Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Investigation of many solid cancers has been

    2018-11-02

    Investigation of many solid cancers has been facilitated by classifying constituent malignant buy Z-IETD-FMK into distinct populations corresponding to the differentiation stages of benign tissue counterparts (Matsui et al., 2004; Tang, 2012). In response to metabolic imbalance, WAT has a capacity to quickly grow in mass, resulting in obesity (Daquinag et al., 2011a; Sun et al., 2011). WAT expansion is as a result of proliferation and differentiation of a progenitor population that is similar to mesenchymal stromal/stem cells (MSC) initially described in the bone marrow (Prockop, 1997; Pittenger et al., 1999; Bianco et al., 2008; Caplan and Correa, 2011). These adipose MSC, termed adipose stromal cells (ASC), serve as progenitors of preadipocytes (Rodeheffer et al., 2008; Tang et al., 2008), ultimately differentiating into white adipocytes, which are large cells accumulating triglycerides in lipid droplets and the main cellular component of WAT (Cinti, 2011; Daquinag et al., 2011a). In addition to ASC, WAT contains endothelial cells and infiltrating leukocytes, which may also contribute to the adipocyte pool in pathological conditions (Daquinag et al., 2011b; Kolonin et al., 2012). Gene expression profiles (Matushansky et al., 2008) and adipogenic potential of liposarcoma cells (Peng et al., 2011) have indicated the mesenchymal origin of liposarcomas, however the possibility of hematopoietic or endothelial cells also undergoing malignant transformation has not been ruled out. We hypothesized that, by analogy with benign cells of adipocyte lineage (Fig. 1A), malignant cells in WDLS and DDLS could be classified as per distinct stages of adipogenesis. Our studies identify four distinct mesenchymal populations of malignant cells in both WDLS and DDLS and establish a protocol by which they can be separated from non-malignant (hematopoietic and endothelial) cells of tumor microenvironment. We show that a population of malignant cells in both WDLS and DDLS has features of ASC, whereas other cell populations have immunophenotypes corresponding to variable degrees of adipocyte differentiation. Our experiments in DDLS xenograft mouse models show that cell populations separated based on distinct immunophenotypes have comparable tumor-initiation capacities and can re-generate the distinct immunophenotypic populations in vivo.
    Materials and methods
    Results
    Discussion The relative rarity of liposarcomas has posed a challenge for investigations of these lethal soft tissue cancers (Kooby et al., 2004; Lahat et al., 2008; Anaya et al., 2009; Gilbert et al., 2009). To begin characterization of their cellular organization, we systematically analyzed multiple WDLS and DDLS surgical specimens. Analysis of freshly isolated human cells based on flow cytometry, FISH, and immunofluorescence microscopy of tissue sections has indicated that malignant cells in both WDLS and DDLS comprise exclusively mesenchymal populations at several distinct stages of adipogenesis. Building on previous reports addressing CD34 and CD36 expression in liposarcomas (Mechtersheimer, 1991), our work provides new information on the distribution of individual cell types distinguished through these markers in WDLS and DDLS. Experiments with Lipo863, the adipogenic DDLS cells with ASC morphology (Peng et al., 2011), demonstrate CD34 and CD36 expression changes in liposarcoma cells upon ex vivo propagation. The capacity of each distinct Lipo863 population identified based on CD36 expression to re-create the initial Lipo863 complexity in the mouse xenograft model indicates immunophenotypic plasticity of malignant liposarcoma cells. This phenomenon may reflect the recently revealed plasticity of benign white adipocytes, which are capable of de-differentiation and trans-differentiation (Cinti, 2011). Based on our combined data and the frequencies and phenotypes of the individual populations isolated from primary human tumors, we propose a hierarchical model of liposarcoma progression (Fig. 4C). According to this model, malignant transformation of one of the cell populations in WAT, which involves 12q13–15 amplification and concomitant molecular changes, leads to the formation of WDLS or DDLS. We hypothesize that the expansion of the malignant liposarcoma populations result in equilibrium of cell phenotypes that differ by the status of differentiation, in which distinct cell populations serve mutually beneficial roles. The observed enrichment of malignant cells with the ASC phenotype in DDLS compared to WDLS could be explained by WDLS progressing to DDLS through progressive transformation of malignant ASC-like cells that eventually over proliferate and dominate. However, it is equally possible that critical additional mutations take place de novo, thus leading to a more aggressive clone forming DDLS with decreased capacity to differentiate. These non-exclusive scenarios may both occur in the clinical context.