Accumulated Chromosomal Instability in Murine Bone Marrow Mesenchymal Stem Cells Leads to Malignant Transformation

Miura, Masako; Miura, Yasuo; Padilla‐Nash, Hesed; Molinolo, Alfredo A.; Fu, Baojin; Patel, Vyomesh; Seo, Byoung‐Moo; Sonoyama, Wataru; Zheng, Jenny J.; Baker, Carl C.; Chen, Wanjun; Ried, Thomas; Shi, Songtao

doi:10.1634/stemcells.2005-0403

Cited by 530 publications

(419 citation statements)

References 31 publications

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“…The spontaneous transformation was accompanied by loss of INK4a gene expression, MYC alteration and high telomerase activity. Similar findings were reported by Miura et al using murine bone marrow-derived mesenchymal stem cells, which resulted in spontaneous fibrosarcoma formation 94 . The transformation process was also associated with chromosomal abnormalities involving MYC and upregulation of telomerase activity.…”

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemsupporting

confidence: 88%

“…The potential spontaneous transformation of somatic stem cells should deserve further attention because of their potential clinical use in tissue regenerative medicine. In light of these previous reports, increased telomerase activity may be responsible, at least in part, for the malignant transformation of human and murine mesenchymal stem cells [91][92][93][94] . This finding is not totally unexpected, as alterations in telomere length and telomerase activity may facilitate cancer development by regulating genomic stability and cell lifespan 95 .…”

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 78%

“…This transformation was associated with deletion of INK4a/ARF locus and KRAS activating mutation 91,92 . More recently, two independent groups have intriguingly reported the spontaneous malignant transformation of similar mesenchymal stem cells in vitro 93,94 . In one report, hMSCs isolated from adipose tissue bypassed senescence and crisis phases, after which 50% of the cells kept proliferating, acquired chromosome instability and were able of generating tumors in immunodeficient mice 93 .…”

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 99%

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Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Section: Telomerase Activity and Telomere Length Regulate Cancer Stemsupporting

confidence: 88%

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 78%

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 99%

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Somatic stem cells and the origin of cancer

2006

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“…Compared to murine MSC, human MSC in long-term culture greatly differ in their behavior. Two recent reports demonstrated that human bone marrowderived MSC are not bound to undergo transformation when propagated in long-term culture (Miura et al, 2006;Zhou et al, 2006), and under the same culture conditions, human MSC do not exhibit obvious chromosomal abnormalities at late passages (Bernardo et al, 2007b . The cells employed in these cultures were however not obtained from healthy individuals but isolated from subcutaneous fat during operation of complicated appendicitis and it is thus likely that they are not comparable to normal MSC Kassem et al, 2005).…”

Section: Msc and Transformation Riskmentioning

confidence: 99%

“…During long-term culture, murine MSC accumulate chromosomal aberrations and exhibit a malignant transformation phenotype (Zhou et al, 2006). The resulting MSC, when implanted into immunecompromised mice using hydroxyapatite/tricalcium phosphate as a carrier, as well as when injected into the tail vein led to sarcoma formation (Miura et al, 2006). Murine MSC also rapidly acquire chromosomal abnormalities in culture, and after infusion, these cells invaded lung parenchyma and formed tumor nodules with the characteristics of differentiated osteosarcomas (Aguilar et al, 2007).…”

Section: Msc and Transformation Riskmentioning

confidence: 99%

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

Lepperdinger

Brunauer

Jamnig

et al. 2008

Experimental Gerontology

116

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Literature Review and Global Consensus on Management of Acute Radiation Syndrome Affecting Nonhematopoietic Organ Systems

Dainiak¹,

Gent²,

Carr³

et al. 2011

Disaster med. public health prep.

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ABSTRACTObjectives:The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature.Methods:English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made.Results:No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients.Conclusions:High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.(Disaster Med Public Health Preparedness. 2011;5:183–201)

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Accumulated Chromosomal Instability in Murine Bone Marrow Mesenchymal Stem Cells Leads to Malignant Transformation

Abstract: ABSTRACT

Cited by 530 publications

References 31 publications

Somatic stem cells and the origin of cancer

Somatic stem cells and the origin of cancer

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

Literature Review and Global Consensus on Management of Acute Radiation Syndrome Affecting Nonhematopoietic Organ Systems

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