Development and Characterization of a Novel Non-Lytic Cancer Immunotherapy Using a Recombinant Arenavirus Vector Platform.

Engineered viral vectors represent a promising strategy to trigger antigen-specific antitumor T cell responses. Arenaviruses have been widely studied because of their ability to elicit potent and protective T cell responses. Here, we provide an overview of a novel intravenously administered, replication-competent, non-lytic arenavirus-based vector technology that delivers tumor antigens to induce antigen-specific anti-cancer T cell responses.

Live-attenuated lymphocytic choriomeningitis virus-based vaccines for active immunotherapy of HPV16-positive cancer.

Infection with human papillomavirus (HPV) is associated with a variety of cancer types and limited therapy options. Therapeutic cancer vaccines targeting the HPV16 oncoproteins E6 and E7 have recently been extensively explored as a promising immunotherapy approach to drive durable antitumor T cell immunity and induce effective tumor control. With the goal to achieve potent and lasting antitumor T cell responses, we generated a novel lymphocytic choriomeningitis virus (LCMV)-based vaccine, TT1-E7E6, targeting HPV16 E6 and E7.

Chemotherapy use in elderly patients with soft tissue sarcoma: a population-based study.

Adjuvant chemotherapy for soft tissue sarcoma (STS) remains controversial while improvement in survival has never been conclusively demonstrated for metastatic STS. We identified individuals in SEER-Medicare with resected or metastatic STS, 1991-2007. Of 2,382 patients with resected STS, 106 (4.

Solid tumor differentiation therapy - is it possible?

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e.

Hiwi mediated tumorigenesis is associated with DNA hypermethylation.

Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined.

A transgenic, mesodermal specific, Dkk1 mouse model recapitulates a spectrum of human congenital limb reduction defects.

Congenital limb reduction defects occurring in isolation of other developmental abnormalities continue to be an important medical problem in which little progress has been made. Herein we generated transgenic mice expressing Dkk1 in an appendicular mesodermal pattern. Prx1-Dkk1 mice recapitulate a full spectrum of human congenital limb reduction defects, without other developmental issues, and have normal life-spans.

PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation.

Objective: Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process.

Methods: We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019.

PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma.

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS.

MicroRNAs in chromosomal translocation-associated solid tumors: learning from sarcomas.

Sarcomas are malignant solid tumors of mesenchymal origin which consist of 10-15% of all pediatric malignancies and associated with significantly high mortality rates despite current therapies. Oncogenic fusion genes, resulting from non-random chromosomal translocations, characterize a subset of sarcomas including rhabdomyosarcoma, the Ewing's sarcoma family of tumors, and synovial sarcoma. As investigators gain further insight into the role that fusion genes play in the development and progression of sarcomas, we are slowly uncovering novel molecules and pathways that are proving to be essential for the growth and maintenance of sarcomas and other malignancies.

Piwis and piwi-interacting RNAs in the epigenetics of cancer.

An increasing body of evidence suggests that cancer cells acquire "stem-like" epigenetic and signaling characteristics during the tumorigenic process, including global DNA hypo-methylation, gene-specific DNA hyper-methylation, and small RNA deregulation. RNAs have been known to be epigenetic regulators, both in stem cells and in differentiated cells. A novel class of small RNAs, called piwi-interacting RNAs (piRNAs), maintains genome integrity by epigenetically silencing transposons via DNA methylation, especially in germline stem cells.

Adjuvant chemotherapy in 2011 for patients with soft-tissue sarcoma.

The mainstay of treatment for adults with soft-tissue sarcomas is wide surgical excision. Half of all patients with adequate local control of high-grade sarcomas develop distant metastases and, despite additional treatment, ultimately die from their disease. This daunting reality has resulted in a three-decade research effort to assess the efficacy of adjuvant therapy for adult soft-tissue sarcomas.

Alternate PAX3 and PAX7 C-terminal isoforms in myogenic differentiation and sarcomagenesis.

Objective: Pax3 and Pax7 are closely related genes that are involved in commitment of cells to a myogenic lineage during skeletal muscle development and regeneration. Several Pax3 and Pax7 transcripts are expressed from the genes, generating different isoforms with potentially distinct DNA binding and transactivation properties. The aim of this study was to investigate the implication of Pax3 and Pax7 C-terminal isoforms during myogenic differentiation and tumorigenesis, since fusions involving these genes are commonly associated with alveolar rhabdomyosarcoma (ARMS).

Chromatin structure predicts epigenetic therapy responsiveness in sarcoma.

To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC(50) value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines.

Characterization and comparison of the properties of sarcoma cell lines in vitro and in vivo.

To expand the available tools for investigating human sarcomas, we characterized the primary properties of 22 common, uncommon, and newly characterized sarcoma cell lines representing eight different histological subtypes. Throughout the characterization process we noticed that in vitro markers and assays are poor indicators of tumorigenicity and that generated xenografts often bear little resemblance to the original histopathology. In vitro properties examined included morphology, proliferation rate, cell cycle characteristics, invasiveness, and immunohistochemical expression of p53 and phospho-AKT.

Epigenetic remodeling of chromatin architecture: exploring tumor differentiation therapies in mesenchymal stem cells and sarcomas.

Sarcomas are the mesenchymal-derived malignant tumors of connective tissues (e.g., fat, bone, and cartilage) presumed to arise from aberrant development or differentiation of mesenchymal stem cells (MSCs).

MFH classification: differentiating undifferentiated pleomorphic sarcoma in the 21st Century.

The essence and origin of malignant fibrous histiocytoma (MFH) have been debated for now close to five decades. Originally characterized as a morphologically unique soft-tissue sarcoma subtype of unclear etiology in 1963, with a following 15 years of research only to conclude that "the issue of histogenesis [of MFH] is largely unresolvable"; it is "now regarded as synonymous with [high grade] undifferentiated pleomorphic sarcoma and essentially represents a diagnosis of exclusion". Yet despite this apparent lack of progress, the first decade of the 21st century has seen some significant progress in terms of defining the origins of MFH.

Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell?

Alveolar rhabdomyosarcoma (ARMS) is a pediatric sarcoma that typically occurs in older children predominantly arising in the trunk and extremities, and exhibits a worse prognosis than other types of rhabdomyosarcomas. Most ARMS tumors have t(2; 13) or t(1; 13) translocations, involving PAX3-FKHR and PAX7-FKHR fusion genes, respectively. These genetic events result in a molecular gain of function of the fusion protein which is proposed, in a yet unspecified mechanism, to perturb the differentiation of muscle progenitor cells.

A developmental model of sarcomagenesis defines a differentiation-based classification for liposarcomas.

The importance of adult stem cells in the development of neoplastic diseases is becoming increasingly well appreciated. We hypothesized that sarcomas of soft tissue could be categorized by their developmental/differentiation status from stem cell to mature tissue, similar to the hematological malignancies. We conducted gene expression analyses during in vitro differentiation of human mesenchymal stem cells into adipose tissue, as a representative mature connective tissue, and identified genes whose expression changed significantly during adipogenesis.

A context dependent role for Wnt signaling in tumorigenesis and stem cells.

The Wnt signal transduction pathway coordinates myriad activities, from development and differentiation to proliferation and tumorigenesis. What is perhaps most remarkable is that Wnt signaling is able to accomplish this diverse set of activities in a cell-specific and differentiation stage-dependent manner. In this review, we will highlight the diverse effect of Wnt signaling on three types of tissue stem cells and their corresponding malignancies.

Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway.

Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH.

The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas.

We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (approximately 80%) compared to other animal models.

Mechanisms of sarcomagenesis.

Sarcomas comprise a heterogeneous group of malignancies that are derived from mesenchymal cells, which under normal circumstances lead to the development of connective tissues such as bone, muscle, fat, and cartilage. During the past decade, insight has been gained regarding the aberrancies that occur during normal development that result in mesenchymal cells transforming into sarcomas. More recently, these insights have led to the development of successful therapies that target the specific mechanisms inherent to individual sarcomas.

PU.1 and pRB interact and cooperate to repress GATA-1 and block erythroid differentiation.

PU.1 and GATA-1 are two hematopoietic specific transcription factors that play key roles in development of the myeloid and erythroid lineages, respectively. The two proteins bind to one another and inhibit each other's function in transcriptional activation and promotion of their respective differentiation programs.

Reversal of tumorigenicity and the block to differentiation in erythroleukemia cells by GATA-1.

Oncogenic transformation usually inhibits normal cell differentiation processes. Certain chemical agents can force some tumor cells to resume their differentiation program and undergo cell cycle arrest, an approach termed differentiation therapy. Mouse erythroleukemia (MEL) cells represent an important cell culture model system for investigating the principles of differentiation therapy.

CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells.

Cell proliferation and differentiation are highly coordinated during normal development. Many tumor cells exhibit both uncontrolled proliferation and a block to terminal differentiation. To understand the mechanisms coordinating these two processes, we have investigated the relation between cyclin-dependent kinase (CDK) activities and the block to differentiation in murine erythroleukemia (MEL) cells.