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In Vivo Modulation of Lymphohemopoietic Stem Cell Populations with Cytokines
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
If stem cell frequency is not regulated by feedback loops involving the sizes of mature peripheral blood cell compartments, what then is it that determines the size of this pool of crucial cells? At present, any answer can only be speculative, but two alternative options may be considered. First, the stem cell pool itself may regulate its own size by some intrinsic, programmed control mechanism. Such intracellular regulation could conceivably be determined by differential expression of transcription factors, or other regulatory elements. Recently, elegant studies have shown that overexpression of HoxB4, a transcription factor important in developing embryonic tissues, induced in vitro and in vivo expansion of pluripotent cell compartments [22,23]. Mice transplanted with HoxB4 transduced marrow cells had perfectly normal blood cell counts, but primitive cell compartments were permanently expanded [22]. This is the first study to our knowledge that has demonstrated that apparently permanent stem cell expansion, without neoplasia, can be achieved in vivo. Obviously, if it turns out that stem cell frequency is indeed determined by intracellular control mechanisms, it will not be very easy to manipulate these compartments in vivo, and the role for exogenously applied cytokines may be limited.
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In the hematopoietic system, other proteins are also able to exhibit these features. The EGR1 transcription factor (as well as EGR2 or EGR3) allows stem cells to go into homeostasis or dormancy to maintain them (Min et al., 2008; reviewed in Kühn et al., 2016). EGR1 has initially identified as activator of p21 and as gatekeeper of the TP53 (Krones-Herzig et al., 2003). Cells (over)expressing EGR1 protein can potentially escape treatment, and are presumably one of the reasons for relapses. A dormant cell needs only to switch back from this dormant state to the normal growth program. Recently, it has been shown that CDK4 but mainly overexpressed CDK6 (under certain stress conditions) re-activates dormant stem cells and causes tumor cell formation (Scheicher et al., 2015). Similarly, other factors have been described, such as HOXB4 (an OCT4 and GATA2 downstream target gene; Huang et al., 2016), which is capable of inducing sufficient amounts of the RUNX1 transcription factor to maintain hematopoietic stem cells (Teichweyde et al., 2017).
Collection and Expansion of Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Recent data indicate that a variety of regulatory molecules that are active in early development, homeobox (HOX) transcription factors, may also play a role in the maintenance of stem cell self-renewal. Multiple HOX family members are expressed in the most primitive hematopoietic stem cell-enriched populations and their expression is down regulated in terminally differentiating CD34- cells.63 Overexpression of the homeobox gene, Hoxb4, in murine64-66 and human cord blood67 stem cells leads to enhanced proliferation of clonogenic progenitors in vitro and an enhanced ability to regenerate the most primitive stem cell compartment following serial transplantation in mice. Importantly, none of the mice in these experiments demonstrated hematological abnormalities following transplantation. HOXB4-transduced murine bone marrow cells led to rapid, extensive and highly polyclonal stem cell expansion in vitro resulting in a 1000-fold net increase of stem cells that retained full lymph-myeloid repopulating potential.68 Together these data suggest that HOXB4 overexpression enhances the rate of stem cell expansion without impairing normal differentiation or causing transformation. Other members of the HOX family, including HOXC4,69 HOXa9,70 LIM-homeobox 2 (LH2)71 and HOX1172 have been shown to have similar effects as HOX4B on stem and early progenitor cell expansion, but in some cases led to immortalization71,72 or transformation70 after prolonged expression. Recent review articles provide an extensive description of the role of HOX genes in normal hematopoiesis and leukemogenesis.73,74 Together these findings suggest exciting new areas for genetic manipulation of HOX genes in hematopoietic stem cell regulation, and in the case of HOXB4, perhaps for therapeutic stem cell expansion.
Hsa-circ_0003420 induces apoptosis in acute myeloid leukemia stem cells and impairs stem cell properties
Published in Immunopharmacology and Immunotoxicology, 2021
Guoqiang Lin, Yingying Fei, Yanming Zhang
Bioinformatics analysis indicated that hsa-circ_0003420 can target IGF2BP1 (Figure 6(A)). We next used the dual-luciferase reporter assay to investigate the direct effect of hsa-circ_0003420 on IGF2BP1. Compared to cells in the control groups, the activity of luciferase, which was fused to the IGF2BP1 3′-UTR, was repressed by 70% in cells transfected with the hsa-circ_0003420 overexpression vector (Figure 6(B)). qPCR and WB analyses were used to assess the effect of hsa-circ_0003420 on IGF2BP1 expression. IGF2BP1 mRNA and protein levels were markedly suppressed following hsa-circ_0003420 overexpression (Figure 6(C,D)). Therefore, IGF2BP1 expression was found to be negatively regulated by hsa-circ_0003420. Additionally, a previous study has indicated that IGF2BP1 affects the replication and tumorigenic potential of leukemia cells through self-renewal by regulating the following key regulatory factors: HOXB4, MYB, and ALDH1A1. Therefore, we also determined the expression of these three factors following hsa-circ_0003420 overexpression and subsequent IGF2BP1 downregulation. Our data revealed that the expression of HOXB4, MYB, and ALDH1A1 was notably reduced in KG-1a cells following hsa-circ_0003420 overexpression (Figure 6(D)).
Exosomes-based cell-free cancer therapy: a novel strategy for targeted therapy
Published in Immunological Medicine, 2021
Mesenchymal stem cells (MSCs) have emerged as a potential solution for tissue repair and wound healing. It has a scalable capacity to mass produce exosomes [45]. MSC-exosomes express galectin-1. Galectin-1 is known to induce apoptosis of activated T cells. Furthermore, MSC could also pack miRNA into exosomes that suppress tumor migration and invasion. MSC-derived exosomes could transfer extracellular miR-143 to osteosarcoma cells, which significantly reduced the migration of osteosarcoma cells. Moreover, secretion of miR-23b by MSC-derived exosomes contributes to cell cycle suppression and dormancy in breast cancer cells, which results in inhibition of migration and invasion of breast cancer cells [45,46]. Exosomes derived from MSCs also induces secretion of IL-6, IFN-γ, TNF-α, and activation of B cells, T cells and APCs. Similarly, HoxB4 contained with MSC-derived exosomes has been shown to affect DC maturation and promote T-cell proliferation, differentiation and activation through WNT signaling [47].
Overexpression of HOXC10 promotes glioblastoma cell progression to a poor prognosis via the PI3K/AKT signalling pathway
Published in Journal of Drug Targeting, 2019
Yong Guan, Yajie He, Shaoping Lv, Xiaoqun Hou, Luo Li, Jianjun Song
Increasing evidences implicates HOX genes in cancer. Recent studies have demonstrated that HOXD9 contributes to cell proliferation or survival in glioma cells [19]. HOXB3, HOXB4 and HOXC6 are expressed in paediatric medulloblastomas and primitive neuroectodermal tumours [11]. Our finding of HOXC10 regulation in GBM also implies a role for HOXC10 outside the nucleus. Further studies will focus on the mechanism of action of HOXC10 in cancer cells, to understand how HOXC10 mediates its effects on proliferation, apoptosis, and invasive phenotypes. In cervical cancer cells, HOXC10 is associated with increased invasiveness [20]. Thushangi et al. also observed high HOXC10 expression in a subset of primary tumours. In addition, knockdown of HOXC10 reduced growth of T47D cells [21]. Consistent with our research, knockdown of HOXC10 inhibited GBM U87 cell proliferation, migration and invasion. Additionally, such growth-promoting effects of HOXC10 on GBM cells might be involve in the PI3K/Akt pathways.