Central Region Of Tumor Research Articles

Estimation of the injection criteria for magnetic hyperthermia therapy based on tumor morphology

Intratumoral multi-injection strategy enhances the efficacy of magnetic nanoparticle hyperthermia therapy (MNPH). In this study, criteria for the selection of injections and their location depending on the tumor shape/geometry are developed. The developed strategy is based on the thermal dosimetry results of different invasive 3D tumor models during MNPH simulation. MNPH simulations are conducted on physical tumor tissue models encased within healthy tissue. The tumor shapes are geometrically divided into a central tumor region containing maximum tumor volume and a peripheral tumor portion protruding in any random direction. The concepts of core and invasive radius are used to geometrically divide the tumor volume. Primary & secondary injections are used to inject MNP fluid into these respective tumor regions based on the invasiveness of the tumor. The optimization strategy is devised based on the zone of influence of primary & secondary injection. Results indicate that the zone of influence of secondary injection lies between 0.7 and 0.8 times the radial distance between the center of the tumor core and branch node point (extreme far endpoint on the invasive tumor surface). Additionally, the multi-injection strategy is more effective when the protrusion volume exceeds 10% of the total volume. The proposed algorithm is used to devise multi-injection strategies for arbitrarily shaped tumors and will assist in pre-planning magnetic nanoparticle hyperthermia therapy.

Recent Development of Transition Metal Complexes as Chemotherapeutic Hypoxia Activated Prodrug (HAP).

Hypoxia is a state characterized by low concentration of Oxygen. Hypoxic state is often found in the central region of solid tumors. Hypoxia is associated with abnormal neovascularization resulted in poor blood flow in tissues and increased proliferation of tumor cells, imbalance between O2 supply and O2 consumption in tumor cells, high concentration of proton and strong reducibility. And, these abnormalities enhance the survival potency of the hypoxic tumours and increase the resistance towards chemotherapy and radiotherapy. One of the approach for treating hypoxic region of tumour is to use reducing environment of hypoxic tumours for reducing a molecule (hypoxia activated prodrug, HAP) and as a result the active drug will be released in hypoxic region in a controlled manner from the prodrug and kill the hypoxic tumour. Co(III) and Pt(IV) complexes with monodentate active drug molecule in the axial position can be reduced to Co(II) and Pt(II) moieties and as a result, the axial ligands (active drug) could come out from the metal center and could show its anticancer activity. In this review we have highlighted the research articles where transition metal-based complexes are used as chemotherapeutic hypoxia activated prodrug molecules which are reported in last 5 years.

RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway

Glucose oxidation via the pentose phosphate pathway serves as the primary cellular mechanism for generating nicotinamide adenine dinucleotide phosphate (NADPH). The central regions of solid tumors typically experience glucose deficiency, emphasizing the need for sustained NADPH production crucial to tumor cell survival. This study highlights the crucial role of RIOK3 in maintaining NADPH production and colorectal cancer (CRC) cell survival during glucose deficiency. Our findings revealed upregulated RIOK3 expression upon glucose deprivation, with RIOK3 knockout significantly reducing cancer cell survival. Mechanistically, RIOK3 interacts with heat shock protein 90α (HSP90α), a chaperone integral to various cellular processes, thereby facilitating HSP90α binding to isocitrate dehydrogenase 1 (IDH1). This interaction further upregulates IDH1 expression, enhancing NADPH production and preserving redox balance. Furthermore, RIOK3 inhibition had no discernible effect on intracellular NADPH levels and cell death rates in HSP90α-knockdown cells. Collectively, our findings suggest that RIOK3 sustains colon cancer cell survival in low-glucose environments through an HSP90α-dependent pathway. This highlights the significance of the RIOK3–HSP90α–IDH1 cascade, providing insights into potential targeted therapeutic strategies for CRC in metabolic stress conditions.

Exploration of oxidized phosphocholine profile in non-small-cell lung cancer.

Introduction: Lung cancer is one of the most frequently studied types of cancer and represents the most common and lethal neoplasm. Our previous research on non-small cell lung cancer (NSCLC) has revealed deep lipid profile reprogramming and redox status disruption in cancer patients. Lung cell membranes are rich in phospholipids that are susceptible to oxidation, leading to the formation of bioactive oxidized phosphatidylcholines (oxPCs). Persistent and elevated levels of oxPCs have been shown to induce chronic inflammation, leading to detrimental effects. However, recent reports suggest that certain oxPCs possess anti-inflammatory, pro-survival, and endothelial barrier-protective properties. Thus, we aimed to measure the levels of oxPCs in NSCLC patients and investigate their potential role in lung cancer. Methods: To explore the oxPCs profiles in lung cancer, we performed in-depth, multi-level metabolomic analyses of nearly 350 plasma and lung tissue samples from 200 patients with NSCLC, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), the two most prevalent NSCLC subtypes and COPD patients as a control group. First, we performed oxPC profiling of plasma samples. Second, we analyzed tumor and non-cancerous lung tissues collected during the surgical removal of NSCLC tumors. Because of tumor tissue heterogeneity, subsequent analyses covered the surrounding healthy tissue and peripheral and central tumors. To assess whether the observed phenotypic changes in the patients were associated with measured oxPC levels, metabolomics data were augmented with data from medical records. Results: We observed a predominance of long-chain oxPCs in plasma samples and of short-chain oxPCs in tissue samples from patients with NSCLC. The highest concentration of oxPCs was observed in the central tumor region. ADC patients showed higher levels of oxPCs compared to the control group, than patients with SCC. Conclusion: The detrimental effects associated with the accumulation of short-chain oxPCs suggest that these molecules may have greater therapeutic utility than diagnostic value, especially given that elevated oxPC levels are a hallmark of multiple types of cancer.

Assessment of 13 essential and toxic trace elements in tumor and peritumoral brain tissues from human glioblastoma.

Trace elements within the brain are important for proper neurological function, but their imbalance has been rarely investigated in glioblastoma. This study enrolled a total of 14 patients with glioblastoma, and the tumor and peritumoral brain tissues were collected while undergoing surgery. The concentrations of Mg, Ca, Cr, Mn, Fe, Co, Cu, Zn, Se, As, Cd, Tl and Pb were determined using a well-evaluated ICP-MS method. The Cu- and Cd-binding proteomes were further analyzed using the anatomic transcriptional atlas from Ivy GAP. Histological evaluation was based on rubeanic acid staining and immunohistochemistry, respectively. The 13 trace element concentrations were obtained, and the highest were Ca, Mn, Fe, Zn and Cu, ranging from a few to dozens of ug/g. Correlation analysis suggested the existence of two intra-correlated clusters: essential metals (Cu-Ca-Zn-Mg) and heavy metals (Pb-As-Cd-Tl-Co-Cr-Mn). Compared to the tumor samples, significantly higher levels of Cu and Cd were observed in the peritumoral region. Further analysis of the Cu- and Cd-binding proteins from the anatomic view suggested that DBH and NOS1 were obviously increased in the leading edge than the central tumor region. Consistent with the above findings, histological evaluation of Cu and DBH further confirmed more copper and DBH expressions in the peritumoral area compared to the tumor core. Trace elements differ in tumor and peritumoral brain zone in glioblastoma, which may associate with tumor angiogenesis.

Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status.

Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep-sequenced a panel of 56 cancer-related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node-positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node-negative and node-positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization.

4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer

Nutrient-limiting conditions are common during cancer development. The coordination of cellular glucose levels and cell survival is a fundamental question in cell biology and has not been completely understood. 4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation, however, whether 4EBP1 could participate in tumor survival by other mechanism except for translational repression function, especially under glucose starvation conditions remains unknown. Here, we found that protein levels of 4EBP1 was up-regulated in the central region of the tumor which always suffered nutrient deprivation compared with the peripheral region. We further discovered that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions, which prevented 4EBP1 from being targeted for ubiquitin-mediated proteasomal degradation by HERC5. After that, 4EBP1 translocated to cytoplasm and interacted with STAT3 by competing with JAK and ERK, leading to the inactivation of STAT3 in the cytoplasm, resulting in apoptosis under glucose withdrawal conditions. Moreover, 4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis in the central region of tumor. These findings highlight a novel mechanism for 4EBP1 as a new cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions, which was different from its classical function as a translational repressor.

Efficient drug delivery to hypoxic tumors using thermosensitive liposomes with encapsulated anti-cancer drug under high intensity pulsed ultrasound

Poor half-life, short circulation, systemic toxicity, insufficient accumulation, and ultimately weak therapeutic response are the most important obstacles in the conventional chemotherapy. Thermosensitive liposomes (TSLs) with encapsulated anti-cancer drug doxorubicin combined with high intensity focused ultrasound (HIFU) has the potential to overcome the shortcomings of conventional chemotherapy through targeted drug delivery. In the HIFU-TSL drug delivery system, complex physicochemical and biological processes are involved; however, many works in this field suffer from a comprehensive analysis. Regarding this, the present study has the novelty of developing an advanced multi-physical and multi-compartment model to simulate the complex processes in conventional and TSL-mediated chemotherapy paired with HIFU-induced hyperthermia. Elaborating the determinant role of tumor microenvironment is another novelty, which was underrepresented in earlier investigations and is noticed in our study through the modeling of hypoxic region. Additionally, unlike previous studies that used the classical bio-heat transfer model, this study has innovation in considering the thermal inertia as well as microstructural interactions in the bio-heat transfer equation. Last by not the least, many researchers evaded the harms of continuous irradiation, which in the present work is replaced by pulsed ultrasound as an emerging method for thermal necrosis and mild hyperthermia. The results reveal that the hypoxic region prevents efficient drug delivery due to the disruption of microvascular network and reduces chemotherapy-induced cell death. A comparison between targeted drug delivery and conventional chemotherapy suggests that TSL-mediated drug delivery leads to increased cell death by more than 100% by providing high circulation time and improved bioavailability. Besides this, increasing the acoustic power (from 3 to 8.7 W) leads to a desirable achievement, which is thermal necrosis of central tumor region and high fraction of killed cells (FKCs). The FKCs in the proposed HIFU-TSL system reaches about 58% (3 W), 60% (4.1 W), 70% (7 W), and 78% (8.7 W) at 24 h after TSL-doxorubicin administration, while this value is about 30% in the conventional chemotherapy. In conclusion, this study confirms the benefits of HIFU-TSL drug delivery system. This method has the potential to be used as a targeted drug delivery system to improve anti-cancer drug efficacy, while considerably prevents the normal tissue damage.

Cell‐Derived Biomimetic 2D Nanoparticles to Improve Cell‐Specific Targeting and Tissue Penetration for Enhanced Magnetic Resonance Imaging

AbstractA critical challenge of nanoparticle‐based imaging diagnosis of cancers is limited accumulation of nanoparticles at the biological target. Here, a cancer cell derived membrane coated 2D layered double hydroxides nanoparticle (CM‐PEG/MnLDH) has been developed to realize both cell‐specific targeting and deep tissue penetration for enhanced magnetic resonance imaging (MRI) of tumors. Using 4T1 breast cancer cells as a model, the biomimetic CM‐PEG/MnLDH exhibited excellent cell‐specific targeting ability with significantly higher accumulation in homologous cancer cells than the nonhomologous cells. Using 3D tumor spheroid cultures, the CM‐PEG/MnLDH demonstrated highly selective binding and deep tissue penetration ability. In vivo imaging revealed that intravenous injection of CM‐PEG/MnLDH provides clear MRI of tumor tissues in a 4T1 mouse model. Particularly, the CM‐PEG/MnLDH showed enhanced imaging performance in the central region of tumors, owing to the cell homing and tissue penetration ability of the biomimetic nanoparticle. In vivo biosafety evaluation of the CM‐PEG/MnLDH showed a high degree of biocompatibility, signifying its suitability for further clinical applications. The biomimetic CM‐PEG/MnLDH nanoparticle featured with cell‐specific targeting ability and deep tissue penetration is a promising MRI contrast agent for precise cancer diagnosis.

Abstract P039: The immune profile of colorectal and pancreas adenocarcinomas: Differences between central and peripheric tumor regions

Abstract Introduction The tumor microenvironment(TME) is a complex system, where malignant cells co-exist and communicate with immune and non-immune cells(1). This interaction can induce an immune response by releasing cytokines that will regulate and recruit immune cells which may promote tumor shrinkage (2). High tumor-infiltrating lymphocytes (TILs) in the TME have been correlated with favorable prognosis in colorectal and pancreatic adenocarcinomas (CRC and PDAC) (3,4). Also, high number of NK cells has been associated with a better prognosis in different solid tumors (5). Therefore, a detailed analysis of immune cells' distribution in the TME could help understand which of these cells have higher tumor-infiltrating capacities and may be used as cell product of immunotherapy. Experimental Procedure Fresh CRC (n=6) and PDAC (n=6) tumor specimens were obtained within 20 minutes after surgery. A specialized pathologist collected the central and peripheric regions (CR and PR, respectively) of the tumor. From each region, half of the specimen was used for immunophenotyping analysis and the other half was cultured with medium enriched in IL-2 (1000 IU/mL) for 12 days. Immunophenotyping was performed using CD45, CD19, CD3, CD4, CD8, CD56, CD16 and LiveDead marker through flow cytometry at days 0, 6 and 12 (% correspond to mean). Formalin-fixed paraffin-embedded blocks were generated with the ‘mirror' sample of the fresh collected specimens and immunohistochemistry (IHC) for CD8 and CD56 was performed. Results In the PR of CRC we identified 12% of B-cells, 66% of T-cells (31% CD4+ and 23% CD8+ T-cells) and 5% of NK cells (17% CD56brightCD16− cells and 24% CD56+CD16+ cells). In the CR of CRC we observed 7% of B-cells, 70% of T-cells (40% CD4+ and 23% CD8+ T-cells), and 6% of NK cells (15% CD56brightCD16− cells and 44% CD56+CD16+ cells). In the PR of PDAC we observed 13% of B-cells, 76% of T-cells (38% CD4+ and 35% CD8+ T-cells) and 3% of NK cells (5% CD56brightCD16− cells and 40% CD56+CD16+ cells). In the CR of PDAC we identified 16% of B-cells, 66% of T-cells (31% CD4+ and 32% CD8+ T-cells) and 10% of NK cells (2% CD56brightCD16− cells and 55% CD56+CD16+ cells). During culture, the % of B-cells decreased while the % of T-cells and NK cells increased. IHC results show that CD8+ T-cells are more abundant in the TME and formed larger clusters than NK cells. Furthermore, although the majority of NK cells were found in the stroma, in some cases NK cells were located inside the malignant epithelium. Conclusions Our data in this small set of specimens show that TME immune cells in PRs and CRs present different phenotypes for both CRC and PDAC. Indeed, the PRs show higher TIL and NK cells' infiltration than the central ones. Among different patients, the distribution and quantity of CD8+ T-cells and NK cells were different, which may have clinical significance. We also observed that immune cells may communicate with tumor cells both in CRC and PDAC since these cells were identified inside the malignant epithelium in some tumor specimens. Citation Format: Andreia Maia, Joana R. Lérias, Luis Miguel Borrego, Mireia Castillo-Martin, Markus Maeurer. The immune profile of colorectal and pancreas adenocarcinomas: Differences between central and peripheric tumor regions [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P039.

Eradication of large established tumors by drug-loaded bacterial particles via a neutrophil-mediated mechanism

The treatment of large established tumors remains a significant challenge and is generally hampered by poor drug penetration and intrinsic drug resistance of tumor cells in the central tumor region. In the present study, we developed bacterial particles (BactPs) to deliver chemotherapeutics into the tumor mass by hijacking neutrophils as natural cell-based carriers. BactPs loaded with doxorubicin, 5-fluorosuracil, or paclitaxel induced significantly greater tumor regression than unconjugated drugs. This effect was mediated by the ability of BactPs to incorporate chemotherapeutics and serve as vascular disrupting agents that trigger innate host responses and recruit phagocytic neutrophils. Vascular disruption resulted in extensive cell death in the central areas of the tumor mass. Recruited neutrophils acted as natural cellular carriers to deliver engulfed BactPs, which ensured drug delivery into the tumor mass and cytotoxic effects in areas that are normally inaccessible to traditional chemotherapy. Thus, BactPs eradicate large established tumors by functioning as vascular disrupters and natural drug carriers for neutrophil-mediated chemotherapy.

Breast cancer proliferation and deterioration-associated metabolic heterogeneity changes induced by exposure of bisphenol S, a widespread replacement of bisphenol A

Exposure to bisphenol A (BPA) is considered to be associated with the increased incidence of breast cancer. As a widespread replacement of BPA, the effect of bisphenol S (BPS) on breast tumor programming has not been studied. We reported that BPS exposure significantly promoted proliferation and deterioration of breast tumor by nonmonotonic dose response. The mechanisms were investigated by molecular biology and mass spectrometry-based lipidomics, proteomics and imaging. BPS exposure induced the spatially intratumor heterogeneity of morphology-driven lipids and proteins. The more significant proliferation resulted from BPS-10 (10 μg/kg body weight /day) exposure was evidenced by the variations of spatial distribution of lipids related to ceramide-sphingomyelin signaling pathway, proteins related to chromosomal stability and cell proliferation in central necrotic regions of breast tumor. In contrast, the BPS-100 exposure obviously accelerated deterioration of breast tumor by the variations of spatial distribution of proteins that were associated with the stability of nucleic acid structure in peripheral neoplastic regions. Accordingly, dysregulation of metabolism and protein function as well as DNA methylation and hypoxic tumor microenvironment could be applied to predict the possibility of tumorigenesis, proliferation and metastasis that might be caused by other bisphenol analogs.

Bacteriolytic Therapy: Tumor Microenvironment Targeting Nano–Bio Emulsion for Synergistic Combinational X‐Ray PDT with Oncolytic Bacteria Therapy (Adv. Healthcare Mater. 13/2020)

In article number 1901812 by Joonseok Lee, Dong-Hyun Kim, and co-workers, a tumor microenvironment targeting nano-bio therapeutic emulsion formulated with multi-functional nanoscintillators and anaerobic C. novyi-NT spores is developed for synergistic combinational cancer therapy. Nano-bio therapeutic emulsion is delivered to tumor sites under CT-image guidance, and effectively treats the normoxic peripheral and hypoxic central tumor region.

Tumor Microenvironment Targeting Nano-Bio Emulsion for Synergistic Combinational X-Ray PDT with Oncolytic Bacteria Therapy.

Various cancer therapies have been developed, but tumor recurrence with incomplete tumor killing and remaining tumor cells/tissues is frequent in monotherapies. Herein, a nano-bio therapeutic emulsion formulated with multifunctional nanoscintillators and anaerobic Clostridium novyi-NT spores for synergistic image-guided combinational cancer therapy is reported. MRI visible nanoscintillators (NSs) are synthesized with a NaGdF4 :Tb,Ce@NaGdF4 core/shell structure for an image-guided X-ray photodynamic therapy (PDT) of the normoxic peripheral tumor. An anaerobic oncolytic bacterium (C. novyi-NT) therapy is combined to treat the hypoxic central tumor tissues. Photosensitizer-coated NSs (PS-NSs) and C. novyi-NT spores are emulsified with clinically available ethiodized oil (Lipiodol) to be the nano-bio therapeutic emulsion and injected into the tumor with computed tomography image guidance. The distribution of nano-bio therapeutic emulsion, including PS-NSs and anaerobic C. novyi-NT spores in the tumor site, is confirmed by both X-ray and T1 -weighted magnetic resonance imaging. Following the image-guided X-ray PDT and anaerobic C. novyi- NT combination treatment, apoptotic cell death in cancer tissues, including both peripheral and central tumor regions, is significantly higher than in the control groups. This combination therapy approach using a nano-bio therapeutic emulsion is expected to overcome the limitations of conventional cancer therapy, resulting in increased cancer-therapeutic efficacy.

4-1BB Agonism Combined With PD-L1 Blockade Increases the Number of Tissue-Resident CD8+ T Cells and Facilitates Tumor Abrogation.

Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical practice, only a fraction of patients can benefit from it with durable responses and subsequent long-term survival. Here, we tested the anti-tumor effect of combining PD-L1 blockade with 4-1BB costimulation in 3LL and 4T1.2 murine tumor models. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice more so than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased the number of intratumoral CD103+CD8+ T cells and altered their distribution. Phenotypically, CD103+CD8+ T cells expressed a higher level of 4-1BB and PD-1 than their CD103− counterparts. Administration of PD-L1 mAb and 4-1BB mAb further increased the cytolytic capacity of CD103+CD8+ T cells. In vivo, CD103−CD8+ T cells could differentiate into CD103+CD8+ progeny cells. In a human setting, more CD8+ T cells differentiated into CD103+CD8+ T cells in the peripheral tumor region of lung cancer tissues than in the central tumor region. Collectively, infiltrated CD103+CD8+ T cells served as a potential effector T cell population. Combining 4-1BB agonism with PD-L1 blockade could increase tumor-infiltrated CD103+CD8+T cells, thereby facilitating tumor regression.

Low-abundance mutations in colorectal cancer patients and healthy adults.

Detecting low-abundance mutations is very important for cancer diagnosis and treatment. Here we describe an improved targeted sequencing analysis that dramatically increases sequencing depth. Seven colorectal cancer (CRC) patients and seven healthy adults were enrolled in this study. We examined genetic mutations in tissue samples from the central and peripheral regions of tumors from the CRC patients and in blood cells from the healthy adults. We observed that each CRC carried larger numbers of mutations more than previously estimated. These included numerous deletion mutations in the tumor tissue. While the cellular morphology in the surrounding normal colonic tissues was healthy, these cells also carried many mutations. Similarly, the blood cells from the healthy donors carried numerous mutations. These findings shed new light on the processes of tumorigenesis and aging, and also present a potentially effective method for detecting low-abundance mutations for cancer diagnosis and targeted treatments.

T2 mapping of molecular subtypes of WHO grade II/III gliomas

BackgroundAccording to the new WHO classification from 2016, molecular profiles have shown to provide reliable information about prognosis and treatment response. The purpose of our study is to evaluate the diagnostic potential of non-invasive quantitative T2 mapping in the detection of IDH1/2 mutation status in grade II-III gliomas.MethodsRetrospective evaluation of MR examinations in 30 patients with histopathological proven WHO-grade II (n = 9) and III (n = 21) astrocytomas (18 IDH-mutated, 12 IDH-wildtype). Consensus annotation by two observers by use of ROI’s in quantitative T2-mapping sequences were performed in all patients. T2 relaxation times were measured pixelwise.ResultsA significant difference (p = 0,0037) between the central region of IDH-mutated tumors (356,83 ± 114,97 ms) and the IDH-wildtype (199,92 ± 53,13 ms) was found. Furthermore, relaxation times between the central region (322,62 ± 127,41 ms) and the peripheral region (211,1 ± 74,16 ms) of WHO grade II and III astrocytomas differed significantly (p = 0,0021). The central regions relaxation time of WHO-grade II (227,44 ± 80,09 ms) and III gliomas (322,62 ± 127,41 ms) did not differ significantly (p = 0,2276). The difference between the smallest and the largest T2 value (so called “range”) is significantly larger (p = 0,0017) in IDH-mutated tumors (230,89 ± 121,11 ms) than in the IDH-wildtype (96,33 ± 101,46 ms). Interobserver variability showed no significant differences.ConclusionsQuantitative evaluation of T2-mapping relaxation times shows significant differences regarding the IDH-status in WHO grade II and III gliomas adding important information regarding the new 2016 World Health Organization (WHO) Classification of tumors of the central nervous system. This to our knowledge is the first study regarding T2 mapping and the IDH1/2 status shows that the mutational status seems to be more important for the appearance on T2 images than the WHO grade.

Intratumoral distribution of YSNSG cyclopeptide in a mouse melanoma model using microdialysis

The YSNSG peptide is a synthetic cyclopeptide targeting αvβ3 integrin with antitumor activity. Previous study has determined main pharmacokinetic parameters in plasma and in tissue in healthy animals using microdialysis. First we aim to assess the impact of a 20 mg/kg dosage instead of 10 mg/kg in tumor growth inhibition. Secondly we aim to investigate the YSNSG peptide distribution in two different tumor regions in animals with melanoma. C57BL/6 mice were exposed at Days 8, 10 and 12 after melanoma cells implantation (B16F1) to different dosage of YSNSG peptide or control, respectively (n = 10 per group). Data analysis was performed at D16, 20 and 24 with a Nonlinear Mixed-Effects (NLME) approach. For pharmacokinetic study n = 8 mice (same disease condition) received YSNSG peptide by intravenous after insertion of two microdialysis probes in central peripheral region of tumor, respectively. Plasma and tissue samples were collected during 2 h. A non-compartmental analysis was performed to determine main pharmacokinetic parameters. There was a significant tumor growth inhibition in mice receiving 20 mg/kg vs Control (p < 0.02). Main plasma parameters were half-life elimination 25.8 ± 8.2 min, volume of distribution 11.9 ± 0.4 mL, clearance 19.8 ± 9.4 mL/h and area under the curve 1,173.6 µg.min/mL. Penetration rate of the YSNSG peptide from plasma to tumor tissue were 3.3 ± 2.1% and 3.4 ± 2.7% in central and peripheral, respectively. Contrary to subcutaneous distribution in healthy animals the distribution of the YSNSG peptide into tumoral tissue is low but seems non-heterogeneous between central and peripheral tumor region.

Regulation and Role of GLI1 in Cutaneous Squamous Cell Carcinoma Pathogenesis.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin tumor in humans. Although current therapies are sufficient to clear the tumor in many cases, the overall risk of cSCC metastasis is still 5%. Alternative treatment options could help to overcome this situation. Here we focused on the role of the Hedgehog (HH) signaling pathway and its interplay with epidermal growth factor receptor (EGFR) signaling in cSCC. The analyses revealed that, despite lack of Sonic HH (SHH) expression, a subset of human cSCC can express GLI1, a marker for active HH signaling, within distinct tumor areas. In contrast, all tumors strongly express EGFR and the hair follicle stem cell marker SOX9 at the highly proliferative tumor-stroma interface, whereas central tumor regions with a more differentiated stratum spinosum cell type lack both EGFR and SOX9 expression. In vitro experiments indicate that activation of EGFR signaling in the human cSCC cell lines SCL-1, MET-1, and MET-4 leads to GLI1 inhibition via the MEK/ERK axis without affecting cellular proliferation. Of note, EGFR activation also inhibits cellular migration of SCL-1 and MET-4 cells. Because proliferation and migration of the cells is also not altered by a GLI1 knockdown, GLI1 is apparently not involved in processes of aggressiveness in established cSCC tumors. In contrast, our data rather suggest a negative correlation between Gli1 expression level and cSCC formation because skin of Ptch +/- mice with slightly elevated Gli1 expression levels is significantly less susceptible to chemically-induced cSCC formation compared to murine wildtype skin. Although not yet formally validated, these data open the possibility that GLI1 (and thus HH signaling) may antagonize cSCC initiation and is not involved in cSCC aggressiveness, at least in a subset of cSCC.

Semaphorin-5A downregulation is associated with enhanced migration and invasion of BRAF-positive melanoma cells under vemurafenib treatment in melanomas with heterogeneous BRAF status.

Tumor heterogeneity affects the efficacy of anticancer treatment as tumor subclones with distinct molecular patterns may be present within one tumor, leading to differing sensitivities to chemotherapeutic agents. In the present study, six melanoma tissue fragments were obtained from different parts of tumor of four patients and then the effect of vemurafenib treatment on biological characteristics and molecular processes of cell cultures was estimated by using MTT-test, apoptosis, migration and invasion assays, PCR real time. There was different BRAF status determined between cells derived from the central and peripheral regions of primary melanoma tumors. BRAF-positive melanoma cells showed an increased apoptotic rate under vemurafenib treatment, as well as increased migration and invasion rates, whereas BRAF-negative melanoma cells did not exhibit such tendency. Furthermore, semaphorin-5A levels were diminished in BRAF-positive cells, but not in BRAF-negative ones, which could be related to increased migration and invasion. Melanoma cells derived from different regions of the same tumor may differ by mutations status, molecular processes and biological response to target therapy. The downregulation of semaphorin-5A may be involved in divergent effects of anticancer agents on tumor cell biology.