Potential Cell Of Origin Research Articles

Abstract A2: Cells of origin of the different subtypes of lung cancer

Abstract Lung cancer is the leading cause of cancer death worldwide. Five-year lung cancer survival is only 15% and lung cancer is responsible for more deaths than prostate, colon, pancreas, and breast cancers combined. Understanding the cellular and molecular mechanism at the origin of lung cancer will generate great insights for better management of the disease. However, the lack of cell surface markers to identify and isolate early progenitor or stem cells in the normal lung represents a gap of knowledge that needs to be filled to identify cells of origin of lung cancers. By macroscopic isolation of different morphological region of the human lung and staining with cell surface markers, we have isolated distinct cell subpopulations by flow cytometry. Interestingly, these markers are expressed in some types of lung cancers but not others. We are characterizing the different subpopulations by immunostaining of cytospun cells and evaluating their in vitro colony formation capacity. In order to address potential cells of origin for the different lung tumor subtypes, gene signatures of the different normal epithelial subpopulations will be compared to the gene expression profiles of lung carcinomas available from public database. These cell surface markers may be critical tools to identify stem/progenitor cells in the normal lung that could be the cell of origin of one type of lung cancer and not others.

Evolution of Mouse Models for Studying CNS Cancer: a Decade of Progress

The first Mouse Models for Human Cancer Consortium (MMHCC) meeting for human nervous system cancer convened in New York City in November of 2000, with the proceedings of that meeting subsequently reported in Oncogene (1).The emphasis of the first meeting was on the comparative pathology of mouse models and corresponding human tumors. Recommendations from the meeting included the need to recapitulate human CNS tumor gene alterations in mouse model tumors, a need for increased emphasis on the molecular characterization of mouse model tumors for establishing consistency with corresponding human tumors, and the need to utilize mouse models in the preclinical evaluation of new therapies for treating CNS cancer. As indicated in the report ofthe 5th MMHCC meeting for nervous system cancer (Montreal, November 2010) in the current issue of Neuro-Oncology (2), these recommendations have proven influential, as most mouse models for CNS cancer are now 1) based on gene alterations suspected ofdriving corresponding human tumor development; 2) routinely subjected to extensive molecular characterization; and 3) are experiencingincreased use for therapeutic hypothesis testing.In addition, the sophistication of current models has increased substantially, with many utilizing information regarding potential cell of origin to regulate the expression or inactivation of genes in precursor cells thought to give rise to corresponding human tumors. Perhaps unforeseen at the 2000 MMHCC meeting was the revitalization of xenograft models for studying CNS cancer, which has been driven by the growing appreciation that histopathologically defined classes of CNS cancer, such as glioblastoma, consist of multiple distinct tumor subtypes, many of which can be propagated as xenografts, and the understanding that individual tumors are composed of distinct subpopulations of cells with distinct biologic properties.As a result of such understanding, human tumor xenografts, established either by direct transplantation from surgical specimens or by transplantation from primary cultures of surgical specimens, are viewed as model systems in their own right. Currently available genetically engineered mouse(GEM) models and human tumor xenografts now allow for detailed investigation of tumor initiation, progression, and response to therapy and have provided investigators with a resource armamentarium for the in-depthstudy of the molecular, cellular, and tumor biology of CNS cancer.It will be of interest to follow the progress during the next 10 years, as GEM modelers will undoubtedly utilize the rapidly growing base of information regarding developmental regulation of gene expression to further refine models for appropriate temporal, spatial, and cellular recapitulation of corresponding human tumor development.

Abstract SY12-03: Getting abreast of the mammary epithelial hierarchy and breast cancer

Abstract To understand relationships between breast tissue, cells of origin and cancer stem cells in breast tumors, it is necessary to dissect the normal mammary epithelial hierarchy. We have isolated discrete populations of mouse and human mammary epithelial cells on the basis of cell-surface markers and defined subpopulations that are highly enriched for mammary stem, luminal progenitor and mature luminal cells. Transcriptome analyses of mouse and human mammary epithelial populations has led to the identification of multiple conserved genes and pathways. Analysis of different mouse models of mammary tumorigenesis using syngeneic transplantation assays and interrogation of molecular profiles has revealed potential cells of origin in preneoplastic tissue and the presence of a definitive cancer stem cell subset in different mouse mammary tumors. The role of the zinc finger transcription factor Gata-3, a critical regulator of luminal cell differentiation and a favourable prognostic indicator in breast cancer, has recently been explored in tumor initiation using mouse models. Gata-3 deficiency was found to increase the tumorigenicity of different epithelial subpopulations, with accompanying cell-fate changes. In the context of human breast tissue, analogous studies have enabled us to pinpoint the cellular defect occurring in precancerous tissue from BRCA1 mutation carriers. These carriers were shown to harbor aberrant luminal progenitor cells. Combined with interrogation of the molecular profiles of the different subtypes of breast cancer, the luminal progenitor was identified as the likely cell of origin for BRCA1-associated basal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY12-03. doi:10.1158/1538-7445.AM2011-SY12-03

NG2-expressing glial precursor cells are a new potential oligodendroglioma cell initiating population in N -ethyl- N -nitrosourea-induced gliomagenesis

Gliomas are the most common primary brain tumor affecting human adults and remain a therapeutic challenge because cells of origin are still unknown. Here, we investigated the cellular origin of low-grade gliomas in a rat model based on transplacental exposure to N-ethyl-N-nitrosourea (ENU). Longitudinal magnetic resonance imaging coupled to immunohistological and immunocytochemical analyses were used to further characterize low-grade rat gliomas at different stages of evolution. We showed that early low-grade gliomas have characteristics of oligodendroglioma-like tumors and exclusively contain NG2-expressing slow dividing precursor cells, which express early markers of oligodendroglial lineage. These tumor-derived precursors failed to fully differentiate into oligodendrocytes and exhibited multipotential abilities in vitro. Moreover, a few glioma NG2+ cells are resistant to radiotherapy and may be responsible for tumor recurrence, frequently observed in humans. Overall, these findings suggest that transformed multipotent NG2 glial precursor cell may be a potential cell of origin in the genesis of rat ENU-induced oligodendroglioma-like tumors. This work may open up new perspectives for understanding biology of human gliomas.

High Expression of the PAX3-FKHR Oncoprotein Is Required to Promote Tumorigenesis of Human Myoblasts

PAX3-FKHR is a fusion oncoprotein generated by the 2;13 chromosomal translocation in alveolar rhabdomyosarcoma (ARMS), a cancer associated with the skeletal muscle lineage. Previous studies determined that high-level PAX3-FKHR expression is a consistent feature in ARMS tumors. To investigate the relationship between expression and phenotype in human myogenic cells, PAX3-FKHR was introduced into immortalized human myoblasts to produce a low overall PAX3-FKHR expression level. Although PAX3-FKHR alone failed to exert transforming activity, a combination of PAX3-FKHR and MYCN induced transforming activity in cell culture assays. Furthermore, myoblasts expressing PAX3-FKHR with or without MYCN formed tumors in SCID mice. These tumors demonstrated invasive features and expressed myogenic markers, consistent with rhabdomyosarcoma. Comparisons of tumor and parental cells revealed that only a subset of parental cells developed into tumors and that tumor cells expressed high PAX3-FKHR levels compared with transduced parental cells. Subcloning of parental PAX3-FKHR/MYCN-transduced myoblasts identified rare high PAX3-FKHR-expressing subclones with high transforming and tumorigenic activity; however, most subclones expressed low PAX3-FKHR and showed neither transforming nor tumorigenic activity. Finally, RNA interference experiments in myoblast-derived tumor and ARMS cells revealed that high PAX3-FKHR expression plays a crucial role in regulating proliferation, transformation, and differentiation. These findings support the premise that high PAX3-FKHR-expressing cells are selected during tumorigenesis.