Tumor Dormancy, Oncogene Addiction, Cellular Senescence, and Self-Renewal Programs

Abstract Exposure to ionizing radiation (IR) and certain chemotherapeutic agents not only causes acute bone marrow (BM) suppression but also leads to long-term residual hematopoietic injury. This later effect has been attributed to the damage to hematopoietic stem cell (HSC) self-renewal. Using a mouse model, we investigated whether IR induces senescence in HSCs, as induction of HSC senescence can lead to the impairment of HSC self-renewal. The results showed that exposure of C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) resulted in a long-lasting quantitative and qualitative reduction in HSCs (Lin− c-kit+ Sca-1+ or LKS+ cells). Compared to control HSCs, HSCs from irradiated BM at 4 weeks after TBI exhibited a significant reduction in day-35 CAFC frequency and deficiency in cell proliferation and colony formation in a single cell culture assay stimulated with SCF/TPO and SCF/TPO/IL-3, respectively. In addition, transplantation of irradiated HSCs (500 LKS+ cells/recipient) produced less than 1% long-term (2-month) engraftment in a competitive repopulation assay while transplantation of the same number of control HSCs resulted in 24.8% engraftment. Furthermore, HSCs from irradiated mice expressed increased levels of p16Ink4a and senescence-associated beta-galactosidase (SA-beta-gal), two commonly used biomarkers of cellular senescence. In contrast, hematopoietic progenitor cells (Lin− c-kit+ Sca-1− or LKS− cells) from irradiated mice did not show significant changes in clonogenesity in a CFU assay and expressed minimal levels of p16Ink4a and SA-beta-gal. These results suggest that exposure to IR can induce senescence selectively in HSCs but not in HPCs. Interestingly, this IR- induced HSC senescence was associated with a prolonged elevation of p21Cip1/Waf1, p16Ink4a and p19ARF mRNA expression, whereas the expression of p27Kip1, p18Ink4c and p19 Ink4d mRNA was not increased. This suggests that p21Cip1/Waf1, p16Ink4a and p19ARF may play an important role in IR-induced senescence in HSCs, since their expression has been implicated in the initiation, establishment and maintenance of cellular senescence. Therefore, these findings provide valuable insights into the mechanisms underlying IR-induced long-term BM damage. This could lead to the discovery of novel molecular targets for intervention to circumvent IR-induced BM toxicity. In addition, understanding how normal HSCs senesce after IR and chemotherapy will help us to elucidate the molecular mechanisms whereby leukemia/cancer stem cells evade these cancer treatments and provide better knowledge of organismal aging.

Download Full-text

Tumor dormancy and oncogene addiction

Apmis ◽

10.1111/j.1600-0463.2008.01037.x ◽

2008 ◽

Vol 116 (7-8) ◽

pp. 629-637 ◽

Cited By ~ 25

Author(s):

DEAN W. FELSHER

Keyword(s):

Tumor Dormancy ◽

Oncogene Addiction

Download Full-text

Reversing Cancer From Inside and Out: Oncogene Addiction, Cellular Senescence, and the Angiogenic Switch

Lymphatic Research and Biology ◽

10.1089/lrb.2008.63403 ◽

2008 ◽

Vol 6 (3-4) ◽

pp. 149-154 ◽

Cited By ~ 15

Author(s):

Dean W. Felsher

Keyword(s):

Cellular Senescence ◽

Oncogene Addiction ◽

Angiogenic Switch

Download Full-text

Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable for cancer immunotherapy

OncoImmunology ◽

10.1080/2162402x.2020.1715767 ◽

2020 ◽

Vol 9 (1) ◽

pp. 1715767 ◽

Cited By ~ 1

Author(s):

Mara De Martino ◽

Mercedes Tkach ◽

Sofía Bruni ◽

Darío Rocha ◽

María F. Mercogliano ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Cellular Senescence ◽

Oncogene Addiction ◽

A Cell

Download Full-text

Non-Coding RNAs Steering the Senescence-Related Progress, Properties, and Application of Mesenchymal Stem Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.650431 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jingyi Cai ◽

Hexu Qi ◽

Ke Yao ◽

Yang Yao ◽

Dian Jing ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Cellular Senescence ◽

The Other ◽

Skeletal System ◽

Self Renewal ◽

Regulatory Processes ◽

Age Related ◽

Non Coding Rnas

The thirst to postpone and even reverse aging progress has never been quenched after all these decades. Unequivocally, mesenchymal stem cells (MSCs), with extraordinary abilities such as self-renewal and multi-directional differentiation, deserve the limelight in this topic. Though having several affable clinical traits, MSCs going through senescence would, on one hand, contribute to age-related diseases and, on the other hand, lead to compromised or even counterproductive therapeutical outcomes. Notably, increasing evidence suggests that non-coding RNAs (ncRNAs) could invigorate various regulatory processes. With even a slight dip or an uptick of expression, ncRNAs would make a dent in or even overturn cellular fate. Thereby, a systematic illustration of ncRNAs identified so far to steer MSCs during senescence is axiomatically an urgent need. In this review, we introduce the general properties and mechanisms of senescence and its relationship with MSCs and illustrate the ncRNAs playing a role in the cellular senescence of MSCs. It is then followed by the elucidation of ncRNAs embodied in extracellular vesicles connecting senescent MSCs with other cells and diversified processes in and beyond the skeletal system. Last, we provide a glimpse into the clinical methodologies of ncRNA-based therapies in MSC-related fields. Hopefully, the intricate relationship between senescence and MSCs will be revealed one day and our work could be a crucial stepping-stone toward that future.

Download Full-text

Inhibition of p38 MAPK Promotes Hematopoietic Stem Cells Self-Renewal and Ex Vivo Expansion.

Blood ◽

10.1182/blood.v114.22.34.34 ◽

2009 ◽

Vol 114 (22) ◽

pp. 34-34

Author(s):

Yong Wang ◽

Joshua Kellner ◽

Daohong Zhou

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

P38 Mapk ◽

Cellular Senescence ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Ex Vivo Expansion ◽

Mouse Bone Marrow ◽

Self Renewal ◽

Hematopoietic Stem

Abstract Abstract 34 Activation of the p38 mitogen-activated protein kinase (p38 MAPK) is implicated in the inhibitory effects of TNF-α, TGF-β, interferons and reactive oxygen species (ROS) on hematopoiesis and self-renewal of hematopoietic stem cells (HSCs). Clinically, overactivated p38 MAPK contributes to the pathogenesis of myelodysplastic syndromes (MDS) and Fanconi anemia. Inhibition of p38 MAPK with pharmacological agents improves hematopoietic progenitors' function in MDS. However, it has yet to be determined if p38 MAPK plays a role in regulation of normal HSC self-renewal and whether inhibition of p38 MAPK can improve HSC ex vivo expansion. In the present study, we found that sorted mouse bone marrow HSCs (Lin− Sca1+ c-kit+ cells or LSK+ cells) exhibited specific activation of p38 MAPK after seven days culture in serum-free medium supplemented with stem cell growth factors (SCF, Tpo and Flt3 ligand). The activation of p38 MAPK was associated with rapid differentiation of HSCs and induction of cellular senescence. Addition of SB203580 (SB, a specific p38 MAPK inhibitor) to the culture abrogated the activation of p38 MAPK, inhibited the induction of cellular senescence and increased the expression of several HSC self-renewing genes (such as CXCR4, HoxB4 and Gfi1). Moreover, HSCs cultured with SB resulted in a significantly greater HSC expansion than HSCs cultured without SB as assessed by flow cytometry and cobblestone area-forming cell (CAFC) assay. Finally, competitive repopulation assays revealed that HSCs expanded with SB produced a dramatic increase in donor-derived engraftments after transplantation to irradiated recipients. These findings suggest that p38 MAPK plays an important role in the regulation of HSC self-renewal and its inhibitors (e.g. SB203580) may be clinically useful in the ex vivo expansion of HSCs. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Hoxa9 Suppresses Cellular Senescence and Sustains the Development of Leukemic Stem Cells Induced by Fusion Proteins In the Absence of Bmi1.

Blood ◽

10.1182/blood.v116.21.1578.1578 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1578-1578

Author(s):

Lan-Lan Smith ◽

Jenny Yeung ◽

Bernd B Zeisig ◽

Ivo Huijbers ◽

Nik Popov ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Cellular Senescence ◽

Fusion Proteins ◽

Hox Genes ◽

Leukemic Stem Cells ◽

Self Renewal ◽

Hematopoietic Stem ◽

Fold Reduction

Abstract Abstract 1578 While self renewal is an essential feature for the maintenance of both normal hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), very little is known about the underlying molecular pathways. Here we report a critical functional interplay between Bmi1 and Hox in establishment of HSCs and LSCs. Using Bmi1-/- bone marrow cells, we observe that leukemia-associated fusion proteins have distinctive Bmi1 requirements. AML1-ETO (AE) and PLZF-RARα (PR) fail to transform Bmi1-/- primary hematopoietic cells, and induce expression of p16/Arf leading to oncogene-induced senescence (OIS). In contrast, MLL-AF9 driving expression of multiple Hox genes can bypass oncogene-induced senescence and exhibits modest Bmi1-dependence for establishment of LSCs, which can induce leukemia upon serial transplants. Since members of Hox genes with proclaimed self-renewal property are specifically up-regulated by MLL fusions in patient samples and our murine models, we asked the question if these Hox genes may partly compensate the functions associated with the loss of Bmi1. To this end, we generated compound Bmi1-/-Hoxa9-/- mice, which have even more compromised hematopoietic stem cell/progenitor compartments than those of Bmi1-/- or Hoxa9-/- mice. Bmi1-/-Hoxa9-/- mice have a greater than eight-fold reduction in the absolute number of Lin-Sca+kit+ (LSK) in the bone marrow as compared to Bmi1-/- mice and a very significant forty-fold reduction for long term hematopoietic stem cells (LT-HSC). More importantly, while MAF9 is able to transform wild type, Bmi1-/- and Hoxa9-/-, it fails to transform Bmi1-/-Hoxa9-/- cells for establishment of LSCs, which can however be resurrected by re-expression of either Bmi1 or Hoxa9, indicating a critical functional interplay between these protein in development of MLL LSCs. Consistent with the known function of Bmi1 in suppressing cellular senescence and the expression of p16/Arf loci, we showed that Hoxa9 alone can also inhibit replicative senescence and Ras-induced senescence in primary human fibroblast. Forced expression of Hoxa9 can suppress p16/Arf expression, as well as cellular senescence induced by AE and PR in Bmi1-/- cells. Together, these results reveal a previously unrecognized functional interplay between Hox and Bmi1 in regulating cell senescence and development of LSCs induced by fusion proteins, which also suggests that synergistic targeting of both molecules may be required for certain LSCs. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells

Blood ◽

10.1182/blood-2010-12-321539 ◽

2011 ◽

Vol 117 (25) ◽

pp. 6801-6812 ◽

Cited By ~ 79

Author(s):

Daniel L. Coutu ◽

Moïra François ◽

Jacques Galipeau

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Bone Development ◽

Fibroblast Growth Factors ◽

Developmentally Regulated ◽

Self Renewal ◽

Mesenchymal Progenitors

Abstract Bone-derived mesenchymal stem cells (MSCs) are important cells for use in cell therapy, tissue engineering, and regenerative medicine, but also to study bone development, homeostasis, and repair. However, little is known about their developmental ontology and in vivo identity. Because fibroblast growth factors (FGFs) play key roles in bone development and their receptors are developmentally regulated in bones, we hypothesized that MSCs should express FGF receptors (FGFRs), reflecting their developmental origin and potential. We show here that FGFR1/2 are expressed by rare mesenchymal progenitors in putative MSC niches in vivo, including the perichondrium, periosteum, and trabecular marrow. FGFR1+ cells often appeared as pericytes. These cells display a characteristic MSC phenotype in vitro when expanded with FGF-2, which appears to maintain MSC stemness by inhibiting cellular senescence through a PI3K/AKT-MDM2 pathway and by promoting proliferation. FGFRs may therefore be involved in MSC self-renewal. In summary, FGFR1/2 are developmentally regulated markers of MSCs in vivo and in vitro and are important in maintaining MSC stemness.

Download Full-text