Wechsler-Reya, Robert; Furnari, Frank B; Vandenberg, Scott R; Rao, P Nagesh; Wahl, Geoffrey M; Bafna, Vineet; Mischel, Paul S

    2017-03-02

    Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

  17. REST regulates oncogenic properties of glioblastoma stem cells

    PubMed Central

    Kamal, Mohamed M.; Sathyan, Pratheesh; Singh, Sanjay K.; Zinn, Pascal O.; Marisetty, Anantha L.; Liang, Shoudan; Gumin, Joy; El-Mesallamy, Hala Osman; Suki, Dima; Colman, Howard; Fuller, Gregory N.; Lang, Frederick F.; Majumder, Sadhan

    2013-01-01

    Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor REST, suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. PMID:22228704

  18. Insulator dysfunction and oncogene activation in IDH mutant gliomas.

    PubMed

    Flavahan, William A; Drier, Yotam; Liau, Brian B; Gillespie, Shawn M; Venteicher, Andrew S; Stemmer-Rachamimov, Anat O; Suvà, Mario L; Bernstein, Bradley E

    2016-01-07

    Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.

  19. Expression of hpttg proto-oncogene in lymphoid neoplasias.

    PubMed

    Sáez, Carmen; Pereda, Teresa; Borrero, Juan J; Espina, Agueda; Romero, Francisco; Tortolero, María; Pintor-Toro, José A; Segura, Dolores I; Japón, Miguel A

    2002-11-21

    Pituitary tumor-transforming gene (pttg) is a distinct proto-oncogene which is expressed in certain normal tissues with high proliferation rate and in a variety of tumors. PTTG is the vertebrate analog of yeast securins Pds1 and Cut2 with a key role in the regulation of sister chromatid separation during mitosis. Impairment of PTTG regulated functions is expected to lead to chromosomal instability and aneuploidy. Human pttg (hpttg) is abundantly expressed in Jurkat T lymphoblastic lymphoma cells but not in normal peripheral blood leukocytes. To obtain additional data on the potential role of hpttg in lymphomagenesis we selected 150 cases of lymphoid tumors for the assessment of hpttg expression in tumor tissues. Immunohistochemical studies on formalin-fixed, paraffin-embedded tissues revealed hPTTG in 38.8% of B-cell lymphomas, 70.2% of T-cell lymphomas, and 73.1% of Hodgkin's lymphomas. Among B-cell lymphomas, the most frequently immunostained tumors were plasma cell tumors, diffuse large cell lymphomas, and follicle center cell lymphomas. In Hodgkin's disease, immunoreactivity was mainly noted in Reed-Sternberg cells. In conclusion, the frequent overexpression of hpttg in many histological subtypes of lymphoma suggests the involvement of this proto-oncogene in lymphomagenesis.

  20. Early regulation of membrane excitability by ras oncogene proteins.

    PubMed Central

    Collin, C; Papageorge, A G; Sakakibara, M; Huddie, P L; Lowy, D R; Alkon, D L

    1990-01-01

    Two electrode voltage clamp conditions were used to study the early effects on ionic membrane channels of the intracellularly injected proto-oncogenic form of c-Ha-ras (c-ras) and its oncogenic counterpart v-Ha-ras (v-ras). These experiments were conducted on isolated somata of identified fully differentiated neurons of the sea snail Hermissenda. 20 min after c-ras, and 10 min after v-ras intracellular injections into type B medial photoreceptors of Hermissenda, the peak amplitude of two outward potassium currents (IA and IC), across the isolated Type B soma membrane begin to decrease. These two currents have been previously isolated by differences in activation and inactivation kinetics and their response to pharmacological blockers. c- or v-ras injections did not have any effect on a voltage-dependent inward calcium current. Reduction of IA preceded that of IC. Current reductions due to c-ras, but not to v-ras injection reversed spontaneously after 40 min. The voltage dependence of the steady state inactivation of IA shifted toward more negative potentials with ras injections. Ras-mediated cell transformations therefore, could involve, perhaps as initial events, prolonged modification of membrane currents. PMID:2207264

  1. Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis

    PubMed Central

    Cardoso, Marta; Maia, Sofia; Paulo, Paula; Teixeira, Manuel R.

    2016-01-01

    The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis. PMID:28050579

  2. Oncogenic programmes and Notch activity: an 'organized crime'?

    PubMed

    Dominguez, Maria

    2014-04-01

    The inappropriate Notch signalling can influence virtually all aspect of cancer, including tumour-cell growth, survival, apoptosis, angiogenesis, invasion and metastasis, although it does not do this alone. Hence, elucidating the partners of Notch that are active in cancer is now the focus of much intense research activity. The genetic toolkits available, coupled to the small size and short life of the fruit fly Drosophila melanogaster, makes this an inexpensive and effective animal model, suited to large-scale cancer gene discovery studies. The fly eye is not only a non-vital organ but its stereotyped size and disposition also means it is easy to screen for mutations that cause tumours and metastases and provides ample opportunities to test cancer theories and to unravel unanticipated nexus between Notch and other cancer genes, or to discover unforeseen Notch's partners in cancer. These studies suggest that Notch's oncogenic capacity is brought about not simply by increasing signal strength but through partnerships, whereby oncogenes gain more by cooperating than acting individually, as in a ring 'organized crime'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Metastatic Pancreatic Cancer Is Dependent on Oncogenic Kras in Mice

    PubMed Central

    Collins, Meredith A.; Brisset, Jean-Christophe; Zhang, Yaqing; Bednar, Filip; Pierre, Josette; Heist, Kevin A.; Galbán, Craig J.; Galbán, Stefanie; di Magliano, Marina Pasca

    2012-01-01

    Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer. PMID:23226501

  4. Artemin promotes oncogenicity, metastasis and drug resistance in cancer cells.

    PubMed

    Hezam, Kamal; Jiang, Jiahao; Sun, Fumou; Zhang, Xinrong; Zhang, Juan

    2017-09-22

    Artemin (ARTN) is a member of glial cell line-derived neurotrophic factor (GDNF) family of ligands, and its signaling is mediated via a multi-component receptor complex including the glycosylphosphatidylinositol-anchored GDNF family receptors a (GFRa1, GFRa3) and RET receptor tyrosine kinase. The major mechanism of ARTN action is via binding to a non-signaling co-receptor. The major function of ARTN is to drive the molecule to induce migration and axonal projection from sympathetic neurons. It also promotes the survival, proliferation and neurite outgrowth of sympathetic neurons in vitro. ARTN triggers oncogenicity and metastasis by the activation of the AKT signaling pathway. Recent studies have reported that the expression of ARTN in hepatocellular carcinoma is associated with increased tumor size, quick relapse and shorter survival. Furthermore, ARTN promotes drug resistance such as antiestrogens, doxorubicin, fulvestrant, paclitaxel, tamoxifen and trastuzumab. Moreover, ARTN also stimulates the radio-therapeutic resistance. This review highlights the proposed roles of ARTN in cancer cells and discusses recent results supporting its emerging role as an oncogenic, metastatic and drug-resisting agent with a special focus on how these new insights may facilitate rational development of ARTN for targeted therapies in the future.

  5. mTOR links oncogenic signaling to tumor cell metabolism.

    PubMed

    Yecies, Jessica L; Manning, Brendan D

    2011-03-01

    As a key regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) has been the subject of intense investigation for its role in tumor development and progression. This research has revealed a signaling network of oncogenes and tumor suppressors lying upstream of mTORC1, and oncogenic perturbations to this network result in the aberrant activation of this kinase complex in the majority of human cancers. However, the molecular events downstream of mTORC1 contributing to tumor cell growth and proliferation are just coming to light. In addition to its better-known functions in promoting protein synthesis and suppressing autophagy, mTORC1 has emerged as a key regulator of cellular metabolism. Recent studies have found that mTORC1 activation is sufficient to stimulate an increase in glucose uptake, glycolysis, and de novo lipid biosynthesis, which are considered metabolic hallmarks of cancer, as well as the pentose phosphate pathway. Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies.

  6. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes

    PubMed Central

    Liem, Michael; Fonseka, Pamali; Atukorala, Ishara; Ozcitti, Cemil; Mechler, Adam; Adda, Christopher G.; Ang, Ching-Seng; Mathivanan, Suresh

    2015-01-01

    Extracellular vesicles (EVs) include the exosomes (30-100 nm) that are produced through the endocytic pathway via the multivesicular bodies and the ectosomes (100-1000 nm) that are released through the budding of the plasma membrane. Despite the differences in the mode of biogenesis and size, reliable markers that can distinguish between exosomes and ectosomes are non-existent. Moreover, the precise functional differences between exosomes and ectosomes remains poorly characterised. Here, using label-free quantitative proteomics, we highlight proteins that could be exploited as markers to discriminate between exosomes and ectosomes. For the first time, a global proteogenomics analysis unveiled the secretion of mutant proteins that are implicated in cancer progression through tumor-derived EVs. Follow up integrated bioinformatics analysis highlighted the enrichment of oncogenic cargo in exosomes and ectosomes. Interestingly, exosomes induced significant cell proliferation and migration in recipient cells compared to ectosomes confirming the oncogenic nature of exosomes. These findings ascertain that cancer cells facilitate oncogenesis by the secretion of mutant and oncoproteins into the tumor microenvironment via exosomes and ectosomes. The integrative proteogenomics approach utilized in this study has the potential to identify disease biomarker candidates which can be later assayed in liquid biopsies obtained from cancer patients. PMID:25944692

  7. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes.

    PubMed

    Keerthikumar, Shivakumar; Gangoda, Lahiru; Liem, Michael; Fonseka, Pamali; Atukorala, Ishara; Ozcitti, Cemil; Mechler, Adam; Adda, Christopher G; Ang, Ching-Seng; Mathivanan, Suresh

    2015-06-20

    Extracellular vesicles (EVs) include the exosomes (30-100 nm) that are produced through the endocytic pathway via the multivesicular bodies and the ectosomes (100-1000 nm) that are released through the budding of the plasma membrane. Despite the differences in the mode of biogenesis and size, reliable markers that can distinguish between exosomes and ectosomes are non-existent. Moreover, the precise functional differences between exosomes and ectosomes remains poorly characterised. Here, using label-free quantitative proteomics, we highlight proteins that could be exploited as markers to discriminate between exosomes and ectosomes. For the first time, a global proteogenomics analysis unveiled the secretion of mutant proteins that are implicated in cancer progression through tumor-derived EVs. Follow up integrated bioinformatics analysis highlighted the enrichment of oncogenic cargo in exosomes and ectosomes. Interestingly, exosomes induced significant cell proliferation and migration in recipient cells compared to ectosomes confirming the oncogenic nature of exosomes. These findings ascertain that cancer cells facilitate oncogenesis by the secretion of mutant and oncoproteins into the tumor microenvironment via exosomes and ectosomes. The integrative proteogenomics approach utilized in this study has the potential to identify disease biomarker candidates which can be later assayed in liquid biopsies obtained from cancer patients.

  8. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer.

    PubMed

    Boutin, Adam T; Liao, Wen-Ting; Wang, Melody; Hwang, Soyoon Sarah; Karpinets, Tatiana V; Cheung, Hannah; Chu, Gerald C; Jiang, Shan; Hu, Jian; Chang, Kyle; Vilar, Eduardo; Song, Xingzhi; Zhang, Jianhua; Kopetz, Scott; Futreal, Andrew; Wang, Y Alan; Kwong, Lawrence N; DePinho, Ronald A

    2017-02-15

    Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Kras(mut) ) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Kras(mut) allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Kras(mut) signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Kras(mut) -driven invasiveness. Genetic extinction of Kras(mut) resulted in specific elimination of the Kras(mut) subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Kras(mut) drives CRC invasion and maintenance of metastases. © 2017 Boutin et al.; Published by Cold Spring Harbor Laboratory Press.

  9. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

    PubMed Central

    Boutin, Adam T.; Liao, Wen-Ting; Wang, Melody; Hwang, Soyoon Sarah; Karpinets, Tatiana V.; Cheung, Hannah; Chu, Gerald C.; Jiang, Shan; Hu, Jian; Chang, Kyle; Vilar, Eduardo; Song, Xingzhi; Zhang, Jianhua; Kopetz, Scott; Futreal, Andrew; Wang, Y. Alan; Kwong, Lawrence N.; DePinho, Ronald A.

    2017-01-01

    Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Krasmut) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Krasmut-driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases. PMID:28289141

  10. Design of a small molecule against an oncogenic noncoding RNA

    PubMed Central

    Velagapudi, Sai Pradeep; Cameron, Michael D.; Haga, Christopher L.; Rosenberg, Laura H.; Lafitte, Marie; Duckett, Derek R.; Phinney, Donald G.; Disney, Matthew D.

    2016-01-01

    The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif–small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm. PMID:27170187

  11. Design of a small molecule against an oncogenic noncoding RNA.

    PubMed

    Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L; Rosenberg, Laura H; Lafitte, Marie; Duckett, Derek R; Phinney, Donald G; Disney, Matthew D

    2016-05-24

    The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.

  12. Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma.

    PubMed

    Singh, Dinesh K; Kollipara, Rahul K; Vemireddy, Vamsidara; Yang, Xiao-Li; Sun, Yuxiao; Regmi, Nanda; Klingler, Stefan; Hatanpaa, Kimmo J; Raisanen, Jack; Cho, Steve K; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara; Mashimo, Tomoyuki; Wang, Shan; Humphries, Caroline G; Mickey, Bruce; Maher, Elizabeth A; Zheng, Hongwu; Kim, Ryung S; Kittler, Ralf; Bachoo, Robert M

    2017-01-24

    Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

  13. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    PubMed Central

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  14. Human U6 promoter drives stronger shRNA activity than its schistosome orthologue in Schistosoma mansoni and human fibrosarcoma cells.

    PubMed

    Duvoisin, Raphaël; Ayuk, Mary A; Rinaldi, Gabriel; Suttiprapa, Sutas; Mann, Victoria H; Lee, Clarence M; Harris, Nicola; Brindley, Paul J

    2012-06-01

    Blood flukes or schistosomes are the causative agents of human schistosomiasis, one of the major neglected tropical diseases. Draft genome sequences have been reported for schistosomes, but functional genomics tools are needed to investigate the role and essentiality of the newly reported genes. Vector based RNA interference can contribute to functional genomics analysis for schistosomes. Using mRNA encoding reporter firefly luciferase as a model target, we compared the performance of a schistosome and a human promoter from the U6 gene in driving shRNA in human fibrosarcoma cells and in cultured schistosomes. Further, both a retroviral [Murine leukemia virus (MLV)] and plasmid (piggyBac, pXL-Bac II) vector were utilized. The schistosome U6 gene promoter was 270 bp in length, the human U6 gene promoter was 264 bp; they shared 41% identity. Following transduction of both HT1080 fibrosarcoma cells and schistosomules of Schistosoma mansoni with pseudotyped MLV virions, stronger knockdown of luciferase activity was seen with the virions encoding the human U6 promoter driven shRNA than the schistosome U6 promoter. A similar trend was seen after transfection of HT1080 cells and schistosomules with the pXL-Bac-II constructs-stronger knockdown of luciferase activity was seen with constructs encoding the human compared to schistosome U6 promoter. The findings indicate that a human U6 gene promoter drives stronger shRNA activity than its schistosome orthologue, not only in a human cancer cell line but also in larval schistosomes. This RNA polymerase III promoter represents a potentially valuable component for vector based RNA interference studies in schistosomes and related platyhelminth parasites.

  15. Human U6 promoter drives stronger shRNA activity than its schistosome orthologue in Schistosoma mansoni and human fibrosarcoma cells

    PubMed Central

    Duvoisin, Raphaël; Ayuk, Mary A.; Rinaldi, Gabriel; Suttiprapa, Sutas; Mann, Victoria H.; Lee, Clarence M.; Harris, Nicola; Brindley, Paul J.

    2011-01-01

    Blood flukes or schistosomes are the causative agents of human schistosomiasis, one of the major neglected tropical diseases. Draft genome sequences have been reported for schistosomes, but functional genomics tools are needed to investigate the role and essentiality of the newly reported genes. Vector based RNA interference can contribute to functional genomics analysis for schistosomes. Using mRNA encoding reporter firefly luciferase as a model target, we compared the performance of a schistosome and a human promoter from the U6 gene in driving shRNA in human fibrosarcoma cells and in cultured schistosomes. Further, both a retroviral (Murine leukemia virus [MLV]) and plasmid (piggyBac, pXL-Bac II) vector were utilized. The schistosome U6 gene promoter was 270 bp in length, the human U6 gene promoter was 264 bp; they shared 41% identity. Following transduction of both HT1080 fibrosarcoma cells and schistosomules of Schistosoma mansoni with pseudotyped MLV virions, stronger knockdown of luciferase activity was seen with the virions encoding the human U6 promoter driven shRNA than the schistosome U6 promoter. A similar trend was seen after transfection of HT1080 cells and schistosomules with the pXL-Bac-II constructs – stronger knockdown of luciferase activity was seen with constructs encoding the human compared to schistosome U6 promoter. The findings indicate that a human U6 gene promoter drives stronger shRNA activity than its schistosome orthologue, not only in a human cancer cell line but also in larval schistosomes. This RNA polymerase III promoter represents a potentially valuable component for vector based RNA interference studies in schistosomes and related platyhelminth parasites. PMID:21953124

  16. Low molecular weight heparin suppresses receptor for advanced glycation end products-mediated expression of malignant phenotype in human fibrosarcoma cells.

    PubMed

    Takeuchi, Akihiko; Yamamoto, Yasuhiko; Munesue, Seiichi; Harashima, Ai; Watanabe, Takuo; Yonekura, Hideto; Yamamoto, Hiroshi; Tsuchiya, Hiroyuki

    2013-06-01

    The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor and its engagement by ligands such as high mobility group box 1 (HMGB1) is implicated in tumor growth and metastasis. Low molecular weight heparin (LMWH) has an antagonistic effect on the RAGE axis and is also reported to exert an antitumor effect beyond the known activity of anticoagulation. However, the link between the anti-RAGE and antitumor activities of LMWH has not yet to be fully elucidated. In this study, we investigated whether LMWH could inhibit tumor cell proliferation, invasion, and metastasis by blocking the RAGE axis using in vitro and in vivo assay systems. Stably transformed HT1080 human fibrosarcoma cell lines were obtained, including human full-length RAGE-overexpressing (HT1080(RAGE)), RAGE dominant-negative, intracellular tail-deleted RAGE-overexpressing (HT1080(dnRAGE)), and mock-transfected control (HT1080(mock)) cells. Confocal microscopy showed the expression of HMGB1 and RAGE in HT1080 cells. The LMWH significantly inhibited HMGB1-induced NFκB activation through RAGE using an NFκB-dependent luciferase reporter assay and the HT1080 cell lines. Overexpression of RAGE significantly accelerated, but dnRAGE expression attenuated HT1080 cell proliferation and invasion in vitro, along with similar effects on local tumor mass growth and lung metastasis in vivo. Treatment with LMWH significantly inhibited the migration, invasion, tumor formation, and lung metastasis of HT1080(RAGE) cells, but not of HT1080(mock) or HT1080(dnRAGE) cells. In conclusion, this study revealed that RAGE exacerbated the malignant phenotype of human fibrosarcoma cells, and that this exacerbation could be ameliorated by LMWH. It is suggested that LMWH has therapeutic potential in patients with certain types of malignant tumors. © 2013 Japanese Cancer Association.

  17. Inhibitory effect of DA-125, a new anthracyclin analog antitumor agent, on the invasion of human fibrosarcoma cells by down-regulating the matrix metalloproteinases.

    PubMed

    Park, Hyen Joo; Chung, Hwa-Jin; Min, Hye-Young; Park, Eun-Jung; Hong, Ji-Young; Kim, Won Bae; Kim, Soon Hoe; Lee, Sang Kook

    2005-12-19

    Matrix metalloproteinases (MMPs), zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. In this study, we examined the influence of DA-125, a new anthracyclin analog, on the gene expression of MMPs (MMP-2, MMP-9 and MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases of MMPs and TIMPs mRNA levels were observed in DA-125-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. Gelatin zymography analysis also showed a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with DA-125 compared to controls. In addition, DA-125 inhibited the invasion, motility and cell migration, and colony formation of tumor cells. These data, therefore, provide direct evidence for the role of DA-125 as a potential cancer chemotherapeutic agent, which can markedly inhibit the invasive capacity of malignant cells. Further, to clarify the transcriptional regulatory pathway, we primarily investigated the role of nuclear factor-kappaB (NF-kappaB) in the expression of MMPs by DA-125 in HT1080 cells. Electrophoretic mobility shift assay demonstrated that DA-125 modulates the binding activity of NF-kappaB. Using the luciferase reporter gene assay, a dose-dependent down-regulation of NF-kappaB-mediated luciferase expression was also observed. These results suggest that DA-125 down-regulates MMPs expression in HT1080 cells through the NF-kappaB-mediated pathway.

  18. Negative effects of G-protein-coupled free fatty acid receptor GPR40 on cell migration and invasion in fibrosarcoma HT1080 cells.

    PubMed

    Ishii, Shuhei; Kitamura, Yuka; Hirane, Miku; Tomimatsu, Ayaka; Fukushima, Kaori; Takahashi, Kaede; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi

    2016-11-01

    G-protein-coupled receptor 40 (GPR40) and GPR120 mediate a variety of biological functions by the binding of long and medium chain free fatty acids. In the present study, we investigated a role of GPR40 in the pathogenesis of fibrosarcoma HT1080 cells. The GPR40 gene expression was detected in HT1080 cells, but not the GPR120 gene. The cell motile and invasive activities were markedly enhanced by GPR40 knockdown, compared with control cells. To evaluate whether GPR40 is involved in the cellular functions of HT1080 cells during anticancer drug treatment, HT1080 cells were maintained in condition medium containing cisplatin (CDDP) (0.01-1.0 μM) for 6 mo. The expression levels of the GPR40 gene was elevated by the long-term CDDP treatment in HT1080 cells, while the GPR120 gene expression remained unchanged. The cell motile and invasive activities of HT1080 cells treated with CDDP were significantly lower than those of untreated cells. In gelatin zymography, the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 of HT1080 cells were enhanced by the long-term CDDP treatment. In addition, GW9508 which is an agonist of GPR40 and GPR120 suppressed the cell motile and invasive activities of HT1080 cells treated with CDDP as well as the MMP activation. These results suggest that GPR40 negatively regulates the tumor progression of fibrosarcoma cells. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  19. Salinomycin causes migration and invasion of human fibrosarcoma cells by inducing MMP-2 expression via PI3-kinase, ERK-1/2 and p38 kinase pathways.

    PubMed

    Yu, Seon-Mi; Kim, Song Ja

    2016-06-01

    Salinomycin (SAL) is a polyether ionophore antibiotic that has recently been shown to regulate a variety of cellular responses in various human cancer cells. However, the effects of SAL on metastatic capacity of HT1080 human fibrosarcoma cells have not been elucidated. We investigated the effect of SAL on migration and invasion, with emphasis on the expression and activation of matrix metalloproteinase (MMP)-2 in HT1080 human fibrosarcoma cells. Treatment of SAL promoted the expression and activation of MMP-2 in a dose- and time-dependent manner, as detected by western blot analysis, gelatin zymography, and real-time polymerase chain reaction. SAL also increased metastatic capacities, as determined by an increase in the migration and invasion of cells using the wound healing assay and the invasion assay, respectively. To confirm the detailed molecular mechanisms of these effects, we measured the activation of phosphoinositide 3 kinase (PI3-kinase) and mitogen-activated protein kinase (MAPK)s (ERK-1/2 and p38 kinase), as detected by the phosphorylated proteins through western blot analysis. SAL treatment increased the phosphorylation of Akt and MAPKs. Inhibition of PI3-kinase, ERK-1/2, and p38 kinase with LY294002, PD98059, and SB203580, respectively, in the presence of SAL suppressed the metastatic capacity by reducing MMP-2 expression, as determined by gelatin zymography. Our results indicate that the PI3-kinase and MAPK signaling pathways are involved in migration and invasion of HT1080 through induction of MMP-2 expression and activation. In conclusion, SAL significantly increases the metastatic capacity of HT1080 cells by inducing MMP-2 expression via PI3-kinase and MAPK pathways. Our results suggest that SAL may be a potential agent for the study of cancer metastatic capacities.

  20. [Nature of cancer explored from the perspective of the functional evolution of proto-oncogenes].

    PubMed

    Watari, Akihiro

    2012-01-01

    The products of proto-oncogene play critical roles in the development or maintenance of multicellular societies in animals via strict regulatory systems. When these regulatory systems are disrupted, proto-oncogenes can become oncogenes, and thereby induce cell transformation and carcinogenesis. To understand the molecular basis for development of the regulatory system of proto-oncogenes during evolution, we screened for ancestral proto-oncogenes from the unicellular choanoflagellate Monosiga ovata (M. ovata) by monitoring their transforming ability in mammalian cells; consequently, we isolated a Pak gene ortholog, which encodes a serine/threonine kinase as a 'primitive oncogene'. We also cloned Pak orthologs from fungi and the multicellular sponge Ephydatia fluviatilis, and compared their regulatory features with that of M. ovata Pak (MoPak). MoPak is constitutively active and induces cell transformation in mammalian cells. In contrast, Pak orthologs from multicellular animals are strictly regulated. Analyses of Pak mutants revealed that structural alterations in the auto-inhibitory domain (AID) are responsible for the enhanced kinase activity and the oncogenic activity of MoPak. Furthermore, we show that Rho family GTPases-mediated regulatory system of Pak kinase is conserved throughout the evolution from unicellular to multicellular animals, but the MoPak is more sensitive to the Rho family GTPases-mediated activation than multicellular Pak. These results show that maturation of AID function was required for the development of the strict regulatory system of the Pak proto-oncogene, and support the potential link between the development of the regulatory system of proto-oncogenes and the evolution of multicellularity. Further analysis of oncogenic functions of proto-oncogene orthologs in the unicellular genes would provide some insights into the mechanisms of the destruction of multicellular society in cancer.

  1. Prediction of oncogenic interactions and cancer-related signaling networks based on network topology.

    PubMed

    Acencio, Marcio Luis; Bovolenta, Luiz Augusto; Camilo, Esther; Lemke, Ney

    2013-01-01

    Cancer has been increasingly recognized as a systems biology disease since many investigators have demonstrated that this malignant phenotype emerges from abnormal protein-protein, regulatory and metabolic interactions induced by simultaneous structural and regulatory changes in multiple genes and pathways. Therefore, the identification of oncogenic interactions and cancer-related signaling networks is crucial for better understanding cancer. As experimental techniques for determining such interactions and signaling networks are labor-intensive and time-consuming, the development of a computational approach capable to accomplish this task would be of great value. For this purpose, we present here a novel computational approach based on network topology and machine learning capable to predict oncogenic interactions and extract relevant cancer-related signaling subnetworks from an integrated network of human genes interactions (INHGI). This approach, called graph2sig, is twofold: first, it assigns oncogenic scores to all interactions in the INHGI and then these oncogenic scores are used as edge weights to extract oncogenic signaling subnetworks from INHGI. Regarding the prediction of oncogenic interactions, we showed that graph2sig is able to recover 89% of known oncogenic interactions with a precision of 77%. Moreover, the interactions that received high oncogenic scores are enriched in genes for which mutations have been causally implicated in cancer. We also demonstrated that graph2sig is potentially useful in extracting oncogenic signaling subnetworks: more than 80% of constructed subnetworks contain more than 50% of original interactions in their corresponding oncogenic linear pathways present in the KEGG PATHWAY database. In addition, the potential oncogenic signaling subnetworks discovered by graph2sig are supported by experimental evidence. Taken together, these results suggest that graph2sig can be a useful tool for investigators involved in cancer research

  2. Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein.

    PubMed Central

    Gullick, W J; Bottomley, A C; Lofts, F J; Doak, D G; Mulvey, D; Newman, R; Crumpton, M J; Sternberg, M J; Campbell, I D

    1992-01-01

    The neu proto-oncogene may be converted into a dominantly transforming oncogene by a single point mutation. Substitution of a valine residue at position 664 in the transmembrane region with glutamic acid activates the tyrosine kinase of the molecule and is associated with increased receptor dimerization. Previously we have proposed a model in which the glutamic acid side chain stabilizes receptor dimerization by hydrogen bonding. Other models have been proposed in which the mutation leads to a conformational change in the transmembrane region mimicking that assumed to occur following binding of a natural ligand. Synthetic peptides representing part of the transmembrane region were prepared. Some residues were replaced with serine in order to improve peptide solubility to allow purification and analysis. Both the peptides containing valine and glutamic acid dissolved in water and in an artificial lipid monolayer. The structures of the peptides were determined by NMR spectroscopy to be alpha-helical. No significant difference in conformation was observed between the two peptides. This result does not support the model proposing a conformational change. The receptor structures determined experimentally do allow alternative models involving receptor transmembrane region packing. Images PMID:1346763

  3. The cyclin D1-CDK4 oncogenic interactome enables identification of potential novel oncogenes and clinical prognosis.

    PubMed

    Jirawatnotai, Siwanon; Sharma, Samanta; Michowski, Wojciech; Suktitipat, Bhoom; Geng, Yan; Quackenbush, John; Elias, Joshua E; Gygi, Steven P; Wang, Yaoyu E; Sicinski, Piotr

    2014-01-01

    Overexpression of cyclin D1 and its catalytic partner, CDK4, is frequently seen in human cancers. We constructed cyclin D1 and CDK4 protein interaction network in a human breast cancer cell line MCF7, and identified novel CDK4 protein partners. Among CDK4 interactors we observed several proteins functioning in protein folding and in complex assembly. One of the novel partners of CDK4 is FKBP5, which we found to be required to maintain CDK4 levels in cancer cells. An integrative analysis of the extended cyclin D1 cancer interactome and somatic copy number alterations in human cancers identified BAIAPL21 as a potential novel human oncogene. We observed that in several human tumor types BAIAPL21 is expressed at higher levels as compared to normal tissue. Forced overexpression of BAIAPL21 augmented anchorage independent growth, increased colony formation by cancer cells and strongly enhanced the ability of cells to form tumors in vivo. Lastly, we derived an Aggregate Expression Score (AES), which quantifies the expression of all cyclin D1 interactors in a given tumor. We observed that AES has a prognostic value among patients with ER-positive breast cancers. These studies illustrate the utility of analyzing the interactomes of proteins involved in cancer to uncover potential oncogenes, or to allow better cancer prognosis.

  4. Cell Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer

    DTIC Science & Technology

    2016-12-01

    Cancer REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average...Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer Michael Lilly, MD Richard Weisbart, MD Medical...0534, entitled Cell- penetrating bispecific antibodies for targeting oncogenic transcription factors in advanced prostate cancer . The research is a

  5. Herpesvirus saimiri strains from three DNA subgroups have different oncogenic potentials in New Zealand white rabbits.

    PubMed Central

    Medveczky, M M; Szomolanyi, E; Hesselton, R; DeGrand, D; Geck, P; Medveczky, P G

    1989-01-01

    Herpesvirus saimiri is a primate tumor virus that induces acute T-cell lymphomas in New World monkeys. Strains of this virus have been previously classified into three groups on the basis of extreme DNA variability of the rightmost region of unique L-DNA. To compare the oncogenic potentials of various strains, we inoculated New Zealand White rabbits with viruses representing groups A, B, and C of herpesvirus saimiri. The results showed that a group C strain were highly oncogenic in New Zealand White rabbits; however, group A or B viruses were not oncogenic in these rabbits. Analysis of DNAs of tumor tissues and lymphoid cell lines established from tumors showed that the viral genome exists in circular episomal form. To identify which part of the genome of the group C strain is responsible for the highly oncogenic phenotype, group B-C recombinant strains were constructed by an efficient drug selection technique. Two group B recombinant strains in which the right-end 9.2 kilobase pairs of unique DNA is replaced by group C virus DNA were oncogenic in rabbits, indicating that the rightmost sequences contribute to the oncogenic properties of the group C strain. Oncogenicity of herpesvirus saimiri has been traditionally evaluated in New World monkeys; infection of rabbits with group C strain 484-77 offers a much more accessible animal model to study the mechanism of oncogenicity of this virus. Images PMID:2547988

  6. Can anti-tumor immunity help to explain “oncogene addiction”?

    PubMed Central

    Restifo, Nicholas P.

    2010-01-01

    Summary “Oncogene addiction” refers to the process of tumor cell death that can occur after inactivation of a single oncogene. In this issue of Cancer Cell, Rakhra, et al. argue that complete tumor clearance after molecular targeted therapies requires a functioning immune system, pointing the way toward radically new combination therapies. PMID:21075303

  7. A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma

    PubMed Central

    Sankar, Savita; Tanner, Jason M.; Bell, Russell; Chaturvedi, Aashi; Randall, R. Lor; Beckerle, Mary C.

    2013-01-01

    Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma. PMID:24043308

  8. Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration

    PubMed Central

    Shin, Seung-Min; Choi, Dong-Ki; Jung, Keunok; Bae, Jeomil; Kim, Ji-sun; Park, Seong-wook; Song, Ki-Hoon; Kim, Yong-Sung

    2017-01-01

    Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely challenging. Here we report the development of a human IgG1 format antibody, RT11, which internalizes into the cytosol of living cells and selectively binds to the activated GTP-bound form of various oncogenic Ras mutants to block the interactions with effector proteins, thereby suppressing downstream signalling and exerting anti-proliferative effects in a variety of tumour cells harbouring oncogenic Ras mutants. When systemically administered, an RT11 variant with an additional tumour-associated integrin binding moiety for tumour tissue targeting significantly inhibits the in vivo growth of oncogenic Ras-mutated tumour xenografts in mice, but not wild-type Ras-harbouring tumours. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology. PMID:28489072

  9. RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer.

    PubMed

    Lodish, Maya B; Stratakis, Constantine A

    2008-04-01

    Hereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of-function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, and will summarize the therapies designed to strategically interfere with the pathologic activation of the RET oncogene.

  10. TRKing down an old oncogene in a new era of targeted therapy

    PubMed Central

    Vaishnavi, Aria; Le, Anh; Doebele, Robert C.

    2014-01-01

    The employment of high-throughput next-generation sequencing techniques in multiple tumor types during the last few years has identified NTRK1, 2, and 3 gene rearrangements encoding novel oncogenic fusions in 19 different tumor types to date. These recent developments have led us to revisit an old oncogene, Trk, (originally identified as OncD), which encodes the TPM3-NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified 32 years ago. However, no drug has yet been approved by the US FDA for cancers harboring this oncogene. This review will discuss the biology of the Trk family of receptors, their role in human cancer, the types of oncogenic alterations, and drugs that are currently in development for this family of oncogene targets. PMID:25527197

  11. Structural Effects of Oncogenic PI3K alpha Mutations

    SciTech Connect

    S Gabelli; C Huang; D Mandelker; O Schmidt-Kittler; B Vogelstein; L Amzel

    2011-12-31

    Physiological activation of PI3K{alpha} is brought about by the release of the inhibition by p85 when the nSH2 binds the phosphorylated tyrosine of activated receptors or their substrates. Oncogenic mutations of PI3K{alpha} result in a constitutively activated enzyme that triggers downstream pathways that increase tumor aggressiveness and survival. Structural information suggests that some mutations also activate the enzyme by releasing p85 inhibition. Other mutations work by different mechanisms. For example, the most common mutation, His1047Arg, causes a conformational change that increases membrane association resulting in greater accessibility to the substrate, an integral membrane component. These effects are examples of the subtle structural changes that result in increased activity. The structures of these and other mutants are providing the basis for the design of isozyme-specific, mutation-specific inhibitors for individualized cancer therapies.

  12. Viral subversion of autophagy impairs oncogene-induced senescence.

    PubMed

    Leidal, Andrew M; Lee, Patrick W K; McCormick, Craig

    2012-07-01

    Many viruses have evolved elegant strategies to co-opt cellular autophagic responses to facilitate viral propagation and evasion of immune surveillance. Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a life-long persistent infection in its human host, and is etiologically linked to several cancers. KSHV gene products have been shown to modulate autophagy but their contribution to pathogenesis remains unclear. Our recent study demonstrated that KSHV subversion of autophagy promotes bypass of oncogene-induced senescence (OIS), an important host barrier to tumor initiation. These findings suggest that KSHV has evolved to subvert autophagy, at least in part, to establish an optimal niche for infection, concurrently dampening host antiviral defenses and allowing the ongoing proliferation of infected cells.

  13. Tumor-derived exosomes in oncogenic reprogramming and cancer progression.

    PubMed

    Saleem, Sarmad N; Abdel-Mageed, Asim B

    2015-01-01

    In multicellular organisms, effective communication between cells is a crucial part of cellular and tissue homeostasis. This communication mainly involves direct cell-cell contact as well as the secretion of molecules that bind to receptors at the recipient cells. However, a more recently characterized mode of intercellular communication-the release of membrane vesicles known as exosomes-has been the subject of increasing interest and intensive research over the past decade. Following the discovery of the exosome-mediated immune activation, the pathophysiological roles of exosomes have been recognized in different diseases, including cancer. In this review, we describe the biogenesis and main physical characteristics that define exosomes as a specific population of secreted vesicles, with a special focus on their role in oncogenic transformation and cancer progression.

  14. Tumor-Derived Exosomes in Oncogenic Reprogramming and Cancer Progression

    PubMed Central

    Saleem, Sarmad N; Abdel-Mageed, Asim B

    2014-01-01

    In multicellular organisms, effective communication between cells is a crucial part of cellular and tissue homeostasis. This communication mainly involves direct cell–cell contact as well as the secretion of molecules that bind to receptors at the recipient cells. However, a more recently characterized mode of intercellular communication — the release of membrane vesicles known as exosomes — has been the subject of increasing interest and intensive research over the past decade. Following the discovery of the exosome-mediated immune activation, the pathophysiological roles of exosomes have been recognized in different diseases, including cancer. In this review, we describe the biogenesis and main physical characteristics that define exosomes as a specific population of secreted vesicles, with a special focus on their role in oncogenic transformation and cancer progression. PMID:25156068

  15. Induction of promyelocytic leukemia (PML) oncogenic domains (PODs) by papillomavirus

    SciTech Connect

    Nakahara, Tomomi; Lambert, Paul F.

    2007-09-30

    Promyelocytic leukemia oncogenic domains (PODs), also called nuclear domain 10 (ND10), are subnuclear structures that have been implicated in a variety of cellular processes as well as the life cycle of DNA viruses including papillomaviruses. In order to investigate the interplay between papillomaviruses and PODs, we analyzed the status of PODs in organotypic raft cultures of human keratinocytes harboring HPV genome that support the differentiation-dependent HPV life cycle. The number of PODs per nucleus was increased in the presence of HPV genomes selectively within the poorly differentiated layers but was absent in the terminally differentiated layers of the stratified epithelium. This increase in PODs was correlated with an increase in abundance of post-translationally modified PML protein. Neither the E2-dependent transcription nor viral DNA replication was reliant upon the presence of PML. Implications of these findings in terms of HPV's interaction with its host are discussed.

  16. Structural effects of oncogenic PI3Kα mutations.

    PubMed

    Gabelli, Sandra B; Huang, Chuan-Hsiang; Mandelker, Diana; Schmidt-Kittler, Oleg; Vogelstein, Bert; Amzel, L Mario

    2010-01-01

    Physiological activation of PI3Kα is brought about by the release of the inhibition by p85 when the nSH2 binds the phosphorylated tyrosine of activated receptors or their substrates. Oncogenic mutations of PI3Kα result in a constitutively activated enzyme that triggers downstream pathways that increase tumor aggressiveness and survival. Structural information suggests that some mutations also activate the enzyme by releasing p85 inhibition. Other mutations work by different mechanisms. For example, the most common mutation, His1047Arg, causes a conformational change that increases membrane association resulting in greater accessibility to the substrate, an integral membrane component. These effects are examples of the subtle structural changes that result in increased activity. The structures of these and other mutants are providing the basis for the design of isozyme-specific, mutation-specific inhibitors for individualized cancer therapies.

  17. Use of glycolytic pathways for inhibiting or measuring oncogenic signaling

    DOEpatents

    Onodera, Yasuhito; Bissell, Mina

    2017-06-27

    Disclosed are methods in which glucose metabolism is correlated to oncogenesis through certain specific pathways; inhibition of certain enzymes is shown to interfere with oncogenic signaling, and measurement of certain enzyme levels is correlated with patient survival. The present methods comprise measuring level of expression of at least one of the enzymes involved in glucose uptake or metabolism, wherein increased expression of the at least one of the enzymes relative to expression in a normal cell correlates with poor prognosis of disease in a patient. Preferably the genes whose expression level is measured include GLUT3, PFKP, GAPDH, ALDOC, LDHA and GFPT2. Also disclosed are embodiments directed towards downregulating the expression of some genes in glucose uptake and metabolism.

  18. CD3-epsilon overexpressed in prothymocytes acts as an oncogene.

    PubMed Central

    Wang, B.; She, J.; Salio, M.; Allen, D.; Lacy, E.; Lonberg, N.; Terhorst, C.

    1997-01-01

    BACKGROUND: Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-epsilon, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-epsilon transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-epsilon signaling leads both to abnormal T lymphocyte death and lymphomagenesis. MATERIALS AND METHODS: Ten independently derived transgenic mouse lines were generated with four different genomic CD3-epsilon constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas. RESULTS: Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-epsilon derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-epsilon transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-epsilon protein were deleted. Analyses of a series of double mutant mice, tgCD3-epsilon x RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-epsilon cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-epsilon x RAG-2null mice. CONCLUSION: The nonenzymatic CD3-epsilon protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-epsilon. Images FIG. 2 FIG. 4 FIG. 5 PMID:9132282

  19. Dimerize RACK1 upon transformation with oncogenic ras

    SciTech Connect

    Chu, L.-Y.; Chen, Y.-H.; Chuang, N.-N. . E-mail: zonnc@sinica.edu.tw

    2005-05-06

    From our previous studies, we learned that syndecan-2/p120-GAP complex provided docking site for Src to prosecute tyrosine kinase activity upon transformation with oncogenic ras. And, RACK1 protein was reactive with syndecan-2 to keep Src inactivated, but not when Ras was overexpressed. In the present study, we characterized the reaction between RACK1 protein and Ras. RACK1 was isolated from BALB/3T3 cells transfected with plasmids pcDNA3.1-[S-ras(Q{sub 61}K)] of shrimp Penaeus japonicus and RACK1 was revealed to react with GTP-K{sub B}-Ras(Q{sub 61}K), not GDP-K{sub B}-Ras(Q{sub 61}K). This selective interaction between RACK1 and GTP-K{sub B}-Ras(Q{sub 61}K) was further confirmed with RACK1 of human placenta and mouse RACK1-encoded fusion protein. We found that RACK1 was dimerized upon reaction with GTP-K{sub B}-Ras(Q{sub 61}K), as well as with 14-3-3{beta} and geranylgeranyl pyrophosphate, as revealed by phosphorylation with Src tyrosine kinase. We reported the complex of RACK1/GTP-K{sub B}-Ras(Q{sub 61}K) reacted selectively with p120-GAP. This interaction was sufficient to dissemble RACK1 into monomers, a preferred form to compete for the binding of syndecan-2. These data indicate that the reaction of GTP-K{sub B}-Ras(Q{sub 61}K) with RACK1 in dimers may operate a mechanism to deplete RACK1 from reaction with syndecan-2 upon transformation by oncogenic ras and the RACK1/GTP-Ras complex may provide a route to react with p120-GAP and recycle monomeric RACK1 to syndecan-2.

  20. Intrinsic Structural Disorder Confers Cellular Viability on Oncogenic Fusion Proteins

    PubMed Central

    Hegyi, Hedi; Buday, László; Tompa, Peter

    2009-01-01

    Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations. PMID:19888473

  1. Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

    SciTech Connect

    Mancuso, Mariateresa; Leonardi, Simona; Giardullo, Paola; Pasquali, Emanuela; Tanori, Mirella; De Stefano, Ilaria; Casciati, Arianna; Naus, Christian C.; Pazzaglia, Simonetta; Saran, Anna

    2013-08-01

    Purpose: To investigate the tissue dependence in transmission of abscopal radiation signals and their oncogenic consequences in a radiosensitive mouse model and to explore the involvement of gap junction intercellular communication (GJIC) in mediating radiation tumorigenesis in off-target mouse skin. Methods and Materials: Patched1 heterozygous (Ptch1{sup +/−}) mice were irradiated at postnatal day 2 (P2) with 10 Gy of x-rays. Individual lead cylinders were used to protect the anterior two-thirds of the body, whereas the hindmost part was directly exposed to radiation. To test the role of GJICs and their major constituent connexin43 (Cx43), crosses between Ptch1{sup +/−} and Cx43{sup +/−} mice were similarly irradiated. These mouse groups were monitored for their lifetime, and skin basal cell carcinomas (BCCs) were counted and recorded. Early responses to DNA damage - Double Strand Breaks (DSBs) and apoptosis - were also evaluated in shielded and directly irradiated skin areas. Results: We report abscopal tumor induction in the shielded skin of Ptch1{sup +/−} mice after partial-body irradiation. Endpoints were induction of early nodular BCC-like tumors and macroscopic infiltrative BCCs. Abscopal tumorigenesis was significantly modulated by Cx43 status, namely, Cx43 reduction was associated with decreased levels of DNA damage and oncogenesis in out-of-field skin, suggesting a key role of GJIC in transmission of oncogenic radiation signals to unhit skin. Conclusions: Our results further characterize the nature of abscopal responses and the implications they have on pathologic processes in different tissues, including their possible underlying mechanistic bases.

  2. Factors affecting responses to murine oncogenic viral infections.

    PubMed Central

    Harvey, J. J.; Rager-Zisman, B.; Wheelock, E. F.; Nevin, P. A.

    1980-01-01

    Silica specifically kills macrophages in vitro, and in vivo has been used as a method of determining the possible immunological or other roles of macrophages in a number of viral infections. In experiments reported here, injection of 30 or 50 mg silica i.p. increased the severity of the oncogenic effects of the murine sarcoma virus (MSV) and Friend virus (FV) in BALB/c mice. Unlike Herpes simplex and Coxsackie B-3 infections, however, passive transfer of adult macrophages to suckling mice did not protect the latter against MSV. In mice injected with silica, histological evidence of the compensatory proliferation of macrophages suggests that precursors of these cells may act as target cells for the virus and that this may override any immunosuppressive response effected by the silica. In addition, there was a considerable enhancing effect on the erythroproliferative response to both MSV and FV by injection of saline 5 h before the virus, and indeed to FV after only a simple abdominal needle puncture. We attributed this to the lymphopenic immunodepressive effects of stress, and our data may explain previously published findings of augmented oncogenic responses in mice after "normal" serum injections. Newborn BALB/c (FV-1b) mice were susceptible to N-tropic FV, but developed resistance by 29 days of age. Antithymocyte serum (ATS) but not silica injections or adult thymectomy ablated this resistance. C57BL (FV-2r) mice were completely resistant to FV; however, those receiving FV and ATS developed late-onset leukaemia histologically characteristic of that produced by the helper component of the FV complex. Images Fig. PMID:6248095

  3. “Hit-and-Run” Transformation by Adenovirus Oncogenes

    PubMed Central

    Nevels, Michael; Täuber, Birgitt; Spruss, Thilo; Wolf, Hans; Dobner, Thomas

    2001-01-01

    According to classical concepts of viral oncogenesis, the persistence of virus-specific oncogenes is required to maintain the transformed cellular phenotype. In contrast, the “hit-and-run” hypothesis claims that viruses can mediate cellular transformation through an initial “hit,” while maintenance of the transformed state is compatible with the loss (“run”) of viral molecules. It is well established that the adenovirus E1A and E1B gene products can cooperatively transform primary human and rodent cells to a tumorigenic phenotype and that these cells permanently express the viral oncogenes. Additionally, recent studies have shown that the adenovirus E4 region encodes two novel oncoproteins, the products of E4orf6 and E4orf3, which cooperate with the viral E1A proteins to transform primary rat cells in an E1B-like fashion. Unexpectedly, however, cells transformed by E1A and either E4orf6 or E4orf3 fail to express the viral E4 gene products, and only a subset contain E1A proteins. In fact, the majority of these cells lack E4- and E1A-specific DNA sequences, indicating that transformation occurred through a hit-and-run mechanism. We provide evidence that the unusual transforming activities of the adenoviral oncoproteins may be due to their mutagenic potential. Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy. PMID:11238835

  4. Pancreatitis promotes oncogenic KrasG12D-induced pancreatic transformation through activation of Nupr1

    PubMed Central

    Grasso, Daniel; Garcia, Maria Noé; Hamidi, Tewfik; Cano, Carla; Calvo, Ezequiel; Lomberk, Gwen; Urrutia, Raul; Iovanna, Juan L

    2014-01-01

    During the initiation stage of pancreatic adenocarcinoma induced by oncogenic Kras, pancreatic cells are exposed to both a protumoral effect and an opposing tumor suppressive process known as oncogene-induced senescence. Pancreatitis disrupts this balance in favor of the transforming effect of oncogenes by lowering the tumor suppressive threshold of oncogene-induced senescence through expression of the stress protein Nupr1. PMID:27308320

  5. Sequence comparison in the crossover region of an oncogenic avian retrovirus recombinant and its nononcogenic parent: Genetic regions that control growth rate and oncogenic potential

    SciTech Connect

    Tsichlis, P.N.; Donehower, L.; Hager, G.; Zeller, N.; Malavarca, R.; Astrin, S.; Skalka, A.M.

    1982-11-01

    NTRE is an avian retrovirus recombinant of the endogeneous nononcogenic Rous-associated virus-0 (RAV-0) and the oncogenic, exogeneous, transformation-defective (td) Prague strain of Rous sarcoma virus B (td-PrRSV-B). Oligonucleotide mapping had shown that the recombinant virus is indistinguishable from its RAV-0 parent except for the 3'-end sequences, which were derived from td-PrRSV-B. However, the virus exhibits properties which are typical of an exogenous virus: it grows to high titers in tissue culture, and it is oncogenic in vivo. To accurately define the genetic region responsible for these properties, the authors determined the nucleotide sequences of the recombinant and its RAV-0 parent by using molecular clones of their DNA. These were compared with sequences already available for PrRSV-C, a virus closely related to the exogenous parent td-PrRSV-B. The results suggested that the crossover event which generated NTRE 7 took place in a region -501 to -401 nucleotides from the 3' end of the td-PrRSV parental genome and that sequences to the right of the recombination region were responsible for its growth properties and oncogenic potential. Since the exogenous-virus-specific sequences are expected to be missing from transformation-defective mutants of the Schmidt-Ruppin strain of RSV, which, like other exogeneous viruses, grow to high tiers in tissue culture and are oncogenic in vivo, the authors concluded that the growth properties and oncogenic potential of the exogeneous viruses are determined by sequences in the U3 region of the long terminal repeat. However, the authors propose that the exogeneous-virus-specific region may play a role in determining the oncogenic spectrum of a given oncogenic virus.

  6. Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

    PubMed Central

    Hafner, Christian; Toll, Agustí; Fernández-Casado, Alejandro; Earl, Julie; Marqués, Miriam; Acquadro, Francesco; Méndez-Pertuz, Marinela; Urioste, Miguel; Malats, Núria; Burns, Julie E.; Knowles, Margaret A.; Cigudosa, Juan C.; Hartmann, Arndt; Vogt, Thomas; Landthaler, Michael; Pujol, Ramón M.; Real, Francisco X.

    2010-01-01

    Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin. PMID:21078999

  7. [Recent findings on the effect and role of oncogenes in carcinogenesis].

    PubMed

    Kremen, J

    1989-04-28

    The tumourous phenotype of cells may be induced by physical, chemical and biological factors. All have the same target, the cell genoma where they can produce minor (e.g. point mutations) or major changes (e.g. reconstruction--chromosomal aberrations, or gene insertion--oncoretroviruses). At present it may be assumed that these factors participate in the activation of proto-oncogenes (cellular oncogenes, c-onc) or in the inactivation of yet not well recognized "tumour suppressor" genes, so-called "anti-oncogenes". So far it was found that deletion of both alleles of "suppressor" genes causes the development of several recessive hereditary tumours (retinoblastoma, Wilms tumours etc.). Activation of proto-oncogenes (by point mutation, amplification, translocation) was found in a number of advanced primary tumours and in metastases. Probably activation of proto-oncogenes will play a more important part in the development of "acquired" tumours and in their progression. The problem of the mutual relationship of proto-oncogenes and "anti-oncogenes" remains so far obscure and controversial.

  8. DNA damage and repair in oncogenic transformation by heavy ion radiation

    NASA Astrophysics Data System (ADS)

    Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

    Energetic heavy ions are present in galactic cosmic rays and solar particle events. One of the most important late effects in risk assessment is carcinogenesis. We have studied the carcinogenic effects of heavy ions at the cellular and molecular levels and have obtained quantitative data on dose-response curves and on the repair of oncogenic lesions for heavy particles with various charges and energies. Studies with repair inhibitors and restriction endonucleases indicated that for oncogenic transformation DNA is the primary target. Results from heavy ion experiments showed that the cross section increased with LET and reached a maximum value of about 0.02 mum^2 at about 500 keV/mum. This limited size of cross section suggests that only a fraction of cellular genomic DNA is important in radiogenic transformation. Free radical scavengers, such as DMSO, do not give any effect on induction of oncogenic transformation by 600 MeV/u iron particles, suggesting most oncogenic damage induced by high-LET heavy ions is through direct action. Repair studies with stationary phase cells showed that the amount of reparable oncogenic lesions decreased with an increase of LET and that heavy ions with LET greater than 200 keV/mum produced only irreparable oncogenic damage. An enhancement effect for oncogenic transformation was observed in cells irradiated by low-dose-rate argon ions (400 MeV/u; 120 keV/mum). Chromosomal aberrations, such as translocation and deletion, but not sister chromatid exchange, are essential for heavy-ion-induced oncogenic transformation. The basic mechanism(s) of misrepair of DNA damage, which form oncogenic lesions, is unknown.

  9. DNA damage and repair in oncogenic transformation by heavy ion radiation

    NASA Technical Reports Server (NTRS)

    Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

    1996-01-01

    Energetic heavy ions are present in galactic cosmic rays and solar particle events. One of the most important late effects in risk assessment is carcinogenesis. We have studied the carcinogenic effects of heavy ions at the cellular and molecular levels and have obtained quantitative data on dose-response curves and on the repair of oncogenic lesions for heavy particles with various charges and energies. Studies with repair inhibitors and restriction endonucleases indicated that for oncogenic transformation DNA is the primary target. Results from heavy ion experiments showed that the cross section increased with LET and reached a maximum value of about 0.02 micrometer2 at about 500 keV/micrometer. This limited size of cross section suggests that only a fraction of cellular genomic DNA is important in radiogenic transformation. Free radical scavengers, such as DMSO, do not give any effect on induction of oncogenic transformation by 600 MeV/u iron particles, suggesting most oncogenic damage induced by high-LET heavy ions is through direct action. Repair studies with stationary phase cells showed that the amount of reparable oncogenic lesions decreased with an increase of LET and that heavy ions with LET greater than 200 keV/micrometer produced only irreparable oncogenic damage. An enhancement effect for oncogenic transformation was observed in cells irradiated by low-dose-rate argon ions (400 MeV/u; 120 keV/micrometer). Chromosomal aberrations, such as translocation and deletion, but not sister chromatid exchange, are essential for heavy-ion-induced oncogenic transformation. The basic mechanism(s) of misrepair of DNA damage, which form oncogenic lesions, is unknown.

  10. DNA damage and repair in oncogenic transformation by heavy ion radiation

    NASA Technical Reports Server (NTRS)

    Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

    1996-01-01

    Energetic heavy ions are present in galactic cosmic rays and solar particle events. One of the most important late effects in risk assessment is carcinogenesis. We have studied the carcinogenic effects of heavy ions at the cellular and molecular levels and have obtained quantitative data on dose-response curves and on the repair of oncogenic lesions for heavy particles with various charges and energies. Studies with repair inhibitors and restriction endonucleases indicated that for oncogenic transformation DNA is the primary target. Results from heavy ion experiments showed that the cross section increased with LET and reached a maximum value of about 0.02 micrometer2 at about 500 keV/micrometer. This limited size of cross section suggests that only a fraction of cellular genomic DNA is important in radiogenic transformation. Free radical scavengers, such as DMSO, do not give any effect on induction of oncogenic transformation by 600 MeV/u iron particles, suggesting most oncogenic damage induced by high-LET heavy ions is through direct action. Repair studies with stationary phase cells showed that the amount of reparable oncogenic lesions decreased with an increase of LET and that heavy ions with LET greater than 200 keV/micrometer produced only irreparable oncogenic damage. An enhancement effect for oncogenic transformation was observed in cells irradiated by low-dose-rate argon ions (400 MeV/u; 120 keV/micrometer). Chromosomal aberrations, such as translocation and deletion, but not sister chromatid exchange, are essential for heavy-ion-induced oncogenic transformation. The basic mechanism(s) of misrepair of DNA damage, which form oncogenic lesions, is unknown.

  11. Clinical correlates in acromegalic patients with pituitary tumors expressing GSP oncogenes.

    PubMed

    Buchfelder, M; Fahlbusch, R; Merz, T; Symowski, H; Adams, E F

    1999-05-01

    We herein review published findings on the clinical characteristics of acromegalic patients harboring pituitary somatotrophinomas expressing adenylyl cyclase activating gsp mutations and present an update of our own data on a large series of 176 patients with and without these oncogenes. Gsp oncogenes are the result of point mutations in either codon 201 or 227 of the Gs-alpha subunit of the Gs-protein which controls adenylyl cyclase. They result ultimately in increased intracellular cAMP levels and thus in excessive growth hormone (GH) secretion. Our large series has allowed us to characterise patients with mutations in codon 201 and the far rarer group possessing codon 227 defects. Both groups were compared with patients without gsp oncogenes. In accordance with previous findings, there was no statistically significant difference in age of the patients belonging to each group, the overall average tumor diameter nor in pre-operative serum GH levels, although the latter showed a tendency to be lower in patients with gsp oncogenes. The distribution of different types of response during an oral glucose tolerance test (no change, paradoxical rise or greater than 50% decrease in serum GH levels) did not differ between the 3 groups. However, the incidence of microadenomas was higher in acromegalics expressing gsp oncogenes in patients possessing mutations in codon 227. Additionally, the incidence of invasiveness was much lower (10% v. 33%) in those tumors with mutations in codon 227. Finally, previous in-vitro data indicating that gsp oncogene-expressing tumors may respond more efficiently to the somatostatin analogue, octreotide, have been confirmed by subsequent in-vivo studies showing a better reduction in serum GH levels in patients with gsp oncogenes. These latter findings suggest that presence of gsp oncogenes may be a marker for good reponsiveness to octreotide. Assessment of gsp oncogene status of surgically removed pituitary somatotrophinomas may thus be

  12. An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes.

    PubMed

    Mohankumar, Kumarasamypet M; Currle, David S; White, Elsie; Boulos, Nidal; Dapper, Jason; Eden, Christopher; Nimmervoll, Birgit; Thiruvenkatam, Radhika; Connelly, Michele; Kranenburg, Tanya A; Neale, Geoffrey; Olsen, Scott; Wang, Yong-Dong; Finkelstein, David; Wright, Karen; Gupta, Kirti; Ellison, David W; Thomas, Arzu Onar; Gilbertson, Richard J

    2015-08-01

    Cancers are characterized by non-random chromosome copy number alterations that presumably contain oncogenes and tumor-suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models, we validate eight new ependymoma oncogenes and ten new ependymoma TSGs that converge on a small number of cell functions, including vesicle trafficking, DNA modification and cholesterol biosynthesis, identifying these as potential new therapeutic targets.

  13. An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes

    PubMed Central

    Mohankumar, Kumarasamypet M.; Currle, David S.; White, Elsie; Boulos, Nidal; Dapper, Jason; Eden, Christopher; Nimmervoll, Birgit; Thiruvenkatam, Radhika; Connelly, Michele; Kranenburg, Tanya A.; Neale, Geoffrey; Olsen, Scott; Wang, Yong-Dong; Finkelstein, David; Wright, Karen; Gupta, Kirti; Ellison, David W.; Thomas, Arzu Onar; Gilbertson, Richard J.

    2015-01-01

    Cancers are characterized by non-random, chromosome copy number alterations that presumably contain oncogenes and tumor–suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here, we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models we validate eight new ependymoma oncogenes and 10 ependymoma TSGs that converge on a small number of cell functions including vesicle trafficking, DNA modification and cholesterol biosynthesis, pinpointing these as potential new therapeutic targets. PMID:26075792

  14. Oncogenically active MYD88 mutations in human lymphoma

    PubMed Central

    Ngo, Vu N.; Young, Ryan M.; Schmitz, Roland; Jhavar, Sameer; Xiao, Wenming; Lim, Kian-Huat; Kohlhammer, Holger; Xu, Weihong; Yang, Yandan; Zhao, Hong; Shaffer, Arthur L.; Romesser, Paul; Wright, George; Powell, John; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, J. R.; Weisenburger, Denny D.; Chan, Wing C.; Staudt, Louis M.

    2016-01-01

    The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy1. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling2,3, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, theMYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations

  15. Cancer genes: rare recombinants instead of activated oncogenes (a review).

    PubMed Central

    Duesberg, P H

    1987-01-01

    The 20 known transforming (onc) genes of retroviruses are defined by sequences that are transduced from cellular genes termed protooncogenes or cellular oncogenes. Based on these sequences, viral onc genes have been postulated to be transduced cellular cancer genes, and proto-onc genes have been postulated to be latent cancer genes that can be activated from within the cell to cause virus-negative tumors. The hypothesis is popular because it promises direct access to cellular cancer genes. However, the existence of latent cancer genes presents a paradox, since such genes are clearly undesirable. The hypothesis predicts that viral onc genes and proto-onc genes are isogenic; that expression of proto-onc genes induces tumors; that activated proto-onc genes transform diploid cells upon transfection, like viral onc genes; and that diploid tumors exist. As yet, none of these predictions is confirmed. Instead: Structural comparisons between viral onc genes, essential retroviral genes, and proto-onc genes show that all viral onc genes are indeed new genes, rather than transduced cellular cancer genes. They are recombinants put together from truncated viral and truncated proto-onc genes. Proto-onc genes are frequently expressed in normal cells. To date, not one activated proto-onc gene has been isolated that transforms diploid cells. Above all, no diploid tumors with activated proto-onc genes have been found. Moreover, the probability of spontaneous transformation in vivo is at least 10(9) times lower than predicted from the mechanisms thought to activate proto-onc genes. Therefore, the hypothesis that proto-onc genes are latent cellular oncogenes appears to be an overinterpretation of sequence homology to structural and functional homology with viral onc genes. Here it is proposed that only rare truncations and illegitimate recombinations that alter the germ-line configuration of cellular genes generate viral and possibly cellular cancer genes. The clonal chromosome

  16. An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

    PubMed

    Kedage, Vivekananda; Selvaraj, Nagarathinam; Nicholas, Taylor R; Budka, Justin A; Plotnik, Joshua P; Jerde, Travis J; Hollenhorst, Peter C

    2016-10-25

    More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma.

  17. rgr oncogene: activation by elimination of translational controls and mislocalization.

    PubMed

    Hernández-Muñoz, Inmaculada; Benet, Marta; Calero, Miguel; Jiménez, Maria; Díaz, Roberto; Pellicer, Angel

    2003-07-15

    Previous studies have identified a novel oncogene, rgr, which has homology to the guanine nucleotide exchange factor (GEF) Ral guanine dissociation stimulator (RALGDS). To determine the mechanism of activation of rgr, the wild-type form was isolated. rgr is expressed physiologically at very low levels, due, at least in part, to a long 5'-untranslated region that contains eight AUGs, which inhibit translation of the main open reading frame. When these regulatory sequences are removed, the wild-type gene is expressed at high levels. An investigation of how this GEF could transform cells showed that RGR interacts with RAS, supporting its involvement as a RAS-GEF. Because RAL is localized mainly to the Golgi, the expression of the RGR protein was identified in RK13 cells, a cell line that expresses endogenous rgr. RGR localizes to endomembranes. To determine its location upon transformation, a green fluorescent protein-RGR fusion protein was used to track the movement of RGR. Increasing amounts of expression result in enhanced localization of RGR to the plasma membrane. These results indicate that rgr is activated when its tight translational controls are eliminated and increased expression allows its relocation to the plasma membrane, where efficient activation of RAS occurs.

  18. Oncogenic role of Merlin/NF2 in glioblastoma.

    PubMed

    Guerrero, P A; Yin, W; Camacho, L; Marchetti, D

    2015-05-14

    Glioblastoma is the most common and aggressive primary brain tumor in adults, with a poor prognosis because of its resistance to radiotherapy and chemotherapy. Merlin/NF2 (moesin-ezrin-radixin-like protein/neurofibromatosis type 2) is a tumor suppressor found to be mutated in most nervous system tumors; however, it is not mutated in glioblastomas. Merlin associates with several transmembrane receptors and intracellular proteins serving as an anchoring molecule. Additionally, it acts as a key component of cell motility. By selecting sub-populations of U251 glioblastoma cells, we observed that high expression of phosphorylated Merlin at serine 518 (S518-Merlin), NOTCH1 and epidermal growth factor receptor (EGFR) correlated with increased cell proliferation and tumorigenesis. These cells were defective in cell-contact inhibition with changes in Merlin phosphorylation directly affecting NOTCH1 and EGFR expression, as well as downstream targets HES1 (hairy and enhancer of split-1) and CCND1 (cyclin D1). Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR.

  19. TEADs mediate nuclear retention of TAZ to promote oncogenic transformation.

    PubMed

    Chan, Siew Wee; Lim, Chun Jye; Loo, Li Shen; Chong, Yaan Fun; Huang, Caixia; Hong, Wanjin

    2009-05-22

    The transcriptional coactivators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. The expression level of TAZ is recently shown to be elevated in invasive breast cancer cells and some primary breast cancers. TAZ is important for breast cancer cell migration, invasion, and tumorigenesis, but the underlying mechanism is not defined. In this study, we show that TAZ interacts with TEAD transcriptional factors. Knockdown of TEADs suppresses TAZ-mediated oncogenic transformation of MCF10A cells. Uncoupling TAZ from Hippo regulation by S89A mutation enhances its transforming ability. Several residues located in the N-terminal region of TAZ are identified to be important for interaction with TEADs, and these same residues are equally important for TAZ to transform MCF10A cells. Mechanistically, TAZ mutants defective in interaction with TEADs fail to accumulate in the nucleus. Live cell imaging of enhanced green fluorescent protein-TAZ and its mutant defective in TEAD interaction suggests that TEAD interaction mediates nuclear retention. These results reveal a novel mechanism for TEADs to regulate nuclear retention and thus the transforming ability of TAZ.

  20. Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase

    PubMed Central

    2015-01-01

    The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines. PMID:25003231

  1. Copper is required for oncogenic BRAF signaling and tumorigenesis

    PubMed Central

    Brady, Donita C.; Crowe, Matthew S.; Turski, Michelle L.; Hobbs, G. Aaron; Yao, Xiaojie; Chaikuad, Apirat; Knapp, Stefan; Xiao, Kunhong; Campbell, Sharon L.; Thiele, Dennis J.; Counter, Christopher M.

    2014-01-01

    The BRAF kinase is mutated, typically V600E, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers1,2. BRAFV600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate and activate the kinases ERK1 and ERK2, stimulating the MAPK pathway to promote cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, as a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, which is increased when co-administered with a BRAFV600E inhibitor5. In this regard, we previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction6. We now show that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced BRAFV600E-driven signaling and tumorigenesis. Conversely, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independent of Cu or an active ERK2 restored tumor growth to cells lacking Ctr1. Importantly, Cu chelators used in the treatment of Wilson disease7 reduced tumor growth of both BRAFV600E-transformed cells and cells resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat BRAFV600E mutation-positive cancers. PMID:24717435

  2. CXCR4 in breast cancer: oncogenic role and therapeutic targeting.

    PubMed

    Xu, Chao; Zhao, Hong; Chen, Haitao; Yao, Qinghua

    2015-01-01

    Chemokines are 8-12 kDa peptides that function as chemoattractant cytokines and are involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled seven-span transmembrane receptors. Chemokines play a fundamental role in the regulation of a variety of cellular, physiological, and developmental processes. Their aberrant expression can lead to a variety of human diseases including cancer. C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 belongs to the superfamily of the seven transmembrane domain heterotrimeric G protein-coupled receptors and is functionally expressed on the cell surface of various types of cancer cells. CXCR4 also plays a role in the cell proliferation and migration of these cells. Recently, CXCR4 has been reported to play an important role in cell survival, proliferation, migration, as well as metastasis of several cancers including breast cancer. This review is mainly focused on the current knowledge of the oncogenic role and potential drugs that target CXCR4 in breast cancer. Additionally, CXCR4 proangiogenic molecular mechanisms will be reviewed. Strict biunivocal binding affinity and activation of CXCR4/CXCL12 complex make CXCR4 a unique molecular target for prevention and treatment of breast cancer.

  3. Fusion oncogenes in salivary gland tumors: molecular and clinical consequences.

    PubMed

    Stenman, Göran

    2013-07-01

    Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB-NFIB fusion specific for adenoid cystic carcinoma, the CRTC1-MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6-NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down-stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms.

  4. Control of autophagy by oncogenes and tumor suppressor genes.

    PubMed

    Maiuri, M C; Tasdemir, E; Criollo, A; Morselli, E; Vicencio, J M; Carnuccio, R; Kroemer, G

    2009-01-01

    Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.

  5. Autocrine Human Growth Hormone Stimulates Oncogenicity of Endometrial Carcinoma Cells

    PubMed Central

    Pandey, Vijay; Perry, Jo K.; Mohankumar, Kumarasamypet M.; Kong, Xiang-Jun; Liu, Shu-Min; Wu, Zheng-Sheng; Mitchell, Murray D.; Zhu, Tao; Lobie, Peter E.

    2008-01-01

    Recent published data have demonstrated elevated levels of human GH (hGH) in endometriosis and endometrial adenocarcinoma. Herein, we demonstrate that autocrine production of hGH can enhance the in vitro and in vivo oncogenic potential of endometrial carcinoma cells. Forced expression of hGH in endometrial carcinoma cell lines RL95-2 and AN3 resulted in an increased total cell number through enhanced cell cycle progression and decreased apoptotic cell death. In addition, autocrine hGH expression in endometrial carcinoma cells promoted anchorage-independent growth and increased cell migration/invasion in vitro. In a xenograft model of human endometrial carcinoma, autocrine hGH enhanced tumor size and progression. Changes in endometrial carcinoma cell gene expression stimulated by autocrine hGH was consistent with the altered in vitro and in vivo behavior. Functional antagonism of hGH in wild-type RL95-2 cells significantly reduced cell proliferation, cell survival, and anchorage-independent cell growth. These studies demonstrate a functional role for autocrine hGH in the development and progression of endometrial carcinoma and indicate potential therapeutic relevance of hGH antagonism in the treatment of endometrial carcinoma. PMID:18450952

  6. CXCR4 in breast cancer: oncogenic role and therapeutic targeting

    PubMed Central

    Xu, Chao; Zhao, Hong; Chen, Haitao; Yao, Qinghua

    2015-01-01

    Chemokines are 8–12 kDa peptides that function as chemoattractant cytokines and are involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled seven-span transmembrane receptors. Chemokines play a fundamental role in the regulation of a variety of cellular, physiological, and developmental processes. Their aberrant expression can lead to a variety of human diseases including cancer. C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 belongs to the superfamily of the seven transmembrane domain heterotrimeric G protein-coupled receptors and is functionally expressed on the cell surface of various types of cancer cells. CXCR4 also plays a role in the cell proliferation and migration of these cells. Recently, CXCR4 has been reported to play an important role in cell survival, proliferation, migration, as well as metastasis of several cancers including breast cancer. This review is mainly focused on the current knowledge of the oncogenic role and potential drugs that target CXCR4 in breast cancer. Additionally, CXCR4 proangiogenic molecular mechanisms will be reviewed. Strict biunivocal binding affinity and activation of CXCR4/CXCL12 complex make CXCR4 a unique molecular target for prevention and treatment of breast cancer. PMID:26356032

  7. Oncogenic potential diverge among human papillomavirus type 16 natural variants

    SciTech Connect

    Sichero, Laura; Simao Sobrinho, Joao; Lina Villa, Luisa

    2012-10-10

    We compared E6/E7 protein properties of three different HPV-16 variants: AA, E-P and E-350G. Primary human foreskin keratinocytes (PHFK) were transduced with HPV-16 E6 and E7 and evaluated for proliferation and ability to grow in soft agar. E-P infected keratinocytes presented the lowest efficiency in colony formation. AA and E-350G keratinocytes attained higher capacity for in vitro transformation. We observed similar degradation of TP53 among HPV-16 variants. Furthermore, we accessed the expression profile in early (p5) and late passage (p30) transduced cells of 84 genes commonly involved in carcinogenesis. Most differences could be attributed to HPV-16 E6/E7 expression. In particular, we detected different expression of ITGA2 and CHEK2 in keratinocytes infected with AA and AA/E-350G late passage cells, respectively, and higher expression of MAP2K1 in E-350G transduced keratinocytes. Our results indicate differences among HPV-16 variants that could explain, at least in part, differences in oncogenic potential attributed to these variants.

  8. Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas

    SciTech Connect

    Duerst, M.; Croce, C.M.; Gissmann, L.; Schwarz, E.; Huebner, K.

    1987-02-01

    The chromosomal locations of cellular sequences flanking integrated papillomavirus DNA in four cervical cell lines and a primary cervical carcinoma have been determined. The two human papillomavirus (HPV) 16 flanking sequences derived from the tumor were localized to chromosomes regions 20pter..-->..20q13 and 3p25..-->..3qter, regions that also contain the protooncogenes c-src-1 and c-raf-1, respectively. The HPV 16 integration site in the SiHa cervical carcinoma-derived cell line is in chromosome region 13q14..-->..13q32. The HPV 18 integration site in SW756 cervical carcinoma cells is in chromosome 12 but is not closely linked to the Ki-ras2 gene. Finally, in two cervical carcinoma cell lines, HeLa and C4-I, HPV 18 DNA is integrated in chromosome 8, 5' of the c-myc gene. The HeLaHPV 18 integration site is within 40 kilobases 5' of the c-myc gene, inside the HL60 amplification unit surrounding and including the c-myc gene. Additionally, steady-state levels of c-myc mRNA are elevated in HeLa and C4-I cells relative to other cervical carcinoma cell lines. Thus, in at least some genital tumors, cis-activation of cellular oncogenes by HPV may be involved in malignant transformation of cervical cells.

  9. The LMO2 oncogene regulates DNA replication in hematopoietic cells

    PubMed Central

    Sincennes, Marie-Claude; Humbert, Magali; Grondin, Benoît; Lisi, Véronique; Veiga, Diogo F. T.; Haman, André; Cazaux, Christophe; Mashtalir, Nazar; Affar, EL Bachir; Verreault, Alain; Hoang, Trang

    2016-01-01

    Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression. PMID:26764384

  10. The LMO2 oncogene regulates DNA replication in hematopoietic cells.

    PubMed

    Sincennes, Marie-Claude; Humbert, Magali; Grondin, Benoît; Lisi, Véronique; Veiga, Diogo F T; Haman, André; Cazaux, Christophe; Mashtalir, Nazar; Affar, El Bachir; Verreault, Alain; Hoang, Trang

    2016-02-02

    Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.

  11. Separase: Function Beyond Cohesion Cleavage and an Emerging Oncogene.

    PubMed

    Kumar, Ravinder

    2016-12-14

    Proper and timely segregation of genetic endowment is necessary for survival and perpetuation of every species. Mis-segregation of chromosomes and resulting aneuploidy leads to genetic instability, which can jeopardize the survival of an individual or population as a whole. Abnormality with segregation of genetic contents has been associated with several medical consequences including cancer, sterility, mental retardation, spontaneous abortion, miscarriages, and other birth related defects. Separase, by irreversible cleavage of cohesin complex subunit, paves the way for metaphase/anaphase transition during the cell cycle. Both over or reduced expression and altered level of separase have been associated with several medical consequences including cancer, as a result separase now emerges as an important oncogene and potential molecular target for medical intervenes. Recently, separase is also found to be essential in separation and duplication of centrioles. Here, I review the role of separase in mitosis, meiosis, non-canonical roles of separase, separase regulation, as a regulator of centriole disengagement, nonproteolytic roles, diverse substrates, structural insights, and association of separase with cancer. At the ends, I proposed a model which showed that separase is active throughout the cell cycle and there is a mere increase in separase activity during metaphase contrary to the common believes that separase is inactive throughout cell cycle except for metaphase. J. Cell. Biochem. 9999: 1-17, 2016. © 2016 Wiley Periodicals, Inc.

  12. Gallium-68: chemistry and radiolabeled peptides exploring different oncogenic pathways.

    PubMed

    Morgat, Clément; Hindié, Elif; Mishra, Anil K; Allard, Michèle; Fernandez, Philippe

    2013-03-01

    Abstract Early and specific tumor detection and also therapy selection and response evaluation are some challenges of personalized medicine. This calls for high sensitive and specific molecular imaging such as positron emission tomography (PET). The use of peptides for PET molecular imaging has undeniable advantages: possibility of targeting through peptide-receptor interaction, small size and low-molecular weight conferring good penetration in the tissue or at cellular level, low toxicity, no antigenicity, and possibility of wide choice for radiolabeling. Among β(+)-emitter radioelements, Gallium-68 is a very attractive positron-emitter compared with carbon-11 or fluorine-18 taking into account its easy production via a (68)Ge/(68)Ga generator and well established radiochemistry. Gallium-68 chemistry is based on well-defined coordination complexes with macrocycle or chelates having strong binding properties, particularly suitable for linking peptides that allow resistance to in vivo transchelation of the metal ion. Understanding specific and nonspecific molecular mechanisms involved in oncogenesis is one major key to develop new molecular imaging tools. The present review focuses on peptide signaling involved in different oncogenic pathways. This peptide signalization might be common for tumoral and non-tumoral processes or could be specific of an oncological process. This review describes gallium chemistry and different (68)Ga-radiolabeled peptides already in use or under development aiming at developing molecular PET imaging of different oncological processes.

  13. The Viral Interferon Regulatory Factors of KSHV: Immunosuppressors or Oncogenes?

    PubMed Central

    Jacobs, Sarah R.; Damania, Blossom

    2011-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) is a large double-stranded DNA gammaherpesvirus, and the etiological agent for three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. To establish and maintain infection, KSHV has evolved unique mechanisms to evade the host immune response. Cellular interferon regulatory factors (IRFs) are a critical part of the host anti-viral immune response. KSHV encodes four homologs of IRFs, vIRF1–4, which inhibit the activity of their cellular counterparts. vIRF1, 2, and 3 have been shown to interact directly with cellular IRFs. Additionally, the vIRFs have other functions such as modulation of Myc, p53, Notch, transforming growth factor-β, and NF-κB signaling. These activities of vIRFs may contribute to KSHV tumorigenesis. KSHV vIRF1 and vIRF3 have been implicated as oncogenes, making the understanding of KSHV vIRF function vital to understanding KSHV pathogenesis. PMID:22566809

  14. Oncogene-like induction of cellular invasion from centrosome amplification

    PubMed Central

    Godinho, Susana A.; Picone, Remigio; Burute, Mithila; Dagher, Regina; Su, Ying; Leung, Cheuk T.; Polyak, Kornelia; Brugge, Joan S.; Thery, Manuel; Pellman, David

    2014-01-01

    Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear1. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost2. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors3, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB24 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. PMID:24739973

  15. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma

    PubMed Central

    Zhao, Ling-Hao; Liu, Xiao; Yan, He-Xin; Li, Wei-Yang; Zeng, Xi; Yang, Yuan; Zhao, Jie; Liu, Shi-Ping; Zhuang, Xue-Han; Lin, Chuan; Qin, Chen-Jie; Zhao, Yi; Pan, Ze-Ya; Huang, Gang; Liu, Hui; Zhang, Jin; Wang, Ruo-Yu; Yang, Yun; Wen, Wen; Lv, Gui-Shuai; Zhang, Hui-Lu; Wu, Han; Huang, Shuai; Wang, Ming-Da; Tang, Liang; Cao, Hong-Zhi; Wang, Ling; Lee, Tin-Lap; Jiang, Hui; Tan, Ye-Xiong; Yuan, Sheng-Xian; Hou, Guo-Jun; Tao, Qi-Fei; Xu, Qin-Guo; Zhang, Xiu-Qing; Wu, Meng-Chao; Xu, Xun; Wang, Jun; Yang, Huan-Ming; Zhou, Wei-Ping; Wang, Hong-Yang

    2016-01-01

    Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation. PMID:27703150

  16. Oncogenic and mutagenic effects of UV in mammalian cells

    NASA Astrophysics Data System (ADS)

    Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

    Ultraviolet light is present in the solar system and can cause major biological effects. The potential cytotoxic, mutagenic, and carcinogenic effects of UV have been studied at cellular and molecular level. Using cultured mouse embryonic fibroblasts (C3H10T1/2), we investigated the induction of mutation and transformation by UV and/or X-rays. Studies were also done with normal human mammary epithelial cells for cell inactivation and mutation induction. Curvlinear dose-response curves were observed for mutation and oncogenic transformation. The interaction between UV and X-rays depends on the sequence of exposure. When UV was given following X-irradiation, there was an additive effect. When UV was given prior to X-irradiation, however, there was a synergistic effect for both cell inactivation and transformation. The basic lesion(s) important for somatic mutation and transformation remains to be determined, and the fundamental mechanism(s) of UV and ionizing radiation interaction remains to be elucidated.

  17. Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics.

    PubMed

    Ancrile, Brooke B; O'Hayer, Kevin M; Counter, Christopher M

    2008-02-01

    The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from an inactive GDP-bound state to an active GTP-bound state. However, in one third of human cancers, RAS is mutated and remains in the constitutively active GTP-bound state. In this oncogenic state, RAS activates a constellation of signaling that is known to promote tumorigenesis. One consequence of this oncogenic RAS signal in cancer cells is the upregulation of the cytokines interleukin (IL)-6, IL-8, and chemokine growth-regulated oncogene 1 (GRO-1). We review the evidence supporting a role for these cytokines in oncogenic RAS-driven solid tumors.

  18. ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress

    SciTech Connect

    Pauklin, Siim . E-mail: spauklin@ut.ee; Kristjuhan, Arnold; Maimets, Toivo; Jaks, Viljar

    2005-08-26

    Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, {beta}-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated in p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53.

  19. Effect of oxygenation, pH and hyperthermia on RSU-1069 in vitro and in vivo with radiation in the FSaIIC murine fibrosarcoma.

    PubMed

    Teicher, B A; Herman, T S; Holden, S A; Rudolph, M B

    1991-08-01

    We have evaluated the combination of the radiosensitizing and bioreductive alkylating agent RSU-1069 with hyperthermia and radiation in an attempt to improve the potential effectiveness of hyperthermia and radiation against locally advanced malignancies. In vitro studies in FSaIIC murine fibrosarcoma cells demonstrated that 1 h exposure to RSU-1069 was more cytotoxic toward hypoxic than normally oxygenated cells at 37 degrees C and pH 7.40 and was only minimally more cytotoxic at hyperthermic temperatures. At pH 6.45, however, RSU-1069 became significantly more toxic toward hypoxic cells and its cytotoxicity was markedly increased at hyperthermic temperatures. In contrast, the ability of this agent to radiosensitize hypoxic FSaIIC cells significantly diminished at pH 6.45. Hoechst 33342 diffusion selected FSaIIC tumor subpopulation studies revealed that hyperthermia and RSU-1069 were more toxic towards dim (hypoxic) cells, while radiation was more toxic towards bright (normally oxygenated) cells. A combination of all three modalities resulted in an equal and significant kill of hypoxic and oxygenated cells. These results suggest that the combination of RSU-1069, local hyperthermia and radiation has considerable clinical potential.

  20. Anti-tumor and anti-invasion effects of a combination of 4-methylumbelliferone and ionizing radiation in human fibrosarcoma cells

    PubMed Central

    Saga, Ryo; Monzen, Satoru; Chiba, Mitsuru; Yoshino, Hironori; Nakamura, Toshiya; Hosokawa, Yoichiro

    2017-01-01

    Hyaluronan (HA) is a major component of the extracellular matrix that is synthesized in excess in cancer tissues. 4-methylumbelliferone (MU) inhibits the synthesis of HA and is closely related to the invasion and metastasis of cancer. However, the effects of MU in conjunction with cancer radiotherapy remain unknown. The present study assessed the anti-tumor and anti-invasion effects of the concomitant use of ionizing radiation (IR) and 100 µM MU on human fibrosarcoma HT1080 cells. Cell viability and cellular invasion potency assays were performed. There was a greater decrease in the viability of cells cultured with a combination of 2 Gy IR and MU compared with untreated control cells. In addition, cell cycle distribution analysis demonstrated that a higher proportion of these cells were in the sub-G1 phase and higher fractions of annexin-V positive, propidium iodide positive cells (i.e., apoptotic cells) were observed. HA concentration in the 2 Gy irradiated culture was similar to that in the non-irradiated control culture, however, it significantly decreased following the administration of both MU alone and 2 Gy IR with MU. Furthermore, treatment with 2 Gy IR and MU resulted in a significant decrease in the invasion rate and matrix metalloproteinase (MMP)-2 and MPP-9 expression. Taken together, these results suggest that the administration of MU with 2 Gy IR is effective at reducing HA production, cell invasion and the metastatic potential of cancer cells. PMID:28123575

  1. Methanolic Fractions of Ornithogalum cuspidatum Induce Apoptosis in PC-3 Prostate Cancer Cell Line and WEHI-164 Fibrosarcoma Cancer Cell Line

    PubMed Central

    Asadi, Hamed; Orangi, Mona; Shanehbandi, Dariush; Babaloo, Zohreh; Delazar, Abbas; Mohammadnejad, Leila; Zare Shahneh, Fatemeh; Valiyari, Samira; Baradaran, Behzad

    2014-01-01

    Purpose: The present study, was aimed to assess the cytotoxic effects of Ornithogalum cuspidatum methanolic fractions on PC-3, prostate cancer cells and WEHI-164, Fibrosarcoma cells. Methods: Methanolic fractions of O. cuspidatum were prepared using solid phase extraction and the cells were treated with different concentrations for 12 and 24 hours. Cytotoxicity and cell viability were measured by MTT assay. ELISA was also employed to assess the histone-associated DNA fragments and the involvement of apoptotic mechanisms. Results: 10 and 20% fractions had not significant cytotoxic effects (p>0.05) but other fractions exerted growth inhibition on both cancer cell lines (p<0.05). After 24h of incubation with 40, 60, 80 and 100% fractions, the IC50 values were: 165, 85, 65 and 45μg/ml on PC-3 cells and 200, 96, 76 and 73μg/ml against WEHI-164 cell line, respectively. ELISA results also revealed that, both cell lines had undergone apoptosis. Conclusion: It is deduced that, 80% and 100% methanolic fractions had significant anti-proliferative and apoptotic impacts on PC-3 and WEHI-164 cells in vitro and could be considered for developing chemo-preventive substances. PMID:25364662

  2. Biological study of the effect of water soluble [N-(2-hydroxybenzyl)-L-aspartato] gallium complexes on breast carcinoma and fibrosarcoma cells.

    PubMed

    Mohsen, Ahmed; Saby, Charles; Collery, Philippe; Sabry, Gilane Mohamed; Hassan, Rasha Elsherif; Badawi, Abdelfattah; Jeannesson, Pierre; Desmaële, Didier; Morjani, Hamid

    2016-10-01

    Two water soluble gallium complexes described as [Ga(III)LCl], where L is the deprotonated form of N-2-hydroxybenzyl aspartic acid derivatives, were synthesized and characterized by (1)H NMR, (13)C NMR, FT-IR, mass spectrometry, and elemental analysis. The 2-(5-chloro-2-hydroxybenzylamino)succinic acid derivative (GS2) has been found to be a promising anticancer drug candidate. This compound was found to be more cytotoxic against human breast carcinoma MDA-MB231 and fibrosarcoma HT-1080 cell lines than the unsubstituted derivative and GaCl3. GS2 was able to induce apoptosis through downregulation of AKT phosphorylation, G2M arrest in cell cycle, and caspase 3/7 pathway. This gallium complex was found to induce an increase in mitochondrial ROS level in HT-1080 cells but not in MDA-MB231 cells. This suggests that the mechanism of action of GS2 would not be mediated by the drug-induced oxidative stress but probably by directly and indirectly inhibiting the AKT cell-signaling pathway.

  3. Radiofrequency ablation and percutaneous permanent iodine-125 implantation as salvage therapy for giant recurrent sclerosing epithelioid fibrosarcoma of the chest wall: A case report

    PubMed Central

    KE, SHAN; DING, XUE-MEI; GAO, JUN; WANG, SHAO-HONG; ZHANG, JUN; KONG, JIAN; SUN, WEN-BING

    2015-01-01

    Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft-tissue sarcoma for which there is no standardized treatment regimen available. The current treatment options for SEF are resection, radiation and chemotherapy. Surgical resection remains the mainstay of therapy for SEF. However, SEF is an aggressive tumor that is prone to repeated local recurrence if not widely excised. Radiation and chemotherapy are less commonly used due to the insensitivity of SEF to these therapies. The treatment of recurrent SEF is even more challenging. The present study describes a patient who presented with a giant recurrent SEF arising from the chest wall that was accompanied by emergent bleeding. The patient was a 70-year-old male who had multiple comorbid diseases, including hypertension and chronic cardiac dysfunction. A computed tomography (CT) scan indicated the involvement of the sternum and anterior mediastinum. However, the patient refused any further surgery. Subsequent to careful discussion and consideration, radiofrequency (RF) ablation and percutaneous iodine-125 implantation was administered. The emergent bleeding was successfully stopped and the tumor was eliminated using RF ablation. Percutaneous iodine-125 implantation under CT guidance established effective control on the growth of the tumor involving the mediastinum. Despite this, the tumor recurred 6 months after treatment. The patient refused any further treatment and was discharged. In conclusion, RF ablation and percutaneous permanent iodine-125 implantation is a feasible and safe salvage therapy for patients with recurrent SEF of the chest wall. PMID:26137032

  4. Successful treatment of an equine preputial fibrosarcoma using 5-fluorouracil/evaluation of the treatment using quantitative PCNA and Ki67 (MIB 1) immunostaining. (case report).

    PubMed

    Roels, S; Ducatelle, R; van De Vijver, B; De Kruif, A

    1998-12-01

    An 18-month-old cross-bred Fjord pony colt presenting a fibrosarcoma of the prepuce with severe infiltrative growth, was treated by topical application of 5-fluorouracil. Biopsies were taken before and after a treatment period of 2 months. As a control, preputial tissue from a healthy horse was biopsied. Tissue sections were stained immunohistochemically for Proliferating Cell Nuclear Antigen (PCNA) and Proliferation related factor--Ki67 (MIB1). Using computerized quantitative image analysis of these sections, Mitotic index (PCNA), Growth Fraction (Ki67) and total nuclear area percentage of the dermis were calculated. The Mitotic index, growth fraction and total nuclear area percentage were significantly (P < 0.001) reduced at the end of the treatment period compared to the initial biopsy tissue, but they still were significantly higher than the control values, due to a remnant inflammatory reaction to the cytostatic drug. After treatment of the lesion, the pony fully recovered with no visible residual lesions on the prepuce. On follow-up 6 months after treatment, the horse showed no signs of recurrence. The success of the present treatment should encourage further clinical trials in cases of malignant fibrous tumours of skin in horses. The quantitative analysis of cell proliferation in biopsies can be used to evaluate treatment follow-up.

  5. Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.

    PubMed

    Ondondo, Beatrice; Jones, Emma; Hindley, James; Cutting, Scott; Smart, Kathryn; Bridgeman, Hayley; Matthews, Katherine K; Ladell, Kristin; Price, David A; Jackson, David G; Godkin, Andrew; Ager, Ann; Gallimore, Awen

    2014-05-01

    The tumor microenvironment comprises newly formed blood and lymphatic vessels which shape the influx, retention and departure of lymphocytes within the tumor mass. Thus, by influencing the intratumoral composition of lymphocytes, these vessels affect the manner in which the adaptive immune system responds to the tumor, either promoting or impairing effective antitumor immunity. In our study, we utilized a mouse model of carcinogen-induced fibrosarcoma to examine the composition of tumor-infiltrating lymphocytes during tumor progression. In particular, we sought to determine whether CD4(+) Foxp3(+) regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor-driven immunosuppression. This was not the case as the proportion of Tregs and effector CD4(+) T cells actually declined within the tumor owing to the unexpected accumulation of naïve T cells. However, we found no evidence for antigen-driven migration of these T cells or for their participation in an antitumor immune response. Our data support the notion that lymphocytes can enter tumors via aberrantly formed blood and lymphatic vessels. Such findings suggest that targeting both the tumor vasculature and lymphatics will alter the balance of lymphocyte subpopulations that enter the tumor mass. A consideration of this aspect of tumor immunology may be critical to the success of solid cancer immunotherapies.

  6. Inhibition of the expression on MMP-2, 9 and morphological changes via human fibrosarcoma cell line by 6,6'-bieckol from marine alga Ecklonia cava.

    PubMed

    Zhang, Chen; Li, Yong; Shi, Xiujuan; Kim, Se-kwon

    2010-01-01

    Matrix Metalloproteinases (MMPs) are a family of zinc-endopeptidases which can degrade extracellular matrix (ECM) components and play important roles in a variety of biological and pathological processes. 6,6'-bieckol isolated and characterized from an edible marine brown alga Ecklonia cava (EC), according to the comprehensive spectral analysis of MS and NMR data. Here the influence of 6,6'-bieckol on expressions of MMPs was examined by zymography and western blot analysis via human fibrosarcoma cell line (HT1080). It is shown that 6,6'-bieckol significantly down regulated the expressions of MMP-2 and -9 in dose-dependent manner. The influence of 6,6'-bieckol on the cell viability and cell behavior of HT1080 cells were also investigated, our dates shown that it suppressed the migration and 3D culture in HT1080 cells. Meanwhile, we explored several signal pathways which may contribute to this process, and found the suppressing of MMPs expressions in HT1080 cells might be due to the suppression of NF-kappaB signal pathway. [BMB reports 2010; 43(1): 62-68].

  7. 5-Azacytidine regulates matrix metalloproteinase-9 expression, and the migration and invasion of human fibrosarcoma HT1080 cells via PI3-kinase and ERK1/2 pathways.

    PubMed

    Yu, Seon-Mi; Kim, Song Ja

    2016-09-01

    Abnormal methylation of promoter CpG islands is one of the hallmarks of cancer cells, and is catalyzed by DNA methyltransferases. 5-azacytidine (5-aza C), a methyltransferase inhibitor, can cause demethylation of promoter regions of diverse genes. Epigenetic processes contribute to the regulation of matrix metalloproteinase (MMP) expression. However, little is known about the mechanisms and effects of 5-aza C on the invasive and migratory capacities of human fibrosarcoma HT1080 cells. In the present study, we found that 5-aza C induces MMP-9 activity, as determined by zymography. HT1080 cell proliferation was determined following 5-aza C administration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle was examined by flow cytometry. 5-aza C treatment inhibited cell proliferation without affecting cell viability. Furthermore, 5-aza C significantly promoted migration and invasion of HT1080 cells. 5-aza C treatment enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and phosphoinositide (PI)3-kinase/Akt, and their inhibitors blocked MMP-9 activity induction, and cellular invasion and migration. Together, these findings suggest that promoter methylation may be one of the mechanisms modulating MMP-9 levels in HT1080 cells, and that 5-aza C-induced MMP-9 production is associated with the activation of ERK and PI3-kinase/Akt signaling pathways.

  8. Down-regulation of phosphoglucose isomerase/autocrine motility factor expression sensitizes human fibrosarcoma cells to oxidative stress leading to cellular senescence.

    PubMed

    Funasaka, Tatsuyoshi; Hu, Huankai; Hogan, Victor; Raz, Avraham

    2007-12-14

    Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is a housekeeping gene product present in all cells, is an essential enzyme of catabolic glycolysis and anabolic gluconeogenesis, and regulates tumor cell growth and metastasis. Because glycolytic enzyme up-regulation of expression contributes to glycolytic flux, leading to increased of cell growth and a resistance to cellular stress of normal fibroblasts whereas down-regulation of PGI/AMF leads to mesenchymal-to-epithelial transition in tumor cells, we examined the involvement of PGI/AMF in overcoming cellular senescence in cancer cells. PGI/AMF cellular expression in HT1080 human fibrosarcoma was down-regulated by small interfering RNA methodology, which resulted in an increased sensitivity to oxidative stress and oxidative stress-induced cellular senescence. Signaling analysis revealed that the senescence pathway involving p21 cyclin-dependent kinase inhibitor was up-regulated in PGI/AMF knockdown cells and that superoxide dismutase is the upstream regulator protein of p21-mediated cellular senescence. A specific inhibitor of PGI/AMF induced cellular senescence and p21 expression in tumor cells exposed to an oxidative stress environment. Taken together, the results presented here suggest that PGI/AMF is involved in oxidative stress-induced cellular senescence and should bring novel insights into the control of cellular growth leading to a new methodology for cancer treatment.

  9. Epinecidin-1, an antimicrobial peptide from fish (Epinephelus coioides) which has an antitumor effect like lytic peptides in human fibrosarcoma cells.

    PubMed

    Lin, Wei-Ju; Chien, Yi-Lun; Pan, Chia-Yu; Lin, Tai-Lang; Chen, Jyh-Yih; Chiu, Shu-Jun; Hui, Cho-Fat

    2009-02-01

    Epinecidin-1, a synthetic 21-mer antimicrobial peptide originally identified from grouper (Epinephelus coioides), specifically exhibited high antimicrobial activities against both Gram-negative and Gram-positive bacteria. In the current study we report on the in vitro cytotoxicity of the peptide, an important factor before it can be considered for further applications in cancer therapy. The cytotoxicity of epinecidin-1 was investigated against several cancer cells (A549, HA59T/VGH, HeLa, HepG2, HT1080, RAW264.7, and U937) and normal cells (AML-12, NIH3T3, and WS-1) with the MTT assay, and the inhibition of cancer cell growth was confirmed by a soft agar assay and scanning electron microscopy. However, cell variations were detected with AO/EtBr staining, while apoptosis and necrosis gene expressions in HT1080 cells after treatment with the epinecidin-1 peptide and Nec-1 showed that epinecidin-1 had an anti-necrosis function in HT1080 cells. The data presented here indicate that epinecidin-1 has in vitro antitumor activity against the HT1080 cell line, and functions like lytic peptides. In addition, our results suggest that epinecidin-1 may prove to be an effective chemotherapeutic agent for human fibrosarcoma cells in the future.

  10. 3-Methyladenine suppresses cell migration and invasion of HT1080 fibrosarcoma cells through inhibiting phosphoinositide 3-kinases independently of autophagy inhibition.

    PubMed

    Ito, Shingo; Koshikawa, Nobuko; Mochizuki, Shigenobu; Takenaga, Keizo

    2007-08-01

    3-Methyladenine (3-MA) inhibits class III phosphoinositide 3-kinase (PI3K) and is widely used as an inhibitor of autophagy. 3-MA has also been shown to stimulate cell death of tumor cells under nutrient-starved conditions by inhibiting autophagy. To explore the possibility of this type of autophagy inhibitors as anticancer drugs, we examined the effects of 3-MA on the phenotypes of highly metastatic human fibrosarcoma HT1080 cells. We report here that although 3-MA did not markedly affect cell survival of the cells under either normal or amino acid-starved conditions, it strongly inhibited the invasiveness of the cells. 3-MA rapidly suppressed actin rich membrane ruffle and/or lamellipodia formation under normal conditions, leading to inhibition of cell migration and invasion of the cells without substantial inhibitions of small GTPase Rac activity and the production of matrix metalloproteinases MMP-2 and MMP-9. 3-MA abolished class I and class II PI3Ks in in vitro lipid kinase assays, and suppressed cell motility of the cells more strongly than the other PI3K inhibitors wortmannin and LY294002. Downregulation of Beclin 1, a protein required for autophagic body formation, by transfection of Beclin 1 siRNA did not inhibit membrane ruffle formation and cell migration. These results suggest that 3-MA suppresses the invasion of HT1080 cells, independently of autophagy inhibition, through inhibition of type I and II PI3Ks and possibly other molecules.

  11. Canthin-6-one alkaloids and a tirucallanoid from Eurycoma longifolia and their cytotoxic activity against a human HT-1080 fibrosarcoma cell line.

    PubMed

    Miyake, Katsunori; Tezuka, Yasuhiro; Awale, Suresh; Li, Feng; Kadota, Shigetoshi

    2010-01-01

    Phytochemical investigation of the stems of Eurycoma longifolia Jack led to the isolation of two new canthin-6-one alkaloids, 4,9-dimethoxycanthin-6-one (1) and 10-hydroxy-11-methoxycanthin-6-one (2), and a new tirucallane-type triterpenoid, 23,24,25-trihydroxytirucall-7-en-3,6-dione (3), along with 37 known compounds. Among these, an oxasqualenoid (4) was isolated as a natural product for the first time. The structures of the isolates were elucidated by spectroscopic and mass spectrometric means. All the isolates were evaluated for their cytotoxic activity against a HT-1080 human fibrosarcoma cell line. Among them, 9,10-dimethoxycanthin-6-one (14, IC50 = 5.0 microM), 10-hydroxy-9-methoxycanthin-6-one (15, IC50 = 7.2 microM), dihydroniloticin (18, IC50 = 8.2 microM), and 14-deacetyleurylene (34, IC50 = 3.2 microM) displayed stronger activity than the positive control 5-FU (IC50 = 9.2 microM).

  12. Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dismutase

    PubMed Central

    Okada, F; Shionoya, H; Kobayashi, M; Kobayashi, T; Tazawa, H; Onuma, K; Iuchi, Y; Matsubara, N; Ijichi, T; Dugas, B; Hosokawa, M

    2006-01-01

    Weakly tumorigenic and nonmetastatic QR-32 cells derived from a fibrosarcoma in C57BL6 mouse are converted to malignant cells once they have grown after being coimplanted with a gelatine sponge which induces inflammation. We administered a newly developed peroral superoxide dismutase (SOD), oxykine, and as control vehicle, gliadin and saline, starting 2 days before the coimplantation and continued daily throughout the experiment. In the oxykine group, tumour incidence was lower (41%) than in the gliadin or saline group (83 and 79%, respectively). The inhibitory effect of oxykine was lost when an individual component of oxykine was administered, that is, SOD alone and gliadin alone. The effect was also abolished when administered by intraperitoneal route. When perfused in situ with nitroblue tetrazolium, an indicator of superoxide formation, the tumour masses from gliadin and saline groups displayed intense formazan deposition, whereas, those from oxykine group had less deposition. Enzymatic activity of SOD was also increased in oxykine group. Arising tumour cells in gliadin and saline groups acquired metastatic phenotype, but those in oxykine group showed reduced metastatic ability. These results suggested that the orally active SOD derivative prevented tumour progression promoted by inflammation, which is thought to be through scavenging inflammatory cell-derived superoxide anion. PMID:16508635

  13. A novel rat fibrosarcoma cell line from transformed bone marrow-derived mesenchymal stem cells with maintained in vitro and in vivo stemness properties.

    PubMed

    Wang, Meng-Yu; Nestvold, Janne; Rekdal, Øystein; Kvalheim, Gunnar; Fodstad, Øystein

    2017-02-09

    Increasing evidence suggests a possible relationship between mesenchymal stem cells (MSCs) and sarcoma. MSCs are hypothesized to be the cells initiating sarcomagenesis, and cancer stem cells (CSCs) sharing features of MSCs have been identified in sarcomas. Here, we report on the characteristics of a bone marrow-derived rat mesenchymal stem cell line that spontaneously transformed in long-term culture. The rat transformed mesenchymal stem cells (rTMSCs) produced soft-tissue fibrosarcomas in immunocompromised mice and immunocompetent rats. In vitro, the rTMSCs displayed increased proliferation capacity compared to the untransformed cell line. The transformed MSCs maintained the mesenchymal phenotype by expression of the stem cell marker CD 90 and the lack of hematopoietic and endothelial markers. Cytogenetic analysis detected trisomy 6 in the rTMSCs. Side population (SP) isolation and tumorsphere cultivation of the transformed cells confirmed the presence of CSCs among the rTMSCs. Importantly, the rTMSCs retained their differentiation capacity towards osteogenic and adipogenic lineages. This transformed MSC-based cell line may be valuable in examining the balance in a mixed cell population between cancer stem cell properties and the ability to differentiate to specific non-transformed cell populations. Moreover, it may also be a useful tool to evaluate the efficacy of novel targeted immunotherapies in vivo.

  14. Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment

    PubMed Central

    Martinez-Outschoorn, Ubaldo E; Curry, Joseph M; Ko, Ying-Hui; Lin, Zhao; Tuluc, Madalina; Cognetti, David; Birbe, Ruth C; Pribitkin, Edmund; Bombonati, Alessandro; Pestell, Richard G; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2013-01-01

    Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of “normal” and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the “bystander” effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for “metabolic symbiosis” between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial “lactate-shuttle”, to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as “partners” for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an “MCT4

  15. Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression

    DTIC Science & Technology

    2016-10-01

    pathway that correlates with motility and metastasis. Based on our preliminary data, PKCε overexpression and Pten loss individually and synergically confer...AWARD NUMBER: W81XWH-14-1-0535 TITLE: Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression PRINCIPAL...Sep 2015 - 29 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer

  16. In Vivo p53 Signaling in Breast Epithelial Cells After Oncogenic Stimulus

    DTIC Science & Technology

    2004-09-01

    AD Award Number: DAMD17-02-1-0605 TITLE: In Vivo p53 Signaling in Breast Epithelial Cells After Oncogenic Stimulus PRINCIPAL INVESTIGATOR: Jamie M...SUBTITLE 5. FUNDING NUMBERS In Vivo p53 Signaling in Breast Epithelial Cells After DAMD17-02-1-0605 Oncogenic Stimulus 6. A UTHOR(S) Jamie M. Hearnes...NUMBER Atlanta, Georgia 31192-0303 E-Mail: Jamie . hearnes@vanderbilt. edu 9. SPONSORING / MONITORING 10. SPONSORING / MONITORING AGENCY NAME(S) AND

  17. Determining the Function of the fps/fes Proto-oncogene in Breast Development and Malignancy

    DTIC Science & Technology

    2005-06-01

    8-98) Prescribed by ANSI Std. Z39.18 Abstract The fps/fes proto-oncogene encodes a 92 kDa protein tyrosine kinase. To understand the physiological...mammary tissue has revealed that Fps (and Fer) interact with protein components of the E- cadherin based adherens junction complex. Specifically, E...Introduction: The fps/fes proto-oncogene encodes a 92 kDa protein tyrosine kinase. To understand the biological

  18. Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.

    PubMed

    Tanaka, Kosuke; Hida, Toyoaki; Oya, Yuko; Yoshida, Tatsuya; Shimizu, Junichi; Mizuno, Tetsuya; Kuroda, Hiroaki; Sakakura, Noriaki; Yoshimura, Kenichi; Horio, Yoshitsugu; Sakao, Yukinori; Yatabe, Yasushi

    2017-05-15

    Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood. Conversely, it has been demonstrated that young age at diagnosis defines unique biology in other cancers. For this report, the effects of young age on lung adenocarcinoma are reported. The authors retrospectively screened 1746 consecutive patients who were diagnosed with stage I through IV adenocarcinoma between 2009 and 2015 and identified 81 who were aged 40 years or younger at diagnosis. The clinical and genetic characteristics of this younger population were analyzed. Of the 81 younger patients identified, 36 (44%) were men, 36 (44%) were never smokers, and the median age was 36 years (range, 26-40 years). Thirty-three patients (41%) harbored anaplastic lymphoma kinase (ALK) translocations, 24 (30%) had epidermal growth factor receptor (EGFR) mutations, and 2 (2%) had v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Rare oncogenic GAs also were studied in patients who had wild-type ALK/EGFR/KRAS adenocarcinoma, including 4 patients with HER2 mutations, 2 with Ret proto-oncogene (RET) translocations, and 2 with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translocations. Notably, oncogenic GAs (P < .001), ALK (P < .001) and ROS1 (P = .033) translocations, and HER2 mutations (P < .001) were associated with young age, and a similar trend was observed for RET translocations (P = .108). Younger patients who had adenocarcinoma without GAs had a significantly worse prognosis compared with older patients without GAs (overall survival, 8.9 vs 16.4 months; P < .001) and patients with GAs (24.9 months; P < .001). Younger patients with adenocarcinoma have a distinctly unique prevalence of oncogenic GAs. Comprehensive oncogenic GA screening is especially recommended for personalized medicine strategies in this population. Cancer 2017;123:1731-1740. © 2017 American Cancer

  19. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    DTIC Science & Technology

    2011-06-01

    phenotype. Oncogenes, such as Her2 , play important roles in uncontrolled proliferation and survival of breast cancer cells. However, cancer cells must...transforming roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast cancer have not been elucidated. In this... signaling in aggressive forms of human breast cancer . Accordingly, we propose that ERLIN2 represents a novel class of oncogenic factors and that

  20. Dana Farber Cancer Institute: Discovery of Novel Oncogenes | Office of Cancer Genomics

    Cancer.gov

    Widespread recurrent copy number alterations are observed across the majority of human cancers, yet the specific targets of such amplified or deleted regions remain undefined. Here, the CTD2 Center at the Dana Farber Cancer Institute took a systematic approach using cDNA overexpression screening to identify and validate oncogenes residing in such amplified regions. In representative examples, these experiments have identified the adaptor proteins CRKL, GAB2, FRS2 and the TLOC and SKIL proteins as novel amplified oncogenes.

  1. Translation Start Sequences Affect the Efficiency of Silencing of Agrobacterium tumefaciens T-DNA Oncogenes1

    PubMed Central

    Lee, Hyewon; Humann, Jodi L.; Pitrak, Jennifer S.; Cuperus, Josh T.; Parks, T. Dawn; Whistler, Cheryl A.; Mok, Machteld C.; Ream, L. Walt

    2003-01-01

    Agrobacterium tumefaciens oncogenes cause transformed plant cells to overproduce auxin and cytokinin. Two oncogenes encode enzymes that convert tryptophan to indole-3-acetic acid (auxin): iaaM (tryptophan mono-oxygenase) and iaaH (indole-3-acetamide hydrolase). A third oncogene (ipt) encodes AMP isopentenyl transferase, which produces cytokinin (isopentenyl-AMP). Inactivation of ipt and iaaM (or iaaH) abolishes tumorigenesis. Because adequate means do not exist to control crown gall, we created resistant plants by introducing transgenes designed to elicit posttranscriptional gene silencing (PTGS) of iaaM and ipt. Transgenes that elicit silencing trigger sequence-specific destruction of the inducing RNA and messenger RNAs with related sequences. Although PTGS has proven effective against a variety of target genes, we found that a much higher percentage of transgenic lines silenced iaaM than ipt, suggesting that transgene sequences influenced the effectiveness of PTGS. Sequences required for oncogene silencing included a translation start site. A transgene encoding a translatable sense-strand RNA from the 5′ end of iaaM silenced the iaaM oncogene, but deletion of the translation start site abolished the ability of the transgene to silence iaaM. Silencing A. tumefaciens T-DNA oncogenes is a new and effective method to produce plants resistant to crown gall disease. PMID:12972655

  2. Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis.

    PubMed

    Mou, Haiwei; Moore, Jill; Malonia, Sunil K; Li, Yingxiang; Ozata, Deniz M; Hough, Soren; Song, Chun-Qing; Smith, Jordan L; Fischer, Andrew; Weng, Zhiping; Green, Michael R; Xue, Wen

    2017-04-04

    Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically up-regulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles' heel in tumors initiated by oncogenic Kras.

  3. Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells

    PubMed Central

    Hollenhorst, Peter C.; Ferris, Mary W.; Hull, Megan A.; Chae, Heejoon; Kim, Sun; Graves, Barbara J.

    2011-01-01

    The aberrant expression of an oncogenic ETS transcription factor is implicated in the progression of the majority of prostate cancers, 40% of melanomas, and most cases of gastrointestinal stromal tumor and Ewing's sarcoma. Chromosomal rearrangements in prostate cancer result in overexpression of any one of four ETS transcription factors. How these four oncogenic ETS genes differ from the numerous other ETS genes expressed in normal prostate and contribute to tumor progression is not understood. We report that these oncogenic ETS proteins, but not other ETS factors, enhance prostate cell migration. Genome-wide binding analysis matched this specific biological function to occupancy of a unique set of genomic sites highlighted by the presence of ETS- and AP-1-binding sequences. ETS/AP-1-binding sequences are prototypical RAS-responsive elements, but oncogenic ETS proteins activated a RAS/MAPK transcriptional program in the absence of MAPK activation. Thus, overexpression of oncogenic ETS proteins can replace RAS/MAPK pathway activation in prostate cells. The genomic description of this ETS/AP-1-regulated, RAS-responsive, gene expression program provides a resource for understanding the role of these ETS factors in both an oncogenic setting and the developmental processes where these genes normally function. PMID:22012618

  4. State of the art address oncogenes and tumor-suppressing genes

    SciTech Connect

    Frazier, M.E.

    1989-05-01

    Cancer has a myriad of causes but, whatever the cause, the changes that result in neoplasia are usually genetic. Although not all DNA damage results in cancer, evidence implicates two broad classes of genes in carcinogenesis. The first class, oncogenes are genes that cause cancer. An oncogene results when there is increased and/or changed expression of the proto-oncogene. Oncogenes are dominant: when activated, they predominate over the activity of any normal alleles in the cell. Thus oncogenes act directly to cause cancer. The second class of genes associated with cancer are tumor-suppressing genes, which either code directly for, or control expression of a wide spectrum of tissue-specific differentiation antigens. Malignancy occurs in a specific cell type when expression of an appropriate tumor-suppressing gene is, homozygously, seriously distorted or completely lacking. Tumor suppressing genes also appear to regulate expression of a third, uncharacterized group of cancer-related genes that act in a recessive manner and are not expressed in the presence of the tumor-suppressing genes. We will first discuss oncogenes, then the tumor-suppressing genes. Experimental data will be used to illustrate key features of the carcinogenic process.

  5. The transcription factor LSF: a novel oncogene for hepatocellular carcinoma

    PubMed Central

    Santhekadur, Prasanna K; Rajasekaran, Devaraja; Siddiq, Ayesha; Gredler, Rachel; Chen, Dong; Schaus, Scott E; Hansen, Ulla; Fisher, Paul B; Sarkar, Devanand

    2012-01-01

    The transcription factor LSF (Late SV40 Factor), also known as TFCP2, belongs to the LSF/CP2 family related to Grainyhead family of proteins and is involved in many biological events, including regulation of cellular and viral promoters, cell cycle, DNA synthesis, cell survival and Alzheimer’s disease. Our recent studies establish an oncogenic role of LSF in Hepatocellular carcinoma (HCC). LSF overexpression is detected in human HCC cell lines and in more than 90% cases of human HCC patients, compared to normal hepatocytes and liver, and its expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic and multi-organ metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance and senescence. LSF transcriptionally regulates thymidylate synthase (TS) gene, thus contributing to cell cycle regulation and chemoresistance. Our studies identify a network of proteins, including osteopontin (OPN), Matrix metalloproteinase-9 (MMP-9), c-Met and complement factor H (CFH), that are directly regulated by LSF and play important role in LSF-induced hepatocarcinogenesis. A high throughput screening identified small molecule inhibitors of LSF DNA binding and the prototype of these molecules, Factor Quinolinone inhibitor 1 (FQI1), profoundly inhibited cell viability and induced apoptosis in human HCC cells without exerting harmful effects to normal immortal human hepatocytes and primary mouse hepatocytes. In nude mice xenograft studies, FQI1 markedly inhibited growth of human HCC xenografts as well as angiogenesis without exerting any toxicity. These studies establish a key role of LSF in hepatocarcinogenesis and usher in a

  6. Immunoprevention of Chemical Carcinogenesis through Early Recognition of Oncogene Mutations

    PubMed Central

    Nasti, Tahseen H.; Rudemiller, Kyle J.; Cochran, J. Barry; Kim, Hee Kyung; Tsuruta, Yuko; Fineberg, Naomi S.; Athar, Mohammad

    2015-01-01

    Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), often harbor an H-ras point mutation, suggesting that it is a poor target for early immunosurveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as 1 d after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope–specific CTLs capable of eliminating Mut H-ras+ preneoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective owing to insufficient effector pool size and/or immunosuppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I epitope–focused lentivector-infected dendritic cell– and DNA-based vaccines were designed to bias toward CTL rather than regulatory T cell induction. Mut H-ras, but not wild-type H-ras, epitope-focused vaccination generated specific CTLs and inhibited DMBA-induced tumor initiation, growth, and progression in preventative and therapeutic settings. Transferred Mut H-ras–specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor-bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes in expanding relevant immunosurveillance effectors to block tumor formation, rather than treating established tumors. PMID:25694611

  7. Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

    PubMed Central

    Bottai, Giulia; Kelly, Catherine M.; Győrffy, Balázs; Székely, Borbala

    2016-01-01

    Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%–20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs. Implications for Practice: Next-generation sequencing is now widely available in the clinic, but interpretation of the results is challenging, and its impact on treatment selection is often limited. This work provides an overview of frequently encountered molecular abnormalities in breast cancer and discusses their potential therapeutic implications. This review emphasizes the importance of administering investigational targeted therapies, or off-label use of approved targeted drugs, in the context of a formal clinical trial or registry programs to facilitate learning about the clinical

  8. Human papillomavirus DNA and oncogene alterations in colorectal tumors.

    PubMed

    Pérez, Luis Orlando; Barbisan, Gisela; Ottino, Anabel; Pianzola, Horacio; Golijow, Carlos Daniel

    2010-09-01

    The aim of the present study is to determine the presence and molecular integrity of high-risk HPV types in colorectal adenocarcinomas and to assess whether viral DNA is related to common proto-oncogene alterations, such as k-ras mutations and c-myc gene amplification, in colorectal cancer. Seventy-five colorectal adenocarcinomas were screened for HPV infection using nested-PCR (MY09/11-GP5+/6+). HPV typing was performed by type-specific PCR for HPV 16 and HPV 18 DNA. Unidentified samples were subsequently sequenced to determine the viral genotype. The physical status of HPV was determined by a nested PCR approach for type-specific E2 sequences. C-myc amplification was assessed by co-amplification with β-globin as control locus, and mutation in k-ras codons 12 and 13 by ARMS-PCR. Overall, HPV was detected in thirty-three colorectal specimens (44%). HPV 16 was the prevalent type (16/75), followed by HPV 18 (15/75), HPV 31 (1/75) and HPV 66 (1/75). E2 disruption was detected in 56.3% of HPV 16 and in 40% of HPV 18 positive tumors. C-myc amplification was detected in 29.4% of cases, while k-ras mutations in 30.7%. There was no significant trend for HPV infection in tumors harboring either k-ras or c-myc alterations. This study demonstrates HPV DNA and viral integration in colorectal tumors, suggesting a potential role of this virus in colorectal carcinogenesis. There was no concurrence, however, of k-ras and c-myc activation with viral infection.

  9. Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

    PubMed Central

    Paugh, Barbara S.; Zhu, Xiaoyan; Qu, Chunxu; Endersby, Raelene; Diaz, Alexander K.; Zhang, Junyuan; Bax, Dorine A.; Carvalho, Diana; Reis, Rui M.; Onar-Thomas, Arzu; Broniscer, Alberto; Wetmore, Cynthia; Zhang, Jinghui; Jones, Chris; Ellison, David W.; Baker, Suzanne J.

    2013-01-01

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. PMID:23970477

  10. Spi-1, Fli-1 and Fli-3 (miR-17-92) oncogenes contribute to a single oncogenic network controlling cell proliferation in friend erythroleukemia.

    PubMed

    Kayali, Samer; Giraud, Guillaume; Morlé, François; Guyot, Boris

    2012-01-01

    Clonal erythroleukemia developing in susceptible mice infected by Friend virus complex are associated with highly recurrent proviral insertions at one of three loci called Spi-1, Fli-1 or Fli-3, leading to deregulated expression of oncogenic Spi-1 or Fli-1 transcription factors or miR-17-92 miRNA cluster, respectively. Deregulated expression of each of these three oncogenes has been independently shown to contribute to cell proliferation of erythroleukemic clones. Previous studies showed a close relationship between Spi-1 and Fli-1, which belong to the same ETS family, Spi-1 activating fli-1 gene, and both Spi-1 and Fli-1 activating multiple common target genes involved in ribosome biogenesis. In this study, we demonstrated that Spi-1 and Fli-1 are also involved in direct miR-17-92 transcriptional activation through their binding to a conserved ETS binding site in its promoter. Moreover, we demonstrated that physiological re-expression of exogenous miR-17 and miR-20a are able to partially rescue the proliferation loss induced by Fli-1 knock-down and identified HBP1 as a target of these miRNA in erythroleukemic cells. These results establish that three of the most recurrently activated oncogenes in Friend erythroleukemia are actually involved in a same oncogenic network controlling cell proliferation. The putative contribution of a similar ETS-miR-17-92 network module in other normal or pathological proliferative contexts is discussed.

  11. Spi-1, Fli-1 and Fli-3 (miR-17-92) Oncogenes Contribute to a Single Oncogenic Network Controlling Cell Proliferation in Friend Erythroleukemia

    PubMed Central

    Kayali, Samer; Giraud, Guillaume; Morlé, François; Guyot, Boris

    2012-01-01

    Clonal erythroleukemia developing in susceptible mice infected by Friend virus complex are associated with highly recurrent proviral insertions at one of three loci called Spi-1, Fli-1 or Fli-3, leading to deregulated expression of oncogenic Spi-1 or Fli-1 transcription factors or miR-17-92 miRNA cluster, respectively. Deregulated expression of each of these three oncogenes has been independently shown to contribute to cell proliferation of erythroleukemic clones. Previous studies showed a close relationship between Spi-1 and Fli-1, which belong to the same ETS family, Spi-1 activating fli-1 gene, and both Spi-1 and Fli-1 activating multiple common target genes involved in ribosome biogenesis. In this study, we demonstrated that Spi-1 and Fli-1 are also involved in direct miR-17-92 transcriptional activation through their binding to a conserved ETS binding site in its promoter. Moreover, we demonstrated that physiological re-expression of exogenous miR-17 and miR-20a are able to partially rescue the proliferation loss induced by Fli-1 knock-down and identified HBP1 as a target of these miRNA in erythroleukemic cells. These results establish that three of the most recurrently activated oncogenes in Friend erythroleukemia are actually involved in a same oncogenic network controlling cell proliferation. The putative contribution of a similar ETS-miR-17-92 network module in other normal or pathological proliferative contexts is discussed. PMID:23056458

  12. Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer.

    PubMed

    Burns, Timothy F; Dobromilskaya, Irina; Murphy, Sara C; Gajula, Rajendra P; Thiyagarajan, Saravanan; Chatley, Sarah N H; Aziz, Khaled; Cho, Yoon-Jae; Tran, Phuoc T; Rudin, Charles M

    2013-04-01

    A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK-driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene-driven NSCLCs. We recently showed that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation-driven and c-Met-amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs represents a novel and promising therapeutic strategy.

  13. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer.

    PubMed

    Hedayati, Mehdi; Zarif Yeganeh, Marjan; Sheikholeslami, Sara; Afsari, Farinaz

    2016-08-01

    Thyroid cancer is the most common endocrine malignancy and accounts for nearly 1% of all of human cancer. Thyroid cancer has four main histological types: papillary, follicular, medullary, and anaplastic. Papillary, follicular, and anaplastic thyroid carcinomas are derived from follicular thyroid cells, whereas medullary thyroid carcinoma (MTC) originates from the neural crest parafollicular cells or C-cells of the thyroid gland. MTC represents a neuroendocrine tumor and differs considerably from differentiated thyroid carcinoma. MTC is one of the aggressive types of thyroid cancer, which represents 3-10% of all thyroid cancers. It occurs in hereditary (25%) and sporadic (75%) forms. The hereditary form of MTC has an autosomal dominant mode of inheritance. According to the present classification, hereditary MTC is classified as a multiple endocrine neoplasi type 2 A & B (MEN2A & MEN2B) and familial MTC (FMTC). The RET proto-oncogene is located on chromosome 10q11.21. It is composed of 21 exons and encodes a transmembrane receptor tyrosine kinase. RET regulates a complex network of signal transduction pathways during development, survival, proliferation, differentiation, and migration of the enteric nervous system progenitor cells. Gain of function mutations in RET have been well demonstrated in MTC development. Variants of MTC result from different RET mutations, and they have a good genotype-phenotype correlation. Various MTC related mutations have been reported in different exons of the RET gene. We proposed that RET genetic mutations may be different in distinct populations. Therefore, the aim of this study was to find a geographical pattern of RET mutations in different populations.

  14. The roles of oncogenic miRNAs and their therapeutic importance in breast cancer.

    PubMed

    O'Bryan, Samia; Dong, Shengli; Mathis, J Michael; Alahari, Suresh K

    2017-02-01

    Since the discovery of tumour suppressive miRNA in 2002, the dysregulation of miRNAs was implicated in many cancers, exhibiting both tumour suppressive and oncogenic roles. Dysregulation of miRNAs was found to be involved in the initiation of oncogenesis, as well as the progression, invasion and metastasis of cancers. While normal miRNA inhibitory functions help regulate gene expression in the cell, oncogenic miRNA, when dysregulated can lead to suppression of critical pathways that control apoptosis, cell cycle progression, growth and proliferation. This suppression allows for the upregulation of pro-oncogenic factors that drive cell survival, growth and proliferation. Due to emerging discoveries, oncogenic miRNAs are proving to be a critical component in cancers, such as breast cancer, and may provide novel avenues for cancer treatment. In this article, we discuss the roles of the most studied oncogenic miRNAs in breast cancer including clusters and families involved as well as the less studied and recently discovered oncogenic miRNAs. These miRNAs provide valuable information into the complexity of regulatory elements affected by their overexpression and the overall impact in the progression of breast cancer. Also, identifying miRNAs causing or leading to resistance or sensitivity to current anti-cancer drugs prior to treatment may lead to an improvement in treatment selection and overall patient response. This review summarizes known and recently discovered miRNAs in literature found to have oncogenic roles in breast cancer initiation and the progression, invasion and metastasis of the disease.

  15. Targeting the function of the HER2 oncogene in human cancer therapeutics

    PubMed Central

    Moasser, Mark M.

    2011-01-01

    The year 2007 marks exactly two decades since HER2 was functionally implicated in the pathogenesis of human breast cancer (Slamon et al. 1987). This finding established the HER2 oncogene hypothesis for the development of some human cancers. An abundance of experimental evidence compiled over the past two decades now solidly supports the HER2 oncogene hypothesis. A direct consequence of this hypothesis was the promise that inhibitors of oncogenic HER2 would be highly effective treatments for HER2-driven cancers. This treatment hypothesis has led to the development and widespread use of anti-HER2 antibodies (trastuzumab) in clinical management resulting in significantly improved clinical anti-tumor efficacies that have transformed the clinical practice of oncology. In the shadows of this irrefutable clinical success, scientific studies have not yet been able to mechanistically validate that trastuzumab inhibits oncogenic HER2 function and it remains possible that the current clinical advances are a consequence of the oncogene hypothesis but not a translation of it. These looming scientific uncertainties suggest that the full promise of the treatment hypothesis may not yet have been realized. The coming decade will see a second generation of HER2 targeting agents brought into clinical testing and a renewed attempt to treat HER2-driven cancers through the inactivation HER2. Here I review the development of treatments that target HER2 in the context of the HER2 oncogene hypothesis, and where we stand with regards to the clinical translation of the HER2 oncogene hypothesis. PMID:17486079

  16. The oncogenic action of ionizing radiation on rat skin

    SciTech Connect

    Burns, F.J.; Garte, S.J.

    1992-01-01

    The multistage theory of carcinogenesis specifies that cells progress to cancer through a series of discrete, irreversible genetic alterations, but data on radiation-induced cancer incidence in rat skin suggests that an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to an electron beam (LET=0.34 keV/[mu]), a neon ion beam (LET=45) or an argon ion beam (LET=125). The rats were observed for tumors at least 78 weeks with squamous and basal cell carcinomas observed. The total cancer yield was fitted by the quadratic equation, and the equation parameters were estimated by linear regression for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces stable, carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable linked event pathway at high LET; either pathway may advance the cell by 1 stage. The proliferative response of rat epidermis following exposure to ionizing radiation was quantified by injection of [sup 14]C-thymidine. The return of these cells to S-phase a second time was detected by a second label ([sup 3]H). When the labeled cells were in G1-phase, the dorsal skin was irradiated with X-rays. All labeling indices were determined. The [sup 14]C labeling index was constant and unaffected by the radiation. The proportion of all cells entering S-phase averaged 3.5% at 18 hr and increased after 44, 52 and 75 hr to average levels of 11.8%, 5. 3%, and 6.6% at 0, 10 and 25 Gy respectively. The proportion of S-phase cells labeled with [sup 14]C increased after 42 hr and remained relatively constant thereafter.

  17. KIBRA attains oncogenic activity by repressing RASSF1A.

    PubMed

    Anuj; Arivazhagan, Lakshmi; Surabhi, Rohan Prasad; Kanakarajan, Archana; Sundaram, Sandhya; Pitani, Ravi Shankar; Mudduwa, Lakmini; Kremerskothen, Joachim; Venkatraman, Ganesh; Rayala, Suresh K

    2017-06-29

    KIBRA-initially identified as a neuronal associated protein is now shown to be functionally associated with other tissue types as well. KIBRA interacts with dyenin light chain 1 and this interaction is essential for oestrogen receptor transactivation in breast cancer cells. KIBRA as a substrate of Cdk1, Aurora kinase and ERK plays an important role in regulating cell cycle, cell proliferation and migration. Despite these evidences, the exact role of KIBRA in cancer progression is not known. We studied the expression of KIBRA in breast tissues and breast cancer cell lines by western blotting, immunohistochemisry (IHC) and RT-PCR. Stable over expression and knockdown clones were generated to study the transforming properties of KIBRA by conventional assays. Xenograft studies were performed in nude mice to study the in vivo tumourigenic efficacy of KIBRA. qPCR array was performed to understand the molecular mechanism behind oncogenic activity of KIBRA. Our results showed that KIBRA is upregulated in breast cancer cells and in malignant human breast tumours by both western blotting and IHC. Interestingly, we found that KIBRA expression level goes up with increase in breast cancer progression in well-established MCF10A model system. Further, results from stable overexpression clones of KIBRA in fibroblasts (Rat-1) and epithelial breast cancer cells (ZR75) and lentiviral short hairpin RNA-mediated knockdown (KD) clones of KIBRA in ZR75 showed increase in transforming properties with KIBRA overexpression and vice-versa. Results also showed that fibroblasts stably overexpressing KIBRA showed increased tumourigenic potential in nude mice. By adopting a quantitative PCR array-based approach, we identified RASSF1A, a tumour suppressor, as a transcriptional target of KIBRA. This is the first study to demonstrate the in vivo tumourigenic property of KIBRA in a nude mouse model and also unravel the underlying molecular mechanism of KIBRA-mediated transformation via repression of

  18. A quantitative comparison of human HT-1080 fibrosarcoma cells and primary human dermal fibroblasts identifies a 3D migration mechanism with properties unique to the transformed phenotype.

    PubMed

    Schwartz, Michael P; Rogers, Robert E; Singh, Samir P; Lee, Justin Y; Loveland, Samuel G; Koepsel, Justin T; Witze, Eric S; Montanez-Sauri, Sara I; Sung, Kyung E; Tokuda, Emi Y; Sharma, Yasha; Everhart, Lydia M; Nguyen, Eric H; Zaman, Muhammad H; Beebe, David J; Ahn, Natalie G; Murphy, William L; Anseth, Kristi S

    2013-01-01

    Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s) and primary human dermal fibroblasts (hDFs) with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM) arrays and proteolytic 3-dimensional (3D) migration was investigated using matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) (PEG) hydrogels ("synthetic extracellular matrix" or "synthetic ECM"). In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced β1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen) despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with β1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18). Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results, we

  19. Derivation of transplantable 7,12-dimethylbenz(a)anthracene-induced chicken fibrosarcoma lines: differences in metastasizing properties and organ specificity

    SciTech Connect

    Galton, J.E.; Xue, B.; Hochwald, G.M.; Thorbecke, G.J.

    1982-08-01

    Transplantable 7,12-dimethylbenz(a)anthracene-induced SC chicken fibrosarcoma (CHCT-NYU) lines were studied for their ability to grow in internal organs after iv injection (artificial metastases) into 1- to 3-week-old chickens. Some tumor lines were recently derived, whereas others were studied after many serial subcutaneous transplantations. Artificial metastases were seen in the stomach, pancreas, lungs, heart, and muscle, and occasionally in the kidneys and liver. Agammaglobulinemic recipients showed more extensive organ involvement than normal recipients of the same age. Whole-body ..gamma..-irradiation enhanced the incidence of artificial metastases, particularly in lungs. Antibody from the serum of a primary tumor-bearing host reduced the growth of the corresponding tumor in many organs. The metastatic pattern of line CHCT-NYU4 was a relatively stable property. However, intravenous transplantation of tumor cells from line CHCT-NYU4 taken from the liver, lungs, and pancreas of a single recipient established sublines with changes in organ specificity. After a few such serial transplants of liver-derived tumor, a line was derived that grew virtually in the liver alone. A subline with preference for growth in lungs was also obtained, but its ability to grow in the pancreas persisted. A pancreas-derived tumor line also grew in the liver and lungs. Subcutaneous transplants of tissue fragments of the lung-derived tumor line caused the appearance of spontaneous metastases in lungs. The incidence of spontaneous metastases with the lung-derived line was much greater than that with the liver-derived line or with the original CHCT-NYU4 line.

  20. Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA-Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells.

    PubMed

    Ming, Xun; Groehler, Arnold; Michaelson-Richie, Erin D; Villalta, Peter W; Campbell, Colin; Tretyakova, Natalia Y

    2017-04-17

    Platinum-based antitumor drugs such as 1,1,2,2-cis-diamminedichloroplatinum(II) (cisplatin), carboplatin, and oxaliplatin are currently used to treat nearly 50% of all cancer cases, and novel platinum based agents are under development. The antitumor effects of cisplatin and other platinum compounds are attributed to their ability to induce interstrand DNA-DNA cross-links, which are thought to inhibit tumor cell growth by blocking DNA replication and/or preventing transcription. However, platinum agents also induce significant numbers of unusually bulky and helix-distorting DNA-protein cross-links (DPCs), which are poorly characterized because of their unusual complexity. We and others have previously shown that DPCs block DNA replication and transcription and causes toxicity in human cells, potentially contributing to the biological effects of platinum agents. In the present work, we have undertaken a system-wide investigation of cisplatin-mediated DNA-protein cross-linking in human fibrosarcoma (HT1080) cells using mass spectrometry-based proteomics. DPCs were isolated from cisplatin-treated cells using a modified phenol/chloroform DNA extraction in the presence of protease inhibitors. Proteins were released from DNA strands and identified by mass spectrometry-based proteomics and immunological detection. Over 250 nuclear proteins captured on chromosomal DNA following treatment with cisplatin were identified, including high mobility group (HMG) proteins, histone proteins, and elongation factors. To reveal the exact molecular structures of cisplatin-mediated DPCs, isotope dilution HPLC-ESI(+)-MS/MS was employed to detect 1,1-cis-diammine-2-(5-amino-5-carboxypentyl)amino-2-(2'-deoxyguanosine-7-yl)-platinum(II) (dG-Pt-Lys) conjugates between the N7 guanine of DNA and the ε-amino group of lysine. Our results demonstrate that therapeutic levels of cisplatin induce a wide range of DPC lesions, which likely contribute to both target and off target effects of this

  1. A Quantitative Comparison of Human HT-1080 Fibrosarcoma Cells and Primary Human Dermal Fibroblasts Identifies a 3D Migration Mechanism with Properties Unique to the Transformed Phenotype

    PubMed Central

    Schwartz, Michael P.; Rogers, Robert E.; Singh, Samir P.; Lee, Justin Y.; Loveland, Samuel G.; Koepsel, Justin T.; Witze, Eric S.; Montanez-Sauri, Sara I.; Sung, Kyung E.; Tokuda, Emi Y.; Sharma, Yasha; Everhart, Lydia M.; Nguyen, Eric H.; Zaman, Muhammad H.; Beebe, David J.; Ahn, Natalie G.; Murphy, William L.; Anseth, Kristi S.

    2013-01-01

    Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s) and primary human dermal fibroblasts (hDFs) with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM) arrays and proteolytic 3-dimensional (3D) migration was investigated using matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) (PEG) hydrogels (“synthetic extracellular matrix” or “synthetic ECM”). In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced β1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen) despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with β1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18). Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results

  2. A distinct chemokine axis does not account for enrichment of Foxp3(+)  CD4(+) T cells in carcinogen-induced fibrosarcomas.

    PubMed

    Ondondo, Beatrice; Colbeck, Emily; Jones, Emma; Smart, Kathryn; Lauder, Sarah N; Hindley, James; Godkin, Andrew; Moser, Bernhard; Ager, Ann; Gallimore, Awen

    2015-05-01

    The frequency of CD4(+)  Foxp3(+) regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumour-infiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4(+)  Foxp3(-) and CD4(+)  Foxp3(+) T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines (CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3CL1), reflected by an enrichment of activated Foxp3(-) and Foxp3(+) T cells expressing T helper type 1-associated chemokine receptors. Notably, we found that CXCR3(+) T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3(-) and Foxp3(+) T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3(+) cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours.

  3. Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells.

    PubMed

    Kim, Aeyung; Im, Minju; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-01-01

    Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly.

  4. The DNA hypomethylating agent, 5-aza-2'-deoxycytidine, enhances tumor cell invasion through a transcription-dependent modulation of MMP-1 expression in human fibrosarcoma cells.

    PubMed

    Poplineau, Mathilde; Schnekenburger, Michael; Dufer, Jean; Kosciarz, Aleksandra; Brassart-Pasco, Sylvie; Antonicelli, Frank; Diederich, Marc; Trussardi-Régnier, Aurélie

    2015-01-01

    In diseases such as cancer, cells need to degrade the extracellular matrix (ECM) and therefore require high protease levels. Thus, aberrant tissue degradation is associated to matrix metalloproteinases (MMPs) overexpression resulting from different mechanisms including epigenetic events. One of the most characterized epigenetic mechanisms is DNA methylation causing changes in chromatin conformation, thereby decreasing the accessibility to the transcriptional machinery and resulting in a robust gene silencing. Modulation of DNA methylation by DNA hypomethylating agents such as 5-aza-2'-deoxycytidine (5-azadC) is widely used in epigenetic anticancer treatments. Here, we focus on the effects of this drug on the expression level of MMP-1, -2, and -9 in human HT1080 fibrosarcoma cells. We demonstrate that 5-azadC increases MMP expression at both mRNA and protein levels, and promotes invasion potential of HT1080 cells. Using broad-spectrum and specific MMP inhibitors, we establish that MMP-1, but not MMP-2 and -9, plays a key role in 5-azadC-enhanced cell invasion. We show that 5-azadC induces MMP-1 expression through a transcriptional mechanism without affecting MMP-1 promoter methylation status. Finally, we demonstrate that 5-azadC treatment increases the nuclear levels of Sp1 and Sp3 transcription factors, and modulates their recruitment to the MMP-1 promoter, resulting in chromatin remodeling associated to 5-azadC-induced MMP-1 expression. All together, our data indicate that the hypomethylating agent 5-azadC modulates, mainly via Sp1 recruitment, MMP-1 expression resulting in an increased invasive potential of HT1080 cells. © 2013 Wiley Periodicals, Inc.

  5. Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells

    PubMed Central

    Kim, Aeyung; Im, Minju; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-01-01

    Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly. PMID:26020238

  6. An Active 32-kDa Cathepsin L Is Secreted Directly from HT 1080 Fibrosarcoma Cells and Not via Lysosomal Exocytosis

    PubMed Central

    Hashimoto, Yoko; Kondo, Chihiro; Katunuma, Nobuhiko

    2015-01-01

    Cathepsin L [EC 3.4.22.15] is secreted via lysosomal exocytosis by several types of cancer cells, including prostate and breast cancer cells. We previously reported that human cultured fibrosarcoma (HT 1080) cells secrete cathepsin L into the medium; this secreted cathepsin is 10-times more active than intracellular cathepsin. This increased activity was attributed to the presence of a 32-kDa cathepsin L in the medium. The aim of this study was to examine how this active 32-kDa cathepsin L is secreted into the medium. To this end, we compared the secreted active 32-kDa cathepsin L with lysosomal cathepsin L by using a novel gelatin zymography technique that employs leupeptin. We also examined the glycosylation and phosphorylation status of the proteins by using the enzymes endoglycosidase H [EC 3.2.1.96] and alkaline phosphatase [EC 3.1.3.1]. Strong active bands corresponding to the 32-kDa and 34-kDa cathepsin L forms were detected in the medium and lysosomes, respectively. The cell extract exhibited strong active bands for both forms. Moreover, both forms were adsorbed onto a concanavalin A-agarose column. The core protein domain of both forms had the same molecular mass of 30 kDa. The 32-kDa cathepsin L was phosphorylated, while the 34-kDa lysosomal form was dephosphorylated, perhaps because of the lysosomal marker enzyme, acid phosphatase. These results suggest that the active 32-kDa form does not enter the lysosomes. In conclusion, our results indicate that the active 32-kDa cathepsin L is secreted directly from the HT 1080 cells and not via lysosomal exocytosis. PMID:26674348

  7. Evaluation of (188)Re-