Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest human cancers, with 1-5% 5-year survival rates (~6-month median survival duration) despite therapy; thus, PDAC represents an unmet therapeutic challenge. PDAC is the major histological subtype, comprising 90% of all pancreatic cancers. It is a highly complex and aggressive malignancy, presenting with early local invasion and metastasis, and is resistant to most therapies, all of which are believed to contribute to its extremely poor prognosis. PDAC is characterized by molecular alterations, including mutations of K-RAS (~90% of cases), TP53, transforming growth factor-β, Hedgehog, WNT and NOTCH signaling pathways. Given that cancer stem cells have a crucial role not only in tumor initiation and progression, but also in drug resistance and relapse or recurrence of various cancer types, they may be excellent targets for effective novel therapeutic approaches. Here, we reviewed recent therapeutic strategies targeting pancreatic cancer stem cells using chemotherapeutics and targeted drugs, non-coding RNAs (i.e., siRNA and miRNAs), immunotherapy, and natural compounds.
Immunotherapy is a promising field that offers alternative methods for treatment of cancer. The current strategy consists of cancer vaccines, monoclonal antibodies, and cellular therapies. Cancer vaccines aim to eradicate cancer cells via immune system. Thus, they may attack these cells derived from any type of cancer, besides their role in preventing cancer. Lymphocytes and dendritic cells are often used in cellular therapy. In addition, monoclonal antibodies are designed to target specific antigens found in cancer cells. Currently, at least 12 clinically approved monoclonal antibodies are being used and many cancer vaccines are being developed with ongoing phase studies for cancer therapy. Relevant studies are focused on glioma and several other cancer types. Correspondingly, the combination of effective methods may enhance the efficacy of immunotherapy. It is thought that particularly immune checkpoint inhibitors will play a crucial role in immunotherapeutic approaches.
Aim: The aim of this study is to investigate the effects of miR150 transfection on NK-like cells differentiated from adipose tissue derived mesenchymal stem cells (AD-MSCs). Methods: NK-like cells were differentiated from AD-MSCs and activated by miR150 transfection. Transfected/non-transfected NK-like cells were characterized by immunohistochemical and RTPCR analyzes. Apoptotic efficiency of the transfected/non-transfected NK-like cells on pancreatic cancer cells PANC1 were determined by TUNEL and RT-PCR. Results: In miR150-transfected cells, the increased expression of NK cell-specific genes such as GZMB, KIR2DL2, CD16, CD56, NKG2D, NKp46 and increased immunoreactivity of NK cell-specific surface marker CD314 (NKG2D) were evident. TUNEL assays showed that NK-like cells with/without transfection induced apoptosis in PANC1 cells in the same manner. The decrease in oncogene expression and the increase in the tumor suppressor gene expression in PANC1 cells upon co-culture with NK-like cells differentiated from AD-MSCs were more prominent following miRNA150 transfection. Conclusion: It was shown in vitro that NK-like cells could be obtained by differentiation from AD-MSCs and their efficiency could be increased via miR150 transfection. The results are encouraging for further clinical studies in improvement of immunotherapeutic approaches for cancer therapy.
Chemotherapeutic agents that cause DNA damage also induce cellular senescence known as therapy-induced senescence (TIS).Cells undergoing senescence may exert detrimental effects by promoting tumor progression in healthy cells or supporting metastases in cancer cells due to "senesence-associated secretory phenotype" (SASP), involving secretion of chemokines, cytokines, metalloproteinases, and growth factors. Death receptors belong to the tumor necrosis factor receptor superfamily and implicated in induction of apoptosis via activation of extrinsic pathway. The most recognized death receptors are FAS (CD95), TNFR1 and TRAIL-R1 / 2 (DR4-DR5) etc. and capable of directly inducing apoptosis in the cell. In this study we aimed to investigate the expression of cell death receptors in response to TIS of breast cancer cells for their potential use in elimination of senescent cells.Doxorubicin and etoposide were used to induce senescence selectively in MCF7 breast cancer cell line. Senescence induction was confirmed by β-galactosidase staining and cell cycle analysis. Activations of p53, p21, and γ-H2AX and expression levels of cell death receptors (FAS (CD95), TNFR1-2 and DR5 were tested by western blot analysis. Apoptosis was measured by Annexin V/7AAD analysis.Here, we show that chemotherapy agents etoposide and doxorubicin induced senescence by arresting MCF-12A and MCF-7 cells in G1 and G2/M phases of cell cycle, respectively. Induction of senescence is confirmed by SA-β-gal staining and by activation of -H2AX, p53 and p21 proteins. Neither etoposide nor doxorubicin induced significant apoptosis in MCF12A or MCF-7 cells.Importantly, TIS increased the protein levels of TNFR1, TNFR2 and DR5 receptors selectively in MCF-7 cells but not in MCF-12A cells. These data suggest that chemotherapy agents induce senescence increased the expression of death receptors in breast cancer cell line MCF-7 thus provide a basis for further investigation of death receptor mediated targeting of senescent cells as potential therapeutic strategy.
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