ABSTRACT
Resistance to chemotherapy poses a major challenge for cancer treatment. Reactivating a stem cell program resembling that seen in embryonic development can lead cancer cells to acquire a stem-cell phenotype characterized by expression of stemness genes, pluripotency, high self-renewal ability, and tumor-initiating capability. These cancer stem cells (CSCs) are usually resistant to anticancer drugs and are likely involved in treatment failure in many cancer types. Ewing sarcoma (ES) is a pediatric cancer type typically resulting from a typical genetic alteration affecting bone or soft tissues. Despite advances in treatment, survival prognostic remains poor for patients with refractory or recurrent disease. Here, we review the increasing evidence indicating that ES tumors contain a CSC subpopulation expressing stem cell genes, including BM1, OCT3/4, NANOG, and SOX2, that plays a role in resistance to drug treatment, and current experimental strategies that successfully counteract chemoresistance mediated by CSCs in ES.
Subject(s)
Antineoplastic Agents , Sarcoma, Ewing , Humans , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplastic Stem Cells/metabolismABSTRACT
Predicting the individual response to chemotherapy is a crucial challenge in cancer treatment. DNA damage caused by antitumor therapies evokes different repair mechanisms responses, such as Nucleotide Excision Repair (NER), whose components are being studied as prognosis biomarkers and target therapies. However, few reports have addressed DNA damages in pediatric Acute Lymphoid Leukemia (ALL). Hence, we conducted an observational follow-up study with pediatric patients to assess DNA damage (by Comet Assay) and gene expression from NER pathway during chemotherapy induction. Bone marrow samples from diagnosis, 15th(D15) and 35th (D35) days of the treatment were collected from 28 patients with ALL. There was no increase in damage index. However, there was a reduction of cells with low damages on D35 compared with diagnosis. NER pathway expression remained the same, however, in a single patient, a significant decrease was observed, maybe due to silencing or downregulation of repair pathways. DNA damage levels and repair may influence the clinical outcome, being involved in drug resistance and risk of relapse. In pediatric ALL, we analyzed for the first time DNA damage and repair behavior in BM samples. Monitoring patient's outcomes will help to access the implication of our findings in survival and relapse rates.
Subject(s)
DNA Damage/drug effects , Induction Chemotherapy/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Bone Marrow/pathology , Child , Comet Assay , DNA Repair , Female , Follow-Up Studies , Humans , Infant , Male , Prognosis , Time FactorsABSTRACT
BACKGROUND: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related receptor kinase B (TrkB) are involved in the maturation of B lymphocytes in the bone marrow (BM), promote cell differentiation in B-cell malignancies, and are associated with poor prognosis in adults with acute leukemia (AL). However, the role of BDNF in pediatric AL remains poorly understood. OBJECTIVE: We carried out a cohort observational study to evaluate BDNF levels in BM or peripheral blood (PB) samples from children with AL. METHODS: BM or PB samples were collected from 57 children and adolescents with acute lymphoid leukemia (ALL), 14 children and adolescents with acute myeloid leukemia (AML), and 44 healthy individuals (HI) of the same age range. RESULTS: BDNF levels at diagnosis in AL patients were significantly lower when compared to HI. Samples from patients in complete remission from disease had higher levels of BDNF compared to those obtained from patients with malignant cells. Moreover, BDNF levels at diagnosis in patients who died were significantly lower compared to those found in survivors. CONCLUSIONS: These findings provide the first evidence for a possible role of BDNF as a marker of active disease and poor prognosis in pediatric AL.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Adolescent , Child , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , PrognosisABSTRACT
Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of ß-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.
Subject(s)
Antineoplastic Agents/pharmacology , Brain-Derived Neurotrophic Factor/biosynthesis , Membrane Glycoproteins/antagonists & inhibitors , Nerve Growth Factor/biosynthesis , Receptor, trkA/antagonists & inhibitors , Receptor, trkB/antagonists & inhibitors , Sarcoma, Ewing/drug therapy , Azepines/pharmacology , Benzamides/pharmacology , Brain-Derived Neurotrophic Factor/genetics , Carbazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Enzyme Inhibitors/pharmacology , Etoposide/pharmacology , Humans , Indole Alkaloids/pharmacology , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/genetics , Nerve Growth Factor/genetics , RNA, Messenger/biosynthesis , Receptor, trkA/biosynthesis , Receptor, trkA/genetics , Receptor, trkB/biosynthesis , Receptor, trkB/genetics , Sarcoma, Ewing/pathology , Tubulin/metabolism , Vincristine/pharmacologyABSTRACT
The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.