Experimental Tumor Models Research Articles

Impact of Timing the Combination of Radiotherapy and PD-1 Inhibitors on Outcomes in Patients with Hepatocellular Carcinoma.

The optimal timing for combining radiotherapy with immunotherapy in patients with hepatocellular carcinoma (HCC) remains uncertain and affects treatment efficacy and patient outcomes. This study aimed to evaluate and compare the efficacy and treatment-related adverse events (TRAEs) of synchronously administered radiotherapy and programmed cell death protein (PD)-1 inhibitors and sequential administration in patients with HCC. We retrospectively enrolled 67 patients with HCC who were undergoing liver radiotherapy and PD-1 inhibitor therapy at two medical centers between July 2017 and April 2023. Additionally, we created an experimental tumor model using 6-week-old female mice to validate our findings. In the concurrent group, the median overall survival was indefinite; however, it was 13 months in the sequential group (95% confidence interval [CI] 6.7-19.3 months, P=0.010). The median progression-free survival was significantly longer in the concurrent group (12 months, 95% CI 9.5-14.5 months) than in the sequential group (7 months, 95% CI 1.3-12.7 months; P=0.043). Grade 3/4 TRAEs occurred in 30.4% (concurrent) and 28.6% (sequential) of patients without any treatment-related deaths. In the mouse model, synchronous treatment significantly inhibited tumor growth compared to sequential treatment (293.4±45.18 mm3 versus 602.7±41.68 mm3; P=0.001). Flow cytometry revealed an increased Tregs/CD3+ T cell ratio and a decreased CD8+/Treg cell ratio post-radiotherapy, suggesting an immunosuppressive tumor microenvironment. Synchronous treatment demonstrated superior efficacy in treating HCC compared to sequential treatment, with manageable adverse events. The rapid increase in Tregs after radiotherapy may contribute to the reduced efficacy of sequential radiotherapy plus PD-1 inhibitors.

Biochemical and cellular mechanisms of immunogenic cell death

Immunogenic cell death (ICD) is a mode of programmed cell death that leads to the activation of anticancer immune response and determines the long-term success of anticancer therapies. Here, we provide a review of the known molecular and cellular mechanisms of ICD. Usually, solid tumor experimental models have been used in ICD studies. However, ascites tumor models may possess some advantages over them. The results of our investigation on the approbation of murine Nemeth-Kellner lymphoma as an experimental ascites tumor model for ICD studies are presented. Keywords: ascites tumor model, biochemical mechanisms, doxorubicin, immunogenic cell death, murine Nemeth-Kellner lymphoma, oxaliplatin

Uterine sarcoma: the possibility of modeling a rare tumor and providing its morphological description

Purpose of the study. To create a model of uterine sarcoma in female white mongrel rats and provide description of its morphological features. Materials and methods. In the in vivo experiment, white mongrel female laboratory rats (n = 20) weighing 250 ± 25 g were used, and the M1 strain of rat sarcoma was used as an experimental tumor model. The studied groups of animals: Group 1 (n = 10) – administration of 0.5 ml of tumor suspension containing 2.5–3.5 × 106 cells using an intravenous catheter with an injection port 22G, 0.9 × 25 mm; group 2 (n = 10) – donors of tumor material with subcutaneous M1 grafting according to the standard method. Xylazine‑ zolethyl anesthesia was used during surgical interventions. The duration of the experiment was 21 days. After killing the animals, median longitudinal histological sections were made from the tumor node, 5–7 microns thick, stained with hematoxylin‑ eosin. Results. Unlike subcutaneous grafting of sarcoma M1, the tumor growing in the uterine horn was characterized by the presence in the abdominal cavity of many nodules and tumor dropouts on the mesentery, i. e. lymph nodes. According to the cellular composition, tumors formed from a suspension of M1 sarcoma cells injected into the right horn of the uterus were characterized by a polymorphocellular type of structure against the background of pronounced neoangiogenesis. Necrosis and hemorrhages were noted in certain sections of the preparations with a polyp‑like tumor form, which corresponds to destructive signs of rapid growth and development of uterine sarcoma. Conclusion. The possibility of modeling a relatively rare tumor by introducing a suspension of M1 sarcoma cells into the right uterine horn of female rats has been established. The nature of multinodular tumor growth with pronounced polymorphism of the cellular composition, areas of necrotization and hemorrhage demonstrates the adequacy of the uterine sarcoma model for the implementation of research tasks in clinical oncology.

Abstract B038: Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion

Abstract Many trial data have shown that cancer immunotherapy can successfully induce long lasting anti-cancer immune responses and increased the survival rate of cancer patients. One of the key challenges facing cancer immunotherapy is the low response rate of cancer patients to immunotherapy, suggesting that these cancer patients may have acquired resistance toward immunotherapy before treatments. Therefore, there is an unmet need for identifying the underlying mechanisms that promote resistance. One important hypothesis is that immune-excluded tumors (so called cold tumors) that lack of functional T cells have been often found in cancer patients who cannot respond well to cancer immunotherapy. To address this, we have successfully established a preclinical model for cold lung tumors, conducted RNA-seq, performed hallmark gene set enrichment analysis (GSEA) on cold tumor cells sorted in vivo, and identified several candidates associated with epithelial-mesenchymal transition, Wnt signaling, type I and II interferon (IFN) signaling, and p53 signaling. We hypothesize that their roles may either promote or inhibit the formation of cold tumors. One of the molecular candidates we identified, a molecule designated as IRC001, represents a crucial proof of concept for our experimental tumor model. We have unveiled a novel role for IRC001 in enhancing anti-tumor immunity, leading to the transformation of cold tumors into hot tumors and facilitating swift tumor regression through pathways reliant on T cells and type I IFN signaling. Our mechanistic studies have shown that IRC001 can trigger type I IFN signaling by engaging STING/TBK-1/IRF3-dependent pathways. To delve deeper into the spatial and molecular distinctions in mouse tumors (± IRC001), we initiated a preliminary study utilizing 10x Genomics/Visium to examine the spatial variations between these tumor types. Significantly, our spatial transcriptomic analysis revealed consistent immune-excluded and immune-enriched characteristics compared to traditional RNA sequencing methods. We conducted an analysis of TCGA datasets (The Cancer Genome Atlas) and observed that elevated IRC001 expression is associated with improved prognosis in SKCM (Skin Cutaneous Melanoma). Furthermore, our bioinformatics analysis revealed that melanoma patients exhibiting heightened IRC001 expression displayed positive responses to immune checkpoint blockade therapies. Therefore, we believe that our experimental tumor model can provide vital insights into the cold tumor microenvironment, shaping future therapeutic strategies, and pinpointing molecular candidates that can assist in selecting patients for successful immunotherapy. Citation Format: Yi-Ting Liao, Li-Mei Chen, Wen-Jye Lin. Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B038.

Radiomics and visual analysis for predicting success of transplantation of heterotopic glioblastoma in mice with MRI

BackgroundQuantifying tumor growth and treatment response noninvasively poses a challenge to all experimental tumor models. The aim of our study was, to assess the value of quantitative and visual examination and radiomic feature analysis of high-resolution MR images of heterotopic glioblastoma xenografts in mice to determine tumor cell proliferation (TCP).MethodsHuman glioblastoma cells were injected subcutaneously into both flanks of immunodeficient mice and followed up on a 3 T MR scanner. Volumes and signal intensities were calculated. Visual assessment of the internal tumor structure was based on a scoring system. Radiomic feature analysis was performed using MaZda software. The results were correlated with histopathology and immunochemistry.Results21 tumors in 14 animals were analyzed. The volumes of xenografts with high TCP (H-TCP) increased, whereas those with low TCP (L-TCP) or no TCP (N-TCP) continued to decrease over time (p < 0.05). A low intensity rim (rim sign) on unenhanced T1-weighted images provided the highest diagnostic accuracy at visual analysis for assessing H-TCP (p < 0.05). Applying radiomic feature analysis, wavelet transform parameters were best for distinguishing between H-TCP and L-TCP / N-TCP (p < 0.05).ConclusionVisual and radiomic feature analysis of the internal structure of heterotopically implanted glioblastomas provide reproducible and quantifiable results to predict the success of transplantation.

Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC. In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo. Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses. RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

Bismuth Nanoparticles Increase Effectiveness of Proton Therapy of Ehrlich Carcinoma.

We studied the antitumor activity of the combined use of local proton irradiation in two modes (10 and 31 Gy) with preliminary intra-tumoral injection of two types of bismuth nanoparticles differing in surface coating: coated with the amphiphilic molecule Pluronic-F127 or Silane-PEG (5 kDa)-COOH polymer. Nanoparticles were used in doses of 0.75 and 1.5 mg/mouse. In two independent series on experimental tumor model (solid Ehrlich carcinoma), bismuth nanoparticles of both modifications injected directly into the tumor enhanced the antitumor effects of proton therapy. Moreover, the radiosensitizing effect of bismuth nanoparticles administered via this route increased with the increasing the doses of nanoparticles and the doses of radiation exposure. In our opinion, these promising data obtained for the first time extend the possibilities of treating malignant neoplasms.

Transplantable Subcutaneous Tumor Models.

Mouse tumor models are essential in cancer research, especially in elucidating malignancy, developing prevention, diagnosis, and new therapeutic approaches. Nowadays, due to standardized ways of maintaining animal colonies and the availability of mouse strains with known genetic backgrounds and approaches to reduce the variability of tumor size between animals, transplantable mouse tumor models can be widely used in translational cancer research. Here, we describe the induction of different subcutaneous tumor models in mice, in particular xenograft and syngeneic that can be used as experimental tumor models.

Severe degranulation of mesenteric mast cells in an experimental rat mammary tumor model.

Breast cancers are one of the most common cancers in women and are responsible for many deaths worldwide. Mast cells are inflammatory cells. Their role in cancers is controversial, and there is limited data on systemic mast cell activation in cancer cases. This study aimed to evaluate systemic mast cell activation in an experimentally induced rat model of breast cancer. Sprague Dawley female rats were divided into control (n = 6) and mammary tumor (n = 12) groups. In the tumor group, 20 mg 7,12-dimethylbenz[a]anthracene (DMBA) dissolved in 1 mL cottonseed oil was administered intragastrically by gavage, and the rats were followed daily until their mammary tumors reached 3 cm in diameter. The control group received only cottonseed oil. Paraffin sections obtained from the mammary tumor tissue were subjected to hematoxylin-eosin, toluidine blue staining, and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Mesenteric tissues from each subject were also stained with toluidine blue. The number and activation status of mast cells in mammary tumors and mesenteric tissues were evaluated. Toluidine blue staining showed that activated mast cells were commonly found in tumor tissues. Based on the mesenteric tissue analysis, severe degranulation of the mesenteric mast cells was found in the tumor-induced groups compared to the control group. This study demonstrated for the first time that systemic mast cell activation develops in both tumoral and mesenteric tissues in an experimental cancer model. However, it is not known at which stage of tumor development it occurs.

LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells.

LTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendritic cell (DC) maturation in the induction of antigen-specific immunity, we investigated the effect of LTX-315 treatment on the maturation of tumor-infiltrating DCs (TiDCs) and the generation of anti-melanoma immunity. We found that LTX-315 treatment induces the maturation of DCs, both indirectly through the release of cancer cell-derived damage-associated molecular patterns (DAMPs)/alarmins and nucleic acids (DNA and RNA) capable of triggering distinct Toll-like receptor (TLR) signaling, and, directly by activating TLR7. The latter results in the ignition of multiple intracellular signaling pathways that promotes DC maturation, including NF-κB, mitogen activated protein kinases (MAPKs), and inflammasome signaling, as well as increased type 1 interferon production. Critically, the effects of LTX-315 on DCs the consequent promotion of anti-melanoma immunity depend on the cytosolic signal transducer myeloid differentiation response gene 88 (MyD88). These results cast light on the mechanisms by which LTX-315 induces DC maturation and hence elicits anticancer immunity, with important implications for the use of LTX-315 as an anticancer immunotherapeutic.

Interference of the Circular RNA Sperm Antigen With Calponin Homology and Coiled-Coil Domains 1 Suppresses Growth and Promotes Apoptosis of Breast Cancer Cells Partially Through Targeting miR-1236-3p/Chromobox 8 Pathway

Noncoding RNAs and RNA modifiers are implicated in cancer radiotherapy. Here, we aimed to investigate the role of sperm antigen with calponin homology and coiled-coil domains 1 (SPECC1)-derived circular RNA (circSPECC1; hsa_circ_0000745) in breast cancer (BC) cells under radiation treatment. Based on quantitative real-time PCR, circSPECC1 was highly upregulated in BC patients’ tumors and cells, and circSPECC1 expression was further increased with the dosage of radiation in BC cells. Moreover, circSPECC1 upregulation was found to be concomitant with higher chromobox 8 (CBX8) and lower microRNA (miR)-1236-3p expression. Functionally, 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2′-deoxyuridine (EdU) and colony formation assays showed that circSPECC1 interference suppressed cell proliferation and long-term survival in BC cells and irradiated BC cells. Xenograft tumor model experiments showed that circSPECC1 knockdown restrained BC tumor growth in vivo. Meanwhile, flow cytometry assay and western blotting revealed an enhanced apoptosis by silencing circSPECC1. Moreover, miR-1236-3p overexpression, similar to circSPECC1 silencing, displayed anti-growth and proapoptosis roles in irradiated BC cells. Mechanistically, dual-luciferase reporter assay and RNA immunoprecipitation assay identified a target relationship between miR-1236-3p and circSPECC1 or CBX8. Also, CBX8 expression could be modulated by circSPECC1 via miR-1236-3p regulation. Collectively, we indicated that inhibiting circSPECC1 could suppress growth and promote apoptosis of BC cells in both irradiated and nonirradiated conditions at least partially via miR-1236-3p/CBX8 axis, confirming that circSPECC1 might be target to develop anticancer drug in BC.

Ethylnitrosourea-induced gliomas: a song in the attic?

It is essential to seek the underlying molecular mechanisms of glioma development, and critical to discover interventions that reduce the incidence and attenuate the growth of gliomas using a well-established in vivo experimental model because glioma is clinically one of the most difficult malignant tumors to treat. Ethylnitrosourea (ENU)-induced glioma in the rat has been extensively utilized as an experimental brain tumor model since the mid-1960s, however, the scientific value of ENU-induced glioma has been underappreciated mainly due to the recent development of transgenic mouse glioma models. Because of the pathophysiological characteristics, which are similar to the high grade human malignant gliomas, ENU-induced glioma is an excellent in vivo model to: a) examine the cell origin, development, and pathophysiology of gliomas; b) investigate anti-tumor effects of calorie restriction (CR) and its underlying mechanisms; and c) discover new preventive and/or therapeutic interventions of glioma. Further exploration of genetic changes during initiation, malignant transformation of glial cells, and progression of glioma as well as CR's anti-tumor effects on cellular processes using cutting edge technology, e.g., spatial transcriptomics, could provide more insight and a deeper understanding of the pathophysiology of gliomas.

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy.

The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.

Potential activity of adiponectin-expressing regulatory T cells against triple-negative breast cancer cells through the cell-in-cell phenomenon.

A population of regulatory T cells (Treg), which reside within thymic nurse cell complexes, express adiponectin and abrogate breast cancer development in transgenic mice. In this study, we examined whether adiponectin-expressing Treg could impair triple-negative breast cancer, which is defined by a lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2. CD4- and CD25-positive cells were sorted from cultured T lymphocytes of a previously characterized experimental thymic tumor model composed of thymic nurse cells and abundant lymphoid stroma. These sorted cells were examined for FOXP3 and adiponectin immunoreactivity and subsequently exposed to triple-negative breast cancer MDA-MB-157 and -231 cells. Adiponectin-expressing Treg were obtained by CD4- and CD25-positive sorting and cell death was induced in triple-negative breast cancer cells through the cell-in-cell phenomenon. Adiponectin-expressing Treg may be candidates for adoptive cell therapy against triple-negative breast cancer.

Multivalent dipeptidyl peptidase IV fragment-nanogold complex inhibits cancer metastasis by blocking pericellular fibronectin

Inhibition of cancer metastasis is a fundamental challenge in cancer treatment. We have previously shown that metastasis of cancer cells in the lung is critically promoted by the interaction between the superficial dipeptidyl peptidase IV (DPP IV) expressed on lung endothelial cells and the pericellular polymeric fibronectin (polyFN) of circulating cancer cells. In the present study, we aimed to search for DPP IV fragments with high avidity to polyFN and develop FN-targeted gold nanoparticles (AuNPs) conjugated with DPP IV fragments for treating cancer metastasis. We first identified a DPP IV fragment encompassing amino acids 29-130 of DPP IV, designated DP4A, which contained FN-binding sites and could specifically bind to FN immobilized on gelatin agarose beads. Furthermore, we conjugated maltose binding protein (MBP)-fused DP4A proteins to AuNPs for fabricating a DP4A-AuNP complex and evaluated its FN-targeted activity in vitro and anti-metastatic efficacy in vivo. Our results show that DP4A-AuNP exhibited higher binding avidity to polyFN than DP4A by 9 folds. Furthermore, DP4A-AuNP was more potent than DP4A in inhibiting DPP IV binding to polyFN. In terms of polyFN-targeted effect, DP4A-AuNP interacted with FN-overexpressing cancer cells and was endocytosed into cells 10 to 100 times more efficiently than untargeted MBP-AuNP or PEG-AuNP with no noticeable cytotoxicity. Furthermore, DP4A-AuNP was superior to DP4A in competitive inhibition of cancer cell adhesion to DPP IV. Confocal microscopy analysis revealed that binding of DP4A-AuNP to pericellular FN induced FN clustering without altering its surface expression on cancer cells. Notably, intravenous treatment with DP4A-AuNP significantly reduced metastatic lung tumor nodules and prolonged the survival in the experimental metastatic 4T1 tumor model. Collectively, our findings suggest that the DP4A-AuNP complex with potent FN-targeted effects may have therapeutic potential for prevention and treatment of tumor metastasis to the lung.

Abstract IA01: Targeting KRAS: Light at the end of the tunnel

Abstract KRAS, an oncogene responsible for at least one fourth of all human cancers, was discovered four decades ago. Yet, the first KRAS selective inhibitor could not be approved until 2021. In spite of this long-awaited breakthrough, approved KRAS inhibitors only block one of the multiple oncogenic isoforms, KRASG12C, an isoform primarily present in lung adenocarcinomas. Moreover, tumor resistance to these KRAS inhibitors is becoming a significant issue in the clinic (Awad et al., N Engl J Med, 2021; Zhao et al., Nature 2021). To provide experimental information that might help to improve current KRAS targeting strategies, we have generated two experimental mouse tumor models of Kras-driven lung adenocarcinoma to compare the therapeutic consequences of eliminating, instead of inhibiting, KRAS oncoproteins. In addition, we have interrogated the molecular mechanisms responsible for the induction of resistance in sotorasib treated KrasG12C/p53 mouse lung adenocarcinomas. We have also investigated the potential role of tampering with KRAS signaling pathways to develop alternative therapeutic strategies against KRAS mutant lung and pancreatic cancers. Previous studies have shown that ablation of RAF1, either by itself, or in combination with the expression of a CDK4 kinase dead isoform, induce significant levels of tumor regression in Kras/p53 driven-lung adenocarcinomas without inducing significant toxicities (Sanclemente et al. Cancer Cell, 2018; Esteban-Burgos et al., PNAS 2020). However, Kras/p53 driven-pancreatic ductal adenocarcinomas (PDAC) are completely resistant to RAF1 ablation, unless RAF1 is deleted in combination with EGFR, an upstream KRAS effector (Blasco et al, Cancer Cell 2019). Yet, ablation of RAF1 and EGFR only resulted in the complete regression of a fraction of PDAC tumors. We have now identified activation of STAT3 as the main mechanism responsible for the resistance of PDAC tumors to RAF1/EGFR ablation. Indeed, combined ablation of RAF1/EGFR/STAT3 completely blocked proliferation of all tested mouse tumor cell lines and organoids. Moreover, all tumors tested in orthotopic allograft models regressed completely with no evidence of tumor regression for at least two months of TMX exposure. Finally, I will discuss potential strategies to pharmacologically validate this triple therapeutic strategy as well as plans to combine it with current KRAS inhibitors. Citation Format: Mariano Barbacid. Targeting KRAS: Light at the end of the tunnel [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA01.

Scandium-44: Diagnostic Feasibility in Tumor-Related Angiogenesis.

Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR), play a crucial role in tumour formation. Radiolabelled imaging probes targeting angiogenic biomarkers serve as valuable vectors in tumour identification. Nowadays, there is a growing interest in novel radionuclides other than gallium-68 (68Ga) or copper-64 (64Cu) to establish selective radiotracers for the imaging of tumour-associated neo-angiogenesis. Given its ideal decay characteristics (Eβ+average: 632 KeV) and a half-life (T1/2 = 3.97 h) that is well matched to the pharmacokinetic profile of small molecules targeting angiogenesis, scandium-44 (44Sc) has gained meaningful attention as a promising radiometal for positron emission tomography (PET) imaging. More recently, intensive research has been centered around the investigation of 44Sc-labelled angiogenesis-directed radiopharmaceuticals. Previous studies dealt with the evaluation of 44Sc-appended avb3 integrin-affine Arg-Gly-Asp (RGD) tripeptides, GRPR-selective aminobenzoyl-bombesin analogue (AMBA), and hypoxia-associated nitroimidazole derivatives in the identification of various cancers using experimental tumour models. Given the tumour-related hypoxia- and angiogenesis-targeting capability of these PET probes, 44Sc seems to be a strong competitor of the currently used positron emitters in radiotracer development. In this review, we summarize the preliminary preclinical achievements with 44Sc-labelled angiogenesis-specific molecular probes.

Low-Dose Aspirin Has Antiproliferative and Apoptosis Effects in HPV16 Tumor Cells and Delays Tumor Development and Growth in an Experimental Model

Objectives: The purpose of this study was to investigate the effect of aspirin on epithelial HPV16-transformed cells and its antitumor effects, in an experimental HPV16-positive tumor model. Design: The design of the study is experimental (in vitro and in vivo). Participants/Materials, Setting, and Methods: SiHa and BMK-16/myc cells were treated with aspirin and cell proliferation was determined by MTT; Caspase-Glo 3/7 Assay was used to determine apoptosis. The tumor-bearing mice group was treated with 50 mg/gr/day of aspirin (orally) during 30 days and the antitumor effect was determined. Results: Here, we provide evidence that aspirin has a negative effect on proliferation and induces apoptosis in the human (SiHa) and murine (BMK-16/myc) HPV16 cells. Furthermore, aspirin showed inhibition of tumor growth, and in mice treated with aspirin prior to implantation of tumor cells, the tumor growth was delayed. Also, the effect of aspirin increased survival in tumor-bearing mice and in mice pre-treated with aspirin. Limitations: It is necessary to carry out in vitro and in vivo studies of the molecular mechanisms involved in the effects of aspirin on tumor cells. Conclusion: Aspirin showed antiproliferative effects in tumor cells and inhibited tumor progression and could be effective as a chemopreventive agent. Thus, aspirin deserves further exploration for the treatment of cervical cancer and other neoplasms.

The Regression of Glioblastoma Multiforme is Time Dependent in the Wild-type Rat Xenograft Model.

Glioblastoma multiforme (GBM) is an aggressive case of primary brain cancer which remains among the most fatal tumors worldwide. Although, some in vitro and in vivo models have been developed for a better understanding of GBM behavior; a natural model of GBM would improve the efficiency of experimental models of human GBM tumors. We aimed the present study to examine the survival and durability of U87 cells in the brain of wild-type rats. U87 cells were intracranially implanted in twenty-one wild-type rats. Tumor size and morphology as well as infiltration of immune cells were investigated at three-time points by H&E and immunohistochemistry (IHC). The results demonstrated that the inoculation of GBM cells led to the infiltration of host defense system cells which caused immunological regression of the tumor mass after six weeks. While the tumors successfully developed without any sign of host defense invasion in the second week of GBM inoculation. Also, a decrease in tumor size and infiltration of immune system cells were observed in the fourth week. These data remarkably suggest that time plays a crucial role in activating the immune system against human GBM tumors in rats; it shows that the regression of tumor mass depends on a time slope. A noticeable proliferation of tumor cells was observed in the rat's brain by the second week.The distant metastatic masses of cancer infiltrated into the adjacent normal tissue by the second week.Tumor mass underwent a noticeable diminution in the size by the fourth week.Cancer cells completely regressed by the sixth week due to immunological reactions.In tumor rejection, the effective mechanism depends on immune system activity and the slope of time. One of the most malignant tumors is the brain tumor in the world. Unfortunately, no effective treatment has yet been found for it. Of course, researchers need efficient animal models to find the appropriate treatment. The xenograft model is one of the tumor models in the laboratory. However, the main challenge is the interaction of the animal's immune system with induced-cancer cells so that the immune system finally rejects the tumor. In this study, we investigated how long the immune system needs to reject induced tumors in the xenograft model completely. For this purpose, we studied the animals in three periods (second week, fourth week, and sixth week). We concluded that the immune system does not recognize the induced cancer cells until the second week of the experiment. It results in the growth of cancer cells and the formation of tumors in the animal brain. However, the immune system begins to recognize the tumor mass after the fourth week which leads to a reduction in metastasis and tumor size. Eventually, the immune system completely rejects the formed tumor in the sixth week.

Recombinant Newcastle Disease Virus kills Liver Cancer in Vitro and in Vivo

Aim: To construct and rescue a recombinant Newcastle disease virus that can express IP10 protein and evaluate its targeted killing effect on liver cancer in vivo and in vitro. Materials &amp; methods: Fluorescence quantitative PCR, western blot and ELISA were used to detect the expression and secretion of IP10 in cells. The H22 mouse liver cancer cells were used to establish subcutaneous tumor-bearing mice experimental animal tumor models, and the tumor growth of mice in each group was observed while receiving treatment with rLasota. Results: The recombinant Newcastle disease virus was successfully constructed and can kill tumor cells successfully. Conclusion: The rLasota-IP10-IRES-EGFP achieves antitumor effects by killing hepatocellular carcinoma cells, enhancing T-lymphocyte infiltration in tumor tissues and inhibiting neovascularization.