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Mouse Models in Personalized Cancer Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
M.E. Beaulieu, T. Jauset, D. Massó-Vallés, L. Soucek, J.R. Whitfield
In summary, there are a growing number of humanized mouse models that resemble more and more the behavior of human cancer and the crosstalk between the tumor and the immune system, although the use of these models for preclinical validation of immunotherapeutic approaches against cancer has not yet been generalized. Nevertheless, there are already a few examples that showcase the potential of humanized mice in the advancement of targeted therapies that can lead to personalized treatment for cancer. For instance, a chimeric defucosylated anti-CCR4 mAb displays potent antitumor activity in humanized mouse models of HL and CTCL that are transplanted with PBMCs from healthy donors. Tumor regression was mediated by robust antibody-dependent cellular cytotoxicity (ADCC), while no effect was observed in the absence of human immune cells (Ito et al., 2009). Importantly, the human version of the antibody (mogamulizumab) has already shown promising results in clinical trials (Remer et al., 2014). In addition, BRG mice engrafted with HSCs and vaccinated with human HER2+ SK-OV-3 ovarian cancer cells showed human immune anti-HER2 responses and reduced lung metastases after a subcutaneous SK-OV-3 cell challenge, when compared to nonvaccinated animals (De Giovanni et al., 2012). Finally, NSG mice engrafted with human PBMCs allowed in vivo validation of a new technique for DC-based immunotherapy in AML, consisting of antigen loading of DCs via electroporation with in vitro-transcribed mRNA encoding leukemia-associated antigens. This method showed efficient induction of antigen-specific T-cell immune responses and enabled the initiation of a clinical phase I/II trial to test its application in AML patients (reviewed by Subklewe et al., 2014).
Dissemination and adhesion of peritoneal cancer cells to the peritoneal wall
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Elly De Vlieghere, Marc Bracke, Laurine Verset, Pieter Demetter, Olivier De Wever
Activated fibroblasts express high levels of α-SMA and are also called myofibroblasts, tumor-associated fibroblasts, or CAFs. CAFs are associated with advanced-stage disease and occurrence of lymph node metastases and omentum metastases (Figure 6.2) [39]. Jones and Rous [22] were probably the first to describe CAFs: experiments in mice showed that injuries to the submesothelial connective tissue greatly favored the lodging and growth of tumor fragments. They found that, as a reaction to the injury, the connective tissue showed a strong proliferation of fibroblast-like cells and that this “conditioned” stroma compared to nonconditioned stroma tumor made fragments more aggressive [22]. Fibroblasts and their activated counterparts modulate the stroma in physiological and pathological processes through both direct cell–cell contacts and their secretome [38]. De Boeck et al. [40] analyzed and compared the secretomes from mesenchymal stem cells (MSCs) treated or not with TGF-β (an activator of MSCs to generate CAFs). Some proteins were unique to CAFs: ECM components (e.g., TNC and several laminin subunits), proteases (e.g., MMP-2 and MMP-3), chemokines and growth factors (e.g., SDF-1, hepatocyte growth factor [HGF], and EGF), and protease inhibitors (TIMP-4). When this secretome was offered to colon cancer cells (HCT8/E11) in vitro, cell invasion into a type I collagen gel was stimulated [40]. Cai et al. [41] compared the effects of normal fibroblasts and CAFs, both isolated from the omentum, on ovarian cancer cells (SK-OV-3) in a 3D model in vitro (mesothelial layer on top of a type I collagen gel with embedded fibroblast) and in an in vivo mouse model (IP injection of cancer cells with or without fibroblasts). They found that normal fibroblast was activated by SK-OV-3 via the secretion of TGF-β. The activated fibroblasts and the CAFs, in contrast to their normal counterparts, were able to promote adhesion and invasion of SK-OV-3 [41]. This was confirmed with ovarian cancer cells isolated from patients [39]. Adding an HGF-blocking antibody could partly counteract the effect of fibroblast activation [41]. HGF produced by the CAFs did not only help them to adhere to the ECM but also affected the integrity of the mesothelial monolayer. Mesothelial cells exposed to CM from peritoneal fibroblasts (NF-2P producing HGF, TGF-β, MMP-2, and MMP-9) rounded up and exfoliated from the peritoneum. Again, blocking HGF partly counteracted this effect [32]. CAFs also produce hyaluronan and high levels of this molecule in the stroma were associated with poor differentiation, serous histological type, advanced stage, and a large residual primary tumor volume, whereas it was not correlated with high CD44 expression on cancer cells [16,27].
Long-Term Glucose Restriction with or without β-Hydroxybutyrate Enrichment Distinctively Alters Epithelial-Mesenchymal Transition-Related Signalings in Ovarian Cancer Cells
Published in Nutrition and Cancer, 2021
Hossein Ghahremani, Saeedeh Nabati, Hanieh Tahmori, Tahmineh Peirouvi, Majid Sirati-Sabet, Siamak Salami
Two Ovarian cancer cell lines, A2780CP (C454) and SK-OV-3 (C209) were obtained from the National Cell Bank of Iran (NCBI) with STD profiling authentication certificates. A2780CP is a cisplatin-resistant variant of A2780 human carcinoma cell line. These cells are also cross-resistant to Melphalan, Adriamycin, and irradiation (38). Another cell line, SK-OV-3 is a human ovarian cancer cell line with epithelial morphology and is resistant to tumor necrosis factor and other cytotoxic drugs such as diphtheria toxin, cisplatin, and Adriamycin (39). Mycoplasma contamination was checked intermittently using a polymerase chain reaction (PCR) test. Glucose-free DMEM (D5030) and (±)-Sodium 3-hydroxybutyrate (54965) were obtained from Sigma‐Aldrich (Merck KGaA, Darmstadt, Germany). Other cell‐culture‐grade chemicals and supplements were procured from Biosera Europe (Nuaille, France) or other suppliers and were used without further purification. Cell culture vessels and consumables were procured from SPL Life Sciences Co., Ltd (Korea).
Photodynamic therapy – hypericin tetraether liposome conjugates and their antitumor and antiangiogenic activity
Published in Drug Delivery, 2019
Nikola Plenagl, Lili Duse, Benjamin Sebastian Seitz, Nathalie Goergen, Shashank Reddy Pinnapireddy, Jarmila Jedelska, Jana Brüßler, Udo Bakowsky
CLSM was used to visualize the uptake of hypericin into SK-OV-3 cells. SK-OV-3 cells were incubated overnight in 12 well plates (90 000 cells/well) with coverslips (15 mm diameter). On the following day, the cells were incubated for 4 h with hypericin liposomes at a final concentration of 1 µM. The cells were subsequently washed with PBS containing Ca2/Mg2+ (pH 7.4) before being fixed with 4% paraformaldehyde for 20 min. The cells were washed again with PBS containing Ca2/Mg2+ (pH 7.4) and counterstained with DAPI (0.1 µg/ml). After another washing step, the coverslips were transferred onto glass slides and mounted using FluorSave™ (Calbiochem Corp, La Jolla, CA). The samples were examined with CLSM (LSM 700; Carl Zeiss, Jena, Germany) using 405 and 555 nm laser lines (for DAPI and hypericin respectively) and the images were acquired using the ZEN software (Carl Zeiss).
Enhanced biological activity of liposomal methylated resveratrol analog 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214) in 3D patient-derived ovarian cancer model
Published in Drug Delivery, 2022
Andrzej Nowicki, Dariusz Wawrzyniak, Mikołaj Czajkowski, Małgorzata Józkowiak, Michał Pawlak, Marcin Wierzchowski, Katarzyna Rolle, Paulina Skupin-Mrugalska, Hanna Piotrowska-Kempisty
It is worthy to notice that the liposomal delivery system possessed highly favorable performance since it did not cause any toxicity by itself but was very effective in the delivery of DMU-214 for the treatment of ovarian cancer. The one exception was the DMPC blank, which has been shown to exert cytotoxicity in the SK-OV-3 cell line (Figure 2). However, only the highest concentrations of DMPC have decreased cell viability. Concomitantly, DMU-214/POPC formulation disclosed the highest therapeutic potency in SK-OV-3 cells, making this liposomal formulation of DMU-214 therapeutically promising in fighting malignancy. Several studies showed that cancer stem-like cells (CSCs) are present in the SK-OV-3 cell line (Ma et al., 2010). Like with other cancers, the presence of a subpopulation of cancer stem-like cells has been associated in ovarian cancer with chemoresistance and tumor relapse (Sánchez-García et al., 2007). CSCs were also found to be resistant to anticancer drugs and irradiation. Thus, CSCs might be a crucial target for DMU-214 therapy. In this study, we employed the SK-OV-3 cell line because it has been widely used for ovarian cancer studies and forms non-adherent spheres with remarkable stem cell properties. Likewise, the patient-derived spheroids retain the biological characteristics of clinical cancers and are instrumental in understanding the chemoresistance of ovarian cancer cells. However, our obtained P-3 patient-derived cell line originally derived as a spheroid culture could not adapt to the adherent culture in a swift. Therefore, we tested the biological activity of the liposomal DMU-214 formulations only in SK-OV-3 monolayer culture.