ABSTRACT
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. Preclinical studies in mice and cell culture experiments with human peripheral blood mononuclear cells demonstrate that arenavirus vectors preferentially infect antigen-presenting cells. This, in conjunction with a non-lytic functional activation of the infected antigen-presenting cells, leads to a robust antigen-specific CD8+ T cell response. T cell migration to, and infiltration of, the tumor microenvironment has been demonstrated in various preclinical tumor models with vectors encoding self- and non-self-antigens. The available data also suggest that arenavirus-based vector therapy can induce immunological memory protecting from tumor rechallenge. Based on promising preclinical data, a phase 1/2 clinical trial was initiated and is currently ongoing to test the activity and safety of arenavirus vectors, HB-201 and HB-202, created using lymphocytic choriomeningitis virus and Pichinde virus, respectively. Both vectors have been engineered to deliver non-oncogenic versions of the human papilloma virus 16 (HPV16) antigens E7 and E6 and will be injected intravenously with or without an initial intratumoral dose. This dose escalation/expansion study is being conducted in patients with recurrent or metastatic HPV16+ cancers. Promising preliminary data from this ongoing clinical study have been reported. Immunogenicity data from several patients demonstrate that a single injection of HB-201 or HB-202 monotherapy is highly immunogenic, as evidenced by an increase in inflammatory cytokines/chemokines and the expansion of antigen-specific CD8+ T cell responses. This response can be further enhanced by alternating injections of HB-202 and HB-201, which has resulted in frequencies of circulating HPV16 E7/E6-specific CD8+ T cells of up to 40% of the total CD8+ T cell compartment in peripheral blood in analyses to date. Treatment with intravenous administration also resulted in a disease control rate of 73% among 11 evaluable patients with head and neck cancer dosed every three weeks, including 2 patients with a partial response.
ABSTRACT
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. This replication-competent vector was stably attenuated using a three-segmented viral genome packaging strategy. Compared to wild-type LCMV, TT1-E7E6 demonstrated significantly reduced viremia and CNS immunopathology. Intravenous vaccination of mice with TT1-E7E6 induced robust expansion of HPV16-specific CD8+ T cells producing IFN-γ, TNF-α and IL-2. In the HPV16 E6 and E7-expressing TC-1 tumor model, mice immunized with TT1-E7E6 showed significantly delayed tumor growth or complete tumor clearance accompanied with prolonged survival. Tumor control by TT1-E7E6 was also achieved in established large-sized tumors in this model. Furthermore, a combination of TT1-E7E6 with anti-PD-1 therapy led to enhanced antitumor efficacy with complete tumor regression in the majority of tumor-bearing mice that were resistant to anti-PD-1 treatment alone. TT1-E7E6 vector itself did not exhibit oncolytic properties in TC-1 cells, while the antitumor effect was associated with the accumulation of HPV16-specific CD8+ T cells with reduced PD-1 expression in the tumor tissues. Together, our results suggest that TT1-E7E6 is a promising therapeutic vaccine for HPV-positive cancers.
Subject(s)
Papillomavirus Vaccines , Uterine Cervical Neoplasms , Animals , CD8-Positive T-Lymphocytes , Female , Humans , Immunotherapy, Active , Lymphocytic choriomeningitis virus , Mice , Mice, Inbred C57BL , Papillomavirus E7 Proteins/genetics , Vaccines, AttenuatedABSTRACT
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 (4.5%) received chemotherapy. High tumor grade, larger tumor size, and malignant fibrous histiocytoma subtype were associated with chemotherapy receipt. Of 365 patients with metastatic STS, 118 (32.4%) received chemotherapy. Younger age, fewer comorbidities, and being married were associated with chemotherapy receipt. Consistent with clinical trials, we found minimal use of chemotherapy. Clinical factors were associated with chemotherapy receipt in nonmetastatic STS.
Subject(s)
Sarcoma/drug therapy , Age Factors , Aged , Aged, 80 and over , Chemotherapy, Adjuvant/statistics & numerical data , Comorbidity , Female , Humans , Male , Medicare/statistics & numerical data , Prognosis , Randomized Controlled Trials as Topic/statistics & numerical data , SEER Program , Sarcoma/epidemiology , Sarcoma/pathology , Social Class , United States/epidemiologyABSTRACT
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. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiationbased therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.
Subject(s)
Sarcoma/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Cell Transformation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/therapeutic use , Humans , PPAR gamma/agonists , Retinoids/therapeutic useABSTRACT
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. RESULTS: This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor. CONCLUSIONS: Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.
Subject(s)
Muscle Development/genetics , NF-kappa B/metabolism , Oncogene Proteins, Fusion/physiology , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Down-Regulation/genetics , Gene Expression Profiling , Gene Regulatory Networks/physiology , Humans , Mice , Microarray Analysis , Muscle Development/physiology , Myoblasts/metabolism , Myoblasts/physiology , NF-kappa B/genetics , Oncogene Proteins, Fusion/genetics , Rhabdomyosarcoma, Alveolar/genetics , Rhabdomyosarcoma, Alveolar/metabolism , Rhabdomyosarcoma, Alveolar/pathology , Signal Transduction/genetics , Signal Transduction/physiology , Up-RegulationABSTRACT
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. Importantly, a close examination of the inheritance pattern suggests that there is a significant degree of incomplete penetrance as progeny of phenotypically positive or phenotypically negative, but genotypically positive Prx1-Dkk1 mice, consistently give rise to both phenotypically positive mice and phenotypically normal-appearing mice. Thus, this heterogeneous phenotype is reproducible with each generation regardless of the phenotype of the parents. We further go on to identify that mesenchymal stem cells from Prx1-Dkk1 mice have limited proliferative ability, but normal differentiation potential, which may explain the mechanism for the limb reduction defects observed. We believe Prx1-Dkk1 mice may prove useful in the future to study the mechanisms underlying the development of congenital limb reduction defects.
Subject(s)
Disease Models, Animal , Intercellular Signaling Peptides and Proteins/genetics , Limb Deformities, Congenital/genetics , Mesoderm/pathology , Animals , Base Sequence , Cell Differentiation , DNA Primers , Female , Homeodomain Proteins/genetics , Immunohistochemistry , Limb Deformities, Congenital/pathology , Male , Mice , Mice, Transgenic , PedigreeABSTRACT
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. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.
Subject(s)
Argonaute Proteins/genetics , Argonaute Proteins/physiology , DNA Methylation/genetics , Sarcoma/etiology , Animals , Base Sequence , Cell Differentiation , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor Proteins/antagonists & inhibitors , Cyclin-Dependent Kinase Inhibitor Proteins/genetics , DNA Methylation/physiology , Down-Regulation , Gene Expression Profiling , Gene Silencing , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mice , Mice, Transgenic , Protein Array Analysis , Sarcoma/genetics , Sarcoma/physiopathology , Sarcoma/therapy , Sarcoma, Experimental/etiology , Sarcoma, Experimental/genetics , Sarcoma, Experimental/physiopathology , Tumor Stem Cell AssayABSTRACT
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. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation-based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.
Subject(s)
Adipocytes/cytology , Dioxoles/pharmacology , Liposarcoma, Myxoid/drug therapy , Liposarcoma, Myxoid/genetics , PPAR gamma/agonists , PPAR gamma/metabolism , Tetrahydroisoquinolines/pharmacology , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Agents, Alkylating/pharmacology , Cell Differentiation , Disease Models, Animal , Drug Synergism , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Neoplasm Transplantation , TrabectedinABSTRACT
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. piRNAs interact exclusively with the Piwi family of proteins. The human Piwi ortholog, Hiwi, has been found to be aberrantly expressed in a variety of human cancers and in some, its expression correlates with poor clinical prognosis. However, there has been little investigation into the potential role that Piwi and piRNAs might play in contributing to the "stem-like" epigenetic state of a cancer. This review will highlight the current evidence supporting the importance of Piwi and piRNAs in the epigenetics of cancer and provide a potential model for the role of Piwi and piRNAs in tumorigenesis.
Subject(s)
Argonaute Proteins/metabolism , Gene Expression Regulation, Neoplastic , Neoplasms/genetics , RNA, Small Interfering/genetics , Animals , DNA Methylation , Epigenesis, Genetic , Humans , Neoplasms/metabolism , Neoplasms/pathology , Neoplastic Stem Cells/metabolism , RNA, Small Interfering/metabolismABSTRACT
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. MicroRNAs (miRs) have been implicated in a diversity of human diseases including cancer. Only recently, has miR deregulation been shown to be an important component of sarcomagenesis. This review summarizes the recent discoveries tying miR deregulation to sarcoma biology and will discuss the potential and feasibility of miRs as novel therapeutic adjuncts to current therapies. The methodological approaches utilized in the study of miR biology and development of miR-based treatment regimens can serve as a paradigm for future investigations in other translocation-associated solid tumors.
Subject(s)
MicroRNAs/genetics , Sarcoma/genetics , Translocation, Genetic/genetics , Animals , Humans , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Sarcoma/drug therapy , Sarcoma/therapyABSTRACT
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). METHODS: Uncommitted (mouse mesenchymal stem cells, MSCs) and committed (C2C12) myogenic precursor cells were stably transfected with PAX3/FKHR and PAXC7/ FKHR fusion genes. We analysed gene and protein expression comparing the newly generated cells with the parental cells, to determine the functional importance of Pax3 and Pax7 C-terminal isoforms. RESULTS: We found that the transcript Pax3c was expressed at low levels in undifferentiated C2C12 and MSCs cells, but its expression levels increased considerably at later stages of differentiation. However, expression levels of Pax3d transcript increased only slightly after differentiation. Pax7 transcripts, present before differentiation in committed C2C12 cells, but absent in uncommitted MSCs, increased noticeably in MSCs after differentiation. We also found that the presence of PAX/FKHR fusions prevented both C2C12 and MSC cells from terminal myogenic differentiation and increased the expression of discrete endogenous Pax3/7 transcripts, in particular Pax3d and Pax7B. CONCLUSIONS: Our results suggest that both Pax3 and Pax7 transcripts are required for commitment of cells to the myogenic lineage, with each transcript having a distinct role. More specifically, the Pax3c isoform may be required for terminal myogenic differentiation whereas the Pax3d isoform may be involved in undifferentiated cell maintenance and/or proliferation.
Subject(s)
Cell Differentiation/physiology , Muscle Cells/cytology , PAX7 Transcription Factor/genetics , PAX7 Transcription Factor/metabolism , Paired Box Transcription Factors/genetics , Paired Box Transcription Factors/metabolism , Rhabdomyosarcoma, Alveolar/genetics , Animals , Cell Line , Cell Lineage/physiology , Humans , Immunohistochemistry , Mesenchymal Stem Cells/cytology , Mice , Muscle Cells/metabolism , PAX3 Transcription Factor , Protein Isoforms/genetics , Protein Isoforms/metabolism , Recombinant Fusion Proteins , Reverse Transcriptase Polymerase Chain Reaction , Rhabdomyosarcoma, Alveolar/metabolism , TransfectionABSTRACT
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. The multitude of histopathological subtypes, each with its own biology and clinical behavior, and the rarity of adult soft-tissue sarcomas as a whole greatly complicate such an assessment. This Perspectives article examines data that support or refute the use of adjuvant chemotherapy in the treatment of soft-tissue sarcomas.
Subject(s)
Antineoplastic Agents/therapeutic use , Sarcoma/drug therapy , Adult , Chemotherapy, Adjuvant , HumansABSTRACT
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. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure.
Subject(s)
Chromatin/chemistry , Chromatin/genetics , Enzyme Inhibitors/pharmacology , Epigenomics , Histone Deacetylase Inhibitors/pharmacology , Sarcoma/genetics , Sarcoma/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cluster Analysis , Drug Synergism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, SCID , Random Allocation , Xenograft Model Antitumor AssaysABSTRACT
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). Appropriate control of stem cell maintenance versus differentiation allows for normal connective tissue development. Current theories suggest that loss of this control--through accumulation of genetic lesions in MSCs at various points in the differentiation process--leads to development of sarcomas, including undifferentiated, high grade sarcoma tumors. The initiation of stem cell differentiation is highly associated with alteration of gene expression, which depends on chromatin remodeling. Epigenetic chromatin modifying agents have been shown to induce cancer cell differentiation and are currently being used clinically to treat cancer. This review will focus on the importance of epigenetic chromatin remodeling in the context of mesenchymal stem cells, sarcoma tumorigenesis and differentiation therapy.
Subject(s)
Cell Differentiation , Chromatin Assembly and Disassembly , Epigenesis, Genetic , Mesenchymal Stem Cells/metabolism , Sarcoma/pathology , Animals , DNA Methylation , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Histone Deacetylase Inhibitors/therapeutic use , Humans , Mesenchymal Stem Cells/pathology , Sarcoma/therapy , Tretinoin/therapeutic useABSTRACT
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. In vivo properties examined included days to tumor formation in NOD/SCID mice, xenograft morphology in several locations and immunohistochemical expression of Ki67, p53 and phospho-AKT. We believe that such an in depth comparison of a large cohort of sarcoma cell lines will be useful in both designing and interpreting experiments aimed at elucidating both the molecular biology and efficacy of therapeutic agents in sarcomas. However, that data generated also suggests a small set of sarcoma cell lines may be inappropriate for generalizations regarding biological behavior of specific sarcoma subtypes. Integration of functional genomics or other more sophisticated assays of cell lines may help bridge the differences in vitro and in vivo.
Subject(s)
Sarcoma/pathology , Animals , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Humans , In Vitro Techniques , Ki-67 Antigen/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Neoplasm Transplantation , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Sarcoma/metabolism , Transplantation, Heterologous , Tumor Suppressor Protein p53/metabolismABSTRACT
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. Perhaps more importantly these origins might also pave the way for novel therapies. This manuscript will highlight MFH's troubled history, discuss recent advances, and comment as to what the coming years may promise and what further needs to be done to make sure that progress continues.
Subject(s)
Histiocytoma, Malignant Fibrous/diagnosis , Mesenchymal Stem Cells/metabolism , Sarcoma/diagnosis , Animals , Diagnosis, Differential , Histiocytoma, Malignant Fibrous/classification , Histiocytoma, Malignant Fibrous/history , History, 21st Century , Humans , Sarcoma/pathologyABSTRACT
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. While a significant amount of work has been done characterizing PAX-FKHR fusion proteins in ARMS and elucidating their involvement in the sarcomagenic process, their relationship to normal skeletal muscle differentiation remains unestablished. In this manuscript we will explore a potential role for mesenchymal stem cells as the cell of origin of ARMS, and the possibility that PAX-FKHR fusion genes may commit these cells to a myogenic lineage while inhibiting terminal differentiation, thus contributing to ARMS formation. We will also review the structure and function of alternate transcripts of PAX3, PAX7, FKHR and the fusion genes PAX3-FKHR and PAX7-FKHR, and discuss the role of these genes and their downstream targets in development of ARMS. Additionally, we will review transgenic mouse models and their ability to mimic the formation of ARMS.
Subject(s)
Mesenchymal Stem Cells/pathology , Rhabdomyosarcoma, Alveolar/metabolism , Rhabdomyosarcoma, Alveolar/pathology , Animals , Cell Differentiation/physiology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Child , Disease Models, Animal , Humans , Mesenchymal Stem Cells/metabolism , Mice , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Mutation , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Paired Box Transcription Factors/genetics , Paired Box Transcription Factors/metabolism , Rhabdomyosarcoma, Alveolar/genetics , Translocation, GeneticABSTRACT
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. Gene clustering and distance correlation analysis allowed the assignment of a unique time point during adipogenesis that strongly correlates to each of the four major liposarcoma subtypes. Using a novel gene expression strategy, in which liposarcomas are compared to their corresponding adipocytic maturing cells, we identified a group of genes overexpressed in liposarcomas that indicate the stage of differentiation arrest, ie, sharing a similar expression profile to adipocytic cells at a corresponding stage of differentiation, and a distinct set of genes overexpressed in liposarcomas that are not found in the corresponding stage of differentiation. We propose that the latter set is enriched for candidate transformation-associated genes. Our results indicate that a degree of developmental maturity can be quantitatively assigned to solid tumors, supporting the notion that transformation of a solid tumor stem cell can occur at distinct stages of maturation.
Subject(s)
Cell Differentiation , Liposarcoma/classification , Liposarcoma/pathology , Adipogenesis/genetics , Cell Dedifferentiation , Cells, Cultured , Cluster Analysis , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Immunoblotting , Lipid Metabolism , Liposarcoma/genetics , Mesenchymal Stem Cells/pathology , Models, Biological , Neoplasm Proteins/metabolismABSTRACT
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.
Subject(s)
Colorectal Neoplasms/metabolism , Epithelial Cells/metabolism , Leukemia/metabolism , Sarcoma/metabolism , Signal Transduction/physiology , Stem Cells/metabolism , Wnt Proteins/metabolism , HumansABSTRACT
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. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/beta-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.