lewis lung cancer
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Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 90
Author(s):  
Julia Geppert ◽  
Alina A. Walth ◽  
Raúl Terrón Expósito ◽  
Doris Kaltenecker ◽  
Pauline Morigny ◽  
...  

Background: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models. Methods: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer. Results: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients. Conclusions: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.


Animals ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 23
Author(s):  
Amy L. Miller ◽  
Johnny V. Roughan

Cancer-bearing mice are at risk of developing anxiety, pain, or malaise. These conditions may not only harm welfare but could also undermine data quality and translational validity in studies to develop therapeutic interventions. We aimed to establish whether, or at what point mice developing lung cancer show these symptoms, what measures can best detect their onset, and if data quality and animal welfare can be enhanced by using non-aversive handling (NAH). Welfare was monitored using various daily methods. At the beginning and end of the study, we also scored behaviour for general welfare evaluation, recorded nociceptive thresholds, and applied the mouse grimace scale (MGS). Cancer caused a decline in daily welfare parameters (body weight, and food and water consumption) beginning at around 4 days prior to euthanasia. As cancer progressed, rearing and walking declined to a greater extent in cancer-bearing versus control mice, while grooming, inactive periods, and MGS scores increased. A decline in nest building capability and food consumption provided a particularly effective means of detecting deteriorating welfare. These changes suggested a welfare problem arose as cancer developed, so similar studies would benefit from refinement, with mice being removed from the study at least 4 days earlier. However, the problem of highly varied tumour growth made it difficult to determine this time-point accurately. There were no detectable beneficial effects of NAH on either data quality or in terms of enhanced welfare.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Wei Lu ◽  
Fenghua Cao ◽  
Lili Feng ◽  
Ge Song ◽  
Yi Chang ◽  
...  

AbstractMyeloid-derived suppressor cells (MDSCs) are derived from bone marrow progenitor cells commonly, which is a heterogeneous cell group composed of immature granulocytes, dendritic cells, macrophages and early undifferentiated bone marrow precursor cells. Its differentiation and immunosuppressive function are regulated by complex network signals, but the specific regulation mechanisms are not yet fully understood. In this study, we found that in mouse of Lewis lung cancer xenograft, long non-coding RNA Snhg6 (lncRNA Snhg6) was highly expressed in tumor-derived MDSCs compared with spleen-derived MDSCs. LncRNA Snhg6 facilitated the differentiation of CD11b+ Ly6G− Ly6Chigh monocytic MDSCs (Mo-MDSCs) rather than CD11b+ Ly6G+ Ly6Clow polymorphonuclear MDSCs (PMN-MDSCs), but did not affect the immunosuppressive function of MDSCs. Notably, lncRNA Snhg6 could inhibit the expression of EZH2 by ubiquitination pathway at protein level rather than mRNA level during the differentiation of mouse bone marrow cells into MDSCs in vitro. EZH2 may be an important factor in the regulation of lncRNA Snhg6 to promote the differentiation of Mo-MDSCs. So what we found may provide new ideas and targets for anti-tumor immunotherapy targeting MDSCs.


2021 ◽  
Author(s):  
Lu Zhang ◽  
Ruonan Bo ◽  
Yi Wu ◽  
Longmeng Li ◽  
Zheng Zhu ◽  
...  

Abstract Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective homing of T effector (Teff) cells to tumours and the immunosuppressive tumour microenvironment (TME). Here, we report a programmable tumour cells/Teff cells bispecific nano-immuno-engager (NIE) that can circumvent these limitations to improve ICB therapy. We have developed 28 nm non-toxic peptidic micellar nanoparticles (NIE-NPs) that bind α3β1 integrin on tumour cells membrane and undergo in situ transformation on surface of tumour cells into nanofibrillar network (NIE-NFs). The nanofibrillar network persistently facilitates cytotoxic T cells’ homing to the proximity of tumour cells via activatable α4β1 integrin ligands, and also allows sustained release of resiquimod to reprogram the TME. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xi Tan ◽  
Cuo Yi ◽  
Yi Zhang ◽  
Najiao Tang ◽  
Yali Xu ◽  
...  

The CD71+ erythroid progenitor cells (CECs) exhibit distinctive immunosuppressive properties and regulate antitumor immunity to enable tumor growth. We presented a novel and non-invasive approach to improving immunity by targeting the splenic CECs via sonoporation generated by ultrasound-targeted microbubble destruction (UTMD). The systematic immunity enhanced by the reduction of PDL-1-expressing CECs also benefits the PDL-1 blockade therapy. In the Lewis lung cancer (LLC) model, the study group was treated by UTMD for 10 min at the splenic area with or without anti-mouse PDL-1 intraperitoneal injection. The frequency of splenic CEC, lymphocyte, and cytokine production was analyzed by flow cytometry. Serum interleukin-2 (IL-2) was tested by ELISA. Tumor volume was evaluated by two-dimensional ultrasound. The UTMD treatment consisted of ultrasound sonication and Sonazoid™ microbubble injection through the caudal vein. The mechanic index (MI) of ultrasound was set between 0.98 and 1.03. The results showed a significant reduction of splenic CECs and increased frequency of CD8+ T cells treated by UTMD treatment in the late-stage tumor. Tumor growth could be inhibited by UTMD combined with PDL-1 blockade therapy. The frequencies of interferon-γ (IFN-γ) producing CD8+ and CD4+ T cells were significantly increased after being treated by the combination of UTMD and PDL-1 blockade, while the reactive oxygen species (ROS) production and the fraction of the TGF-β-producing CD11b+ cells were significantly decreased. These preliminary findings suggest that UTMD enhances immune response and facilitates PDL-1 blockade therapy by targeting immunosuppressive CECs in the spleen. Our study provides new aspects and possibilities for treating cancer-related infection and tumor control in oncology.


2021 ◽  
Author(s):  
Juan Tang ◽  
Youling Gong

Abstract OBJECTIVE: The purpose of this study was to investigate the synergistic anti-tumor effects of phloretin (Ph) and radiotherapy (RT) on Lewis lung cancer (LLC), and the mechanisms involved. METHODS:The proliferative rate of Lewis cells treated with phloretin was detected by MTT assay; Clone formation experiments were used to demonstrate the synergistic effect of phloretin and radiotherapy; Mice engrafted with the LLC cells were given intraperitoneal injections of saline, phloretin with or without RT. Tumor models were established by laterally transplanting LLC cells in the right thigh of C57BL/J mice. They were randomly divided into four groups, namely saline group, phloretin group, radiotherapy group, phloretin combined with radiotherapy group. 10Gy radiotherapy was performed during the administration. PET-CT was used to detect 18F-FDG uptake in tumor tissue; immunohistochemistry was used to detect Ki67 expression in tumor tissue; cell apoptosis was detected by flow cytometry. RESULTS: Different concentrations of phloretin inhibited the proliferation of Lewis cells in a time and dose-dependent manner (P<0.05). The radiotherapy sensitization ratio (SER) of 50μg Phloretin was 1.645 in the LLC cells. The combination of Phloretin and RT increased survival compared to free Phloretin and RT (p<0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Phloretin combination therapy significantly reduced 18F-FDG uptake, increased apoptosis and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. CONCLUSION: phloretin combined with radiotherapy has a synergistic anti-tumor effect, possibly by promoting apoptosis, as well as inhibiting proliferation rate and glucose transport.


2021 ◽  
Vol 11 ◽  
Author(s):  
Kai Niu ◽  
Xie-Wan Chen ◽  
Yu Qin ◽  
Lu-Ping Zhang ◽  
Rong-Xia Liao ◽  
...  

The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC.


Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2234
Author(s):  
Anbharasi Lakshmanan ◽  
Roman A. Akasov ◽  
Natalya V. Sholina ◽  
Polina A. Demina ◽  
Alla N. Generalova ◽  
...  

Formulation of promising anticancer herbal drug curcumin as a nanoscale-sized curcumin (nanocurcumin) improved its delivery to cells and organisms both in vitro and in vivo. We report on coupling nanocurcumin with upconversion nanoparticles (UCNPs) using Poly (lactic-co-glycolic Acid) (PLGA) to endow visualisation in the near-infrared transparency window. Nanocurcumin was prepared by solvent-antisolvent method. NaYF4:Yb,Er (UCNP1) and NaYF4:Yb,Tm (UCNP2) nanoparticles were synthesised by reverse microemulsion method and then functionalized it with PLGA to form UCNP-PLGA nanocarrier followed up by loading with the solvent-antisolvent process synthesized herbal nanocurcumin. The UCNP samples were extensively characterised with XRD, Raman, FTIR, DSC, TGA, UV-VIS-NIR spectrophotometer, Upconversion spectrofluorometer, HRSEM, EDAX and Zeta Potential analyses. UCNP1-PLGA-nanocurcumin exhibited emission at 520, 540, 660 nm and UCNP2-PLGA-nanocurmin showed emission at 480 and 800 nm spectral bands. UCNP-PLGA-nanocurcumin incubated with rat glioblastoma cells demonstrated moderate cytotoxicity, 60–80% cell viability at 0.12–0.02 mg/mL marginally suitable for therapeutic applications. The cytotoxicity of UCNPs evaluated in tumour spheroids models confirmed UCNP-PLGA-nanocurcumin therapeutic potential. As-synthesised curcumin-loaded nanocomplexes were administered in tumour-bearing laboratory animals (Lewis lung cancer model) and showed adequate contrast to enable in vivo and ex vivo study of UCNP-PLGA-nanocurcumin bio distribution in organs, with dominant distribution in the liver and lungs. Our studies demonstrate promise of nanocurcumin-loaded upconversion nanoparticles for theranostics applications.


Author(s):  
Min Ai ◽  
Shuang‐shuang Li ◽  
Hong Chen ◽  
Xi‐ting Wang ◽  
Jiang‐nan Sun ◽  
...  

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