The aging effect of chemotherapy on cultured human mesenchymal stem cells

Buttiglieri, Stefano; Ruella, Marco; Risso, Alessandra; Spatola, Tiziana; Silengo, Lorenzo; Avvedimento, Enrico V.; Tarella, Corrado

doi:10.1016/j.exphem.2011.08.009

Cited by 67 publications

(63 citation statements)

References 53 publications

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“…This analysis was performed on one UC only. Telomere length was determined using a Southern Blot analysis as previously described [19]. 2 μ g of DNA were digested by mixing Hinf I (20 U) and Rsa I (20 U; Roche Diagnostic, Mannheim, Germany) and incubated at 37°C for 2 hours.…”

Section: Methodsmentioning

confidence: 99%

Minced Umbilical Cord Fragments as a Source of Cells for Orthopaedic Tissue Engineering: An In Vitro Study

Marmotti

Mattia

Bruzzone

et al. 2012

Stem Cells International

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A promising approach for musculoskeletal repair and regeneration is mesenchymal-stem-cell- (MSC-)based tissue engineering. The aim of the study was to apply a simple protocol based on mincing the umbilical cord (UC), without removing any blood vessels or using any enzymatic digestion, to rapidly obtain an adequate number of multipotent UC-MSCs. We obtained, at passage 1 (P1), a mean value of 4, 2 × 106 cells (SD 0,4) from each UC. At immunophenotypic characterization, cells were positive for CD73, CD90, CD105, CD44, CD29, and HLA-I and negative for CD34 and HLA-class II, with a subpopulation negative for both HLA-I and HLA-II. Newborn origin and multilineage potential toward bone, fat, cartilage, and muscle was demonstrated. Telomere length was similar to that of bone-marrow (BM) MSCs from young donors. The results suggest that simply collecting UC-MSCs at P1 from minced umbilical cord fragments allows to achieve a valuable population of cells suitable for orthopaedic tissue engineering.

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Section: Methodsmentioning

confidence: 99%

Minced Umbilical Cord Fragments as a Source of Cells for Orthopaedic Tissue Engineering: An In Vitro Study

Marmotti

Mattia

Bruzzone

et al. 2012

Stem Cells International

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“…Clinically, patients receiving chemotherapy and irradiation treatment have also been reported to have an increased marrow fat content [9]. Moreover, enhanced adipogenic differentiation potential of marrow cells by doxorubicin, methotrexate and 5-fluorouracil (5-FU) has been reported in cell culture or animal studies involving usage of these drugs individually [10][11][12], suggesting components of CAF and CMF for adjuvant breast cancer chemotherapy may be associated with increased marrow adiposity. Despite the treatment advances in combating breast cancer in recent years, it remains unclear whether the current preferred CEF regimen is associated with bone and bone marrow toxicities as with CAF or CMF.…”

Section: Introductionmentioning

confidence: 99%

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

et al. 2015

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The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.

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“…At a cellular level, doxorubicin has been reported to inhibit cell proliferation and parameters of cell differentiation in MC3T3 mouse osteoblasts [9]. Interestingly, Buttiglieri et al have recently reported that doxorubicin treatment in cultured human mesenchymal stem cells reduced clonogenic ability and decreased osteoblast differentiation, accompanied by increased adipogenic potential [10]. These adverse effects heighten the concern for breast cancer patients who have received doxorubicin as a part of their treatment regimen, because these patients are already at high risk for bone loss and pathological fracture.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-Mediated Bone Loss in Breast Cancer Bone Metastases Is Driven by an Interplay between Oxidative Stress and Induction of TGFβ

et al. 2013

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Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFβ antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

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The aging effect of chemotherapy on cultured human mesenchymal stem cells

Cited by 67 publications

References 53 publications

Minced Umbilical Cord Fragments as a Source of Cells for Orthopaedic Tissue Engineering: An In Vitro Study

Minced Umbilical Cord Fragments as a Source of Cells for Orthopaedic Tissue Engineering: An In Vitro Study

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

Doxorubicin-Mediated Bone Loss in Breast Cancer Bone Metastases Is Driven by an Interplay between Oxidative Stress and Induction of TGFβ

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