Biomedical subjects

Daniel W Fults

Publications and source records attributed to Daniel W Fults.

10 recordsLinked to original sources

PubMed2006

N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma.

Medulloblastoma is a malignant brain tumor that arises in the cerebellum in children, presumably from granule neuron precursors (GNP). Advances in patient treatment have been hindered by a paucity of animal models that accurately reflect the molecular pathogenesis of human tumors. Aberrant activation of the Sonic hedgehog (Shh) and insulin-like growth factor (IGF) pathways is associated with human medulloblastomas. Both pathways are essential regulators of GNP proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3beta-dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown. Here we report a high frequency of medulloblastoma formation in mice following postnatal overexpression of Shh in cooperation with N-myc. Overexpression of N-myc, alone or in combination with IGF signaling mediators or with the Shh target Gli1, did not cause tumors. Thus, Shh has transforming functions in addition to induction of N-myc and Gli1. This tumor model will be useful for testing novel medulloblastoma therapies and providing insight into mechanisms of hedgehog-mediated transformation.

Animals↗

PubMed2006

Tuberous sclerosis: a syndrome of incomplete tumor suppression.

Tuberous sclerosis (TS) is a congenital neurocutaneous syndrome (or phacomatosis) characterized by widespread development of hamartomas in multiple organs. For affected individuals, neurological and psychiatric complications are the most disabling and lethal features. Although the clinical phenotype of TS is complex, only three lesions characterize the neuropathological features of the disease: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The latter is a benign brain tumor of mixed neuronal and glial origin. Tuberous sclerosis is caused by loss-of-function mutations in one of two genes, TSC1 or TSC2. The normal cellular proteins encoded by these genes, hamartin and tuberin, respectively, form a heterodimer that suppresses cell growth in the central nervous system by dampening the phosphatidylinositol 3-kinase signal transduction pathway. The authors review the clinical and neuropathological features of TS as well as recent research into the molecular biology of this disease. Through this work, investigators are beginning to resolve the paradoxical findings that malignant cancers seldom arise in patients with TS, even though the signaling molecules involved are key mediators of cancer cell growth.

Animals↗

PubMed2006

Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications.

Neurofibromatosis 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors. Significant advances have been made in the research of the cellular, genetic, and molecular biology of NF1. The NF1 gene was identified by positional cloning. The functions of its protein product, neurofibromin, in RAS signaling and in other signal transduction pathways are being elucidated, and the important roles of loss of heterozygosity and haploinsufficiency in tumorigenesis are better understood. The Schwann cell was discovered to be the cell of origin for neurofibromas, but understanding of a more complicated interplay of multiple cell types in tumorigenesis, specifically recruited heterogeneous cell types such as mast cells and fibroblasts, has important implications for surgical therapy of these tumors. This review summarizes the most recent NF1 and neurofibroma literature describing the pathogenesis and treatment of nerve sheath tumors. Understanding the biological underpinnings of tumorigenesis in NF1 has implications for future surgical and medical management of neurofibromas.

Animals↗

PubMed2005

Modeling medulloblastoma with genetically engineered mice.

Medulloblastoma is a malignant tumor that arises in the cerebellum in children, presumably by transformation of granule neuron precursor cells. In vivo models of medulloblastoma in genetically engineered mice have shown that activation of signal transduction pathways that stimulate proliferation and inhibit differentiation of neural progenitor cells during cerebellar development initiate medulloblastoma formation. Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma. By revealing which cell signaling proteins can initiate medulloblastoma formation, mouse models have enabled investigators to identify molecular targets for designing new therapies. Small-molecule inhibitors of the Shh/Patched and PI3K pathways are potential chemotherapeutic agents for patients with medulloblastoma.

Animals↗

PubMed2005

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Antineoplastic Agents↗

PubMed2004

Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice.

Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in neural progenitor cells of the cerebellum induces MBs in mice. The incomplete penetrance of tumor formation in mice, coupled with the low frequency of mutations in Shh/Ptc pathway genes in human tumors, suggests that other signaling molecules cooperate with Shh to enhance MB formation. We modeled the ability of insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell-type-specific manner. We used RCAS retroviral vectors to target expression of Shh, IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella of newborn mice. The incidence of Shh-induced tumor formation (15%) was enhanced by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors when expressed independently. The induced tumors showed upregulated expression of insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt, mimicking activated IGF signaling found in human MBs. These results indicate that combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis.

Animals↗

PubMed2004

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.

The phosphatidylinositol 3'-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3'-kinase catalytic subunits, were identified in a significant fraction (25-30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major "hot spots" located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.

Astrocytoma↗

PubMed2003

Spontaneous hemorrhage associated with a pilomyxoid astrocytoma. Case report.

Pilomyxoid astrocytomas have been identified as a more aggressive variant of pilocytic astrocytomas that occur in infants and in young children. These tumors are characterized by a perivascular arrangement of pilocytic cells that has a monomorphous architecture with uniform, elongated bipolar cells loosely ranged within a prominent myxoid background. The authors present the case of a 24-year-old man with a pilomyxoid astrocytoma of the temporal lobe, who presented with a hemorrhage. The patient underwent gross-total tumor resection, and no evidence of residual or recurrent tumor was found on magnetic resonance images at the 6-month follow-up examination. The occurrence of a pilomyxoid astrocytoma in an adult suggests that this tumor is not limited to children. The tumor described in this report is unique because of its presentation with a hemorrhage, which has not been previously described in cases of pilomyxoid astrocytomas and is rarely found in those of pilocytic astrocytomas. Although this tumor predominantly exhibited the pattern of a pilomyxoid astrocytoma, there was a small focus of pilocytic astrocytoma, indicating that there is a spectrum of histological components found in these tumors and that certain elements may be associated with a more aggressive phenotype. In this paper the authors review the literature on pilomyxoid astrocytomas and discuss the unique aspects of this particular tumor presentation.

Adult↗

PubMed2002

Rig is a novel Ras-related protein and potential neural tumor suppressor.

The Ras superfamily consists of a large group of monomeric GTPases demonstrating homology to Ras oncoproteins. Although structurally similar, Ras-superfamily proteins are functionally diverse. Whereas some members exhibit oncogenic properties, others may serve as tumor suppressors. We have identified a novel Ras-related protein that suppresses cell growth and have designated it Rig (Ras-related inhibitor of cell growth). Overexpression of Rig inhibited Ras-mediated cellular transformation and activation of downstream signaling in NIH 3T3 cells. rig mRNA is expressed at high levels in normal cardiac and neural tissue. However, Rig protein expression is frequently lost or down-regulated in neural tumor-derived cell lines and primary human neural tumors. Moreover, expression of exogenous Rig in human astrocytoma cells suppressed growth. Rig has a C-terminal CAAX motif that codes for posttranslational modification by both farnesyl and geranylgeranyl isoprenoid lipids. Consequently, Rig may play a role in the cellular response to farnesyl transferase inhibitors. Rig bears 63% overall sequence homology to a recently described Ras-family member Noey2, a tumor suppressor in breast and ovarian tissue. Therefore, Rig and Noey2 may represent a new subfamily of Ras-like tumor suppressors.

3T3 Cells↗

PubMedDate not supplied

c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice.

Medulloblastomas are malignant brain tumors that arise in the cerebella of children. The presumed cells-of-origin are undifferentiated precursors of granule neurons that occupy the external granule layer (EGL) of the developing cerebellum. The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation. Two known mitogens for neural progenitors are the c-Myc oncoprotein and Sonic hedgehog (Shh), a crucial determinant of embryonic pattern formation in the central nervous system. We modeled the ability of c-Myc and Shh to induce medulloblastoma in mice using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell type-specific manner. We targeted the expression of Shh and c-Myc to nestin-expressing neural progenitor cells by injecting replication-competent ALV splice acceptor (RCAS) vectors into the cerebella of newborn mice. Following injection with RCAS-Shh alone, 3/32 (9%) mice developed medulloblastomas and 5/32 showed multifocal hyperproliferation of the EGL, possibly a precursor stage of medulloblastoma. Following injection with RCAS-Shh plus RCAS-Myc, 9/39 (23%) mice developed medulloblastomas. We conclude that nestin-expressing neural progenitors, present in the cerebellum at birth, can act as the cells-of-origin for medulloblastoma, and that c-Myc cooperates with Shh to enhance tumorigenicity.

Animals↗