Tumors Developed Research Articles

Specific overexpression of 15-lipoxygenase in endothelial cells promotes cancer cell death in an in vivo Lewis lung carcinoma mouse model

PurposeLipoxygenases (LOX) have been implicated in carcinogenesis, however both pro- and anti-carcinogenic effects have been reported in different cancer models. Using transgenic mice, which specifically overexpress human 15-lipoxygenase (ALOX15) in endothelial cells (EC), we previously demonstrated significant inhibition of tumor development. In the Lewis lung carcinoma (LLC) model, the primary tumor developed similarly in both wild type (WT) and ALOX15 overexpressing mice. However, metastases development was significantly inhibited in the transgenic mice. Here, we explored the molecular basis for the anti-metastatic effect of endothelial cell specific ALOX15 overexpression. Materials/methodsWe used ALOX15 overexpressing mice, and in-vitro cell model to evaluate the molecular effect of ALOX15 on EC and LLC cells. ResultsWhen LLC cells were injected in WT and ALOX15 overexpressing mice, we observed a higher degree of apoptosis and necrosis in primary and metastatic tumors of ALOX15 overexpressing animals. These anti-carcinogenic and anti-metastatic effects were paralleled by augmented expression of cyclin-dependent kinase inhibitor 1A (CDKN1A; p21) and of the peroxisome proliferators-activated receptor (PPAR)γ and by downregulation of the steady state concentrations of connexin26 mRNA. Consistent with these in vivo effects, ALOX15 overexpression in LLC and HeLa cancer cells in vitro significantly reduced cell viability in culture. In contrast, similar treatment of non-cancerous B2B epithelial cells did not impact cell viability. ConclusionsTaken together, our data suggests that endothelial cell specific overexpression of ALOX15 promotes apoptosis and necrosis in primary and metastatic tumors in mice, by upregulation of P21 and PPARγ expression in adjacent cancer cells.

The role of opioids in cancer progression.

The role of opioids in cancer progression.

Identification of Sex Differences in Tumor-Specific T Cell Infiltration in Bladder Tumor-Bearing Mice Treated with BCG Immunotherapy

BACKGROUND: Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumor-specific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. OBJECTIVE: To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. METHOD: We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. RESULTS: We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations. Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8+ T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy whereas regulatory T cells had higher levels of the exhaustion marker PD-1 in female mice. CONCLUSIONS: We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

Патогенетические механизмы лекарственных повреждений печени

Drug-induced liver damage (DILD) is a common condition that can lead in some cases to acute liver failure and unfavorable patient outcomes. DILD development mechanisms are of two main types. The first is a direct dose-dependent type and the second is dose-independent idiosyncratic one. Cytochrome P450 system is of great importance in the genesis of direct DILD, since during drugs metabolism highly toxic metabolites can be formed in this liver enzymatic system. As a result, hepatocytes die destructing mitochondria and thus blocking the production of cell energy substrates, triggering oxidative stress and lipid peroxidation. It also leads to direct DNA damage and activation of signaling pathways for apoptosis. In most cases idiosyncratic DILD is associated with individual genetically determined predisposition with a wide range of clinical manifestations. In case of this type of DILD, the immune cells are sensitized to hepatocytes activating humoral and cellular immune response and rather often forming antibodies to some structural element of hepatocytes. The structure of antigens of the main histocompatibility complex as well as receptor-mediated interactions with Fas-ligand participation, interferon gamma and tumor necrosis factor play a certain role in the development of idiosyncratic DILD. By present, hypotheses of immune system activation in idiosyncratic DILD have been proposed, including haptenization hypothesis; the hypothesis of direct interaction of drugs with the molecules of major histocompatibility complex and subsequent activation of the immune system; the hypothesis of changes in structural sequences of endogenous biologically active peptides with impaired interaction in the backbones of major histocompatibility complex and occurrence of autoimmune reactions. Finally, there is the hypothesis of multiple determinants, which postulates that there are various risk factors (for example, genetic polymorphisms, gender, age, etc.) that contribute to DILD onset in case of comorbidity. DILD mechanisms can also be considered according to clinical and morphological type of liver damage. One can distinguish cholestatic DILD type, vascular type, steatosis, and the type when liver tumor develops. The cholestatic DILD type is clinically expressed by cholestasia or inability of bile to enter the lumen of small intestine as a result of abnormal secretion of bile acids by hepatocytes or obstruction of biliary tract. Hepatic steatosis is histologically determined as deposition of triglycerides within hepatocytes. Drug-induced steatosis is reversible unless steatohepatitis or cirrhosis has developed. Vascular DILD type is associated with damage of stellate and endothelial liver cells, lining sinusoidal capillaries. Edema, thrombosis of small intrahepatic vessels, develop as a result of it, leading to obstruction of venous outflow (and impaired lymph outflow), expansion of sinusoids, pressure overload and hepato-hepatic necrosis, and, in some cases, to centrilobular fibrosis. This pathology is known as sinusoidal obstruction syndrome or venous-occlusive disease. DILD type with the development of liver tumor includes hepatocellular adenoma, hepatocellular carcinoma, cholangiocarcinoma. Awareness of pathogenetic DILD correlations is important in real clinical practice, since, on the one hand, it allows to optimize the diagnostic search for the cause of liver disease, and on the other hand, it increases the effectiveness of approaches to treat and prevent such conditions.

Pineal Gland Tumor Microenvironment.

A wide and heterogeneous variety of tumors develop from the pineal gland. Pineal parenchymal tumors, germ cell tumors, and glial tumors represent most of them. The molecular profiles and tumor microenvironment play a key role in the development and progression of pineal gland tumors. Consequently, they represent important factors that may determine the efficacy of the different treatment modalities and the clinical outcome. Current literature is scarce regarding the microenvironment research of pineal gland tumors. Here, we review the cellular and molecular profile of the pineal gland tumor microenvironment.

BT-10 A RARE CASE OF RADIATION-INDUCED GLIOBLASTOMA 29 YEARS AFTER TREATMENTS OF GERMINOMA

BACKGROUNDGerminoma is one of the most radiosensitive tumors. Although radiotherapy (RT) can lead to long term-survival, it has the possibility to cause adverse effects. One of the more serious side effects include radiation-induced tumors that can contribute to a life-long prognosis.Case presentationA 40-year-old man was diagnosed with left basal ganglia germinoma at the age of 11 years old. Postoperatively, he received whole-brain radiotherapy 40Gy, focal radiotherapy 9.26Gy, and craniospinal irradiation. After these treatments, he was free from tumor recurrence or a secondary tumor during the long-term follow up. However, after 29 years, he began experiencing aphasia. A Magnetic Resonance Imaging (MRI) showed a developing 4.5cm round mass in the left parietal lobe with marked surrounding edema. He underwent surgical resection of the tumor at the left partial lobe. Pathological examination showed the tumor to consist of unclear pleomorphism, and the diffuse proliferation of heterocyst. Therefore, the pathologic diagnoses concluded as glioblastoma (Ki-67 labeling index was 50%). Conclusion: The tumor developed in the previously irradiated field, and it was not present prior to the RT. He did not suffer from pathologies favoring the development of the tumor. The interval between the radiation exposure and the onset of the second tumor was approximately 29 years, and the histotype of the tumor differed from the original tumor. Considering these clinical features, we diagnosed the glioblastoma as a radiation-induced tumor. Radiation-induced malignant glioma occurs frequently in patients after the treatment for acute lymphoblastic leukemia. Therefore, the radiation-induced malignant glioma after the treatment for germinoma is rare. Regardless of age, histology, and RT dosages, the patient has the possibility to develop radiation-induced malignant glioma. In conclusion, it is necessary to have careful monitoring even after 20–30 years of RT.

Metachronous intraductal papillary mucinous neoplasms disseminate via the pancreatic duct following resection.

Metachronous development of intraductal papillary mucinous neoplasms in the remnant pancreas following resection is a significant clinical burden. Our aim was to characterize the clinicopathological and molecular features of the patients with metachronous tumor development to identify predictive factors and the possible route(s) of dissemination. Seventy-four patients who underwent resection of intraductal papillary mucinous neoplasms with no invasive compartment or associated carcinoma were retrospectively analyzed. In patients with metachronous tumor development, targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical detection of four proteins (p53, SMAD4, p16, and β-catenin) were performed on both primary and metachronous tumors. The distributions of microscopic neoplastic lesions were examined at surgical margins and in apparently normal tissue apart from the primary tumor. During the median follow-up period of 52 months, 9 patients (12%) developed metachronous tumors in the remnant pancreas. Primary tumors located in the body/tail of the pancreas (odds ratio, 15; 95% confidence interval, 1.6-131) and of the pancreatobiliary type (odds ratio, 6.1; 95% confidence interval, 1.1-35.7) were identified as significant risk factors for subsequent metachronous tumor development. Eight of the nine patients shared molecular aberrations between their primary and metachronous tumors, suggesting migrations from the primary tumor to the pancreatic duct as the cause of metachronous tumor development. Our data suggest that these post-resection metachronous tumors develop by skip dissemination of the primary tumor, potentially via the pancreatic duct. The development of strategies to better predict and prevent this form of tumor progression is necessary.

Treatment of Asymptomatic Meningioma With Gamma Knife Radiosurgery: Long-Term Follow-up With Volumetric Assessment and Clinical Outcome.

Some patients are diagnosed with asymptomatic meningioma(s) after undergoing a screening CT and MRI for minor ailments or postresection. To help clinicians in decision making for treatment of asymptomatic meningiomas. A single center retrospective cohort study of 117 patients with 122 tumors treated with Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden). Patients were followed with longitudinal imaging and clinical evaluations. Tumor volumetry and developments of new signs or symptoms after GKRS were the end points in the study. Median patient age at GKRS was 60 yr (range 21-86 yr) with a median clinical follow-up of 53 mo (range 20-252 mo). The median pre-GKRS tumor volume was 3.6±3.8 cc (±standard deviation). Tumors were treated with a median margin dose of 14±2 Gy. At last follow-up, median tumor volume was 2.5±3.6 cc. Radiological progression-free survival (PFS) rates were 97% and 94.4% at 5 yr and 10 yr, respectively. Clinical PFS rates were 86% and 70% at 5 yr and 10 yr, respectively. Development of neurological complications was seen in 21 (18%) patients, and 11 (52%) of them had undergone surgical resection prior to GKRS. GKRS is a reasonable treatment strategy for asymptomatic meningiomas and compares favorably to natural history studies in terms of tumor control and neurological preservation. It results in relatively low morbidity in previously untreated meningiomas and serves as an appealing alternative treatment modality for recurrent meningiomas in asymptomatic patients.

Fostering open collaboration in drug development for paediatric brain tumours.

Brain tumours have become the leading cause of child mortality from cancer. Indeed, aggressive brainstem tumours, such as diffuse intrinsic pontine glioma (DIPG), are nearly uniformly fatal. These tumours display a unique set of driver mutations that distinguish them from adult gliomas and define new opportunity for the development of precision medicines. The specific association of ACVR1 mutations with DIPG tumours suggests a direct link to neurodevelopment and highlights the encoded bone morphogenetic protein receptor kinase ALK2 as a promising drug target. Beneficial effects of ALK2 inhibition have now been observed in two different in vivo models of DIPG. Nonetheless, such tumours present a huge challenge for traditional economic models of drug development due to their small market size, high failure rate, tumour location and paediatric population. Moreover, a toolkit of different investigational drugs may be needed to fully address the heterogeneity of these tumours in clinical trials. One new business model is suggested by M4K Pharma, a recent virtual start up that aims to align diffuse academic and industry research into a collaborative open science drug discovery programme. Fostering scientific collaboration may offer hope in rare conditions of dire unmet clinical need and provide an alternative route to affordable medicines.

DNA Nanorobot Delivers Antisense Oligonucleotides Silencing c-Met Gene Expression for Cancer Therapy

Antisense oligonucleotides are considered to be a promising strategy for cancer therapy because of their high specificity and minimal side effects. They can bind specifically to mRNA silencing the expression of target genes. However, ssDNA cannot enter cells in large quantities, which limits its applications. Tetrahedral framework nucleic acids (tFNA) are considered to be optimal nanoscopic drug carriers because of their editability and biocompatibility. Most importantly, they can be modified with functional molecules. The over-expression of c-Met is associated with a wide variety of tumor occurrences, developments, drug resistance and prognoses. Activation of HGF/c-Met signaling pathways can promote cell migration and invasion in cancer. Therefore, blocking the expression of c-Met is a valid technique for cancer therapy. In this study, we used tFNA as carriers to deliver antisense oligonucleotides, which can bind to c-Met mRNA with high specificity and affinity, into cells resulting in the inhibition of c-Met expression for cancer therapy.

IL-32\u03b3 suppresses lung cancer stem cell growth via inhibition of ITGAV-mediated STAT5 pathway

The cancer stem cells (CSCs) are thought to be responsible for cancer initiation, recurrence, and metastasis via a multifactorial process. IL-32γ has been known to inhibit several tumor developments. However, the role of IL-32γ in CSCs is unknown. The role of IL-32γ on tumor development was assessed in IL-32γ transgenic (Tg) mice allograft and xenograft model. In the in vitro assay, we analyzed CSC growth and apoptosis in cells with IL-32γ overexpression by cell viability assay and tumor-sphere formation assay. In addition, expression of cell proliferation, apoptosis markers, and signaling molecules was determined by western blot analysis. IL-32γ suppressed CD133+ CSC-induced allograft model in IL-32γ Tg mice and xenograft model. Tumor-sphere formation and cell viability assay revealed a greater inhibition of CSC proliferation and antineoplastic activity of IL-32γ in CD133+ CSCs as compared with normal cancer cells. The inhibitory effects of IL-32γ on tumor development were associated with inhibition of the STAT5 pathway. In addition, inhibition of STAT5 increased cleavage of caspase-3, but suppressed CD133 expression and colony formation. Web-based gene network analysis showed that IL-32 is correlated with ITGAV, an integrin gene. Our result revealed that knockdown of ITGAV by siRNA inhibited the phosphorylation of STAT5. Moreover, we identified that ITGAV overexpression reversed the effect of IL-32γ on phosphorylation of STAT5 and the expression of CD133. Our results demonstrate that IL-32γ negatively regulates CD133+ CSC proliferation and tumor development and suggest that IL-32γ has great potential for use in the treatment of cancer progression.

A phase I study of oncolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium: Cohort 1 results.

4102 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed and one such option is hepatic intralesional (IL) rose bengal disodium (PV-10), an oncolytic immunotherapy under development for solid tumours. Methods: This phase 1 study is evaluating the safety, tolerability and reduction of biochemical markers and symptoms resulting from percutaneous administration of PV-10 in 12 subjects with progressive mNEN with hepatic lesions not amenable to resection or other potentially curative therapy. Target lesion(s) must be 1.0 - 3.9 cm in longest diameter. In Cohort 1 (n = 6) subjects receive PV-10 to a single hepatic lesion per treatment cycle, and can receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. Cohort 2 (n = 6) subjects may receive injection of multiple lesions per treatment cycle. The primary endpoint is safety. Secondary endpoints include objective response rate (ORR) assessed by contrast enhanced CT and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21). Results: Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior SSA and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway. Clinical trial information: NCT02693067.

A Novel 3D In Vitro Platform for Pre-Clinical Investigations in Drug Testing, Gene Therapy, and Immuno-oncology

Tumors develop within complex cell-to-cell interactions, with accessory cells playing a relevant role starting in the early phases of cancer progression. This event occurs in a three-dimensional (3D) environment, which to date, has been difficult to reproduce in vitro due to its complexity. While bi-dimensional cultures have generated substantial data, there is a progressive awareness that 3D culture strategies may rapidly increase the understanding of tumor development and be used in anti-cancer compound screening and for predicting response to new drugs utilizing personalized approaches. However, simple systems capable of rapidly rebuilding cancer tissues ex-vivo in 3D are needed and could be used for a variety of applications. Therefore, we developed a flat, handheld and versatile 3D cell culture bioreactor that can be loaded with tumor and/or normal cells in combination which can be monitored using a variety of read-outs. This biocompatible device sustained 3D growth of tumor cell lines representative of various cancers, such as pancreatic and breast adenocarcinoma, sarcoma, and glioblastoma. The cells repopulated the thin matrix which was completely separated from the outer space by two gas-permeable membranes and was monitored in real-time using both microscopy and luminometry, even after transportation. The device was tested in 3D cytotoxicity assays to investigate the anti-cancer potential of chemotherapy, biologic agents, and cell-based therapy in co-cultures. The addition of luciferase in target cancer cells is suitable for comparative studies that may also involve parallel in vivo investigations. Notably, the system was challenged using primary tumor cells harvested from lung cancer patients as an innovative predictive functional assay for cancer responsiveness to checkpoint inhibitors, such as nivolumab. This bioreactor has several novel features in the 3D-culture field of research, representing a valid tool useful for cancer investigations, drug screenings, and other toxicology approaches.

Dietary Polyphenols, Resveratrol and Pterostilbene Exhibit Antitumor Activity on an HPV E6-Positive Cervical Cancer Model: An in vitro and in vivo Analysis.

Human papilloma virus (HPV)-induced cervical cancer is one of the most frequent cancers in women residing in underdeveloped countries. Natural compounds like polyphenols continue to be of scientific interest as non-toxic effective alternative treatments. Our previous work showed the efficacy of two polyphenols, resveratrol, and pterostilbene on human HeLa cells. Here we explored the in vitro anti-cancer activity and in vivo anti-tumor potential of these two structurally similar compounds on HPV oncogene E6 and E7 positive murine TC1 cells. In vitro analysis confirmed the cytotoxic potential of both resveratrol and pterostilbene compounds with each having a low IC50 value and each showing the ability to downregulate viral oncogene E6. Further in vivo studies on TC1 tumors developing in mice indicated that treatment with either resveratrol or pterostilbene can significantly inhibit tumor development, with both compounds capable of downregulating E6 and VEGF tumor protein levels. Interestingly, the decrease in tumor size in pterostilbene was associated with tumor cell apoptosis, as indicated by an upregulation of activated caspase-3 whereas in resveratrol-treated mice it was accompanied by arrest of cell cycle, as indicated by a downregulation of PCNA. Thus, resveratrol and pterostilbene can serve as potential antineoplastic agents against HPV E6+ tumors and may suppress tumor growth via two different mechanisms.

A physicist’s view of the similarities and differences between tuberculosis and cancer

In 2015 in the United States 612,000 persons died from cancer whereas only 470 died from tuberculosis (TB), a disease which was the main cause of death around 1900. How can one explain such a huge discrepancy in treatment progress? A statistical and medical comparison between TB and cancer will give some clues.What makes the question of particular interest is the fact that TB and cancer also share important features. Both TB and cancer can affect several organs, e.g. the lungs, brain, bones, intestines, skin. What in cancer is called “malignant neoplasm” (tumor) is called “granuloma” in TB. By isolating malignant cells from the rest of the body, such clusters protect the host’s organism but at the same time they are “secure beachheads” from where malignant cells can wander off to new locations. Thus, metastatic tumors have a TB parallel in the form of secondary granulomas.To investigate this parallel more closely we use the age-specific response of organs. Called spectrometric analysis in a previous paper (Berrut et al. 2017), this method provides information about how fast tumors develop and how serious they become. A characterization of the response to TB of organ j is given by the following (age-dependent) death ratio: Tj(t)=(death by TB of type j at age t)∕(all TB deaths at age t).The development of cancer tumors can be described by similar profile functions Cj(t).It appears that for the same organ Tj(t) is similar in shape to Cj(t). In other words, the idiosyncrasies of each organ are more determinant than the functional differences between TB and cancer. Such observations bring to light vulnerabilities in the way the immune system provides protection to various organs.

Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine

BackgroundMismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2LoxP/LoxP (Msh2−/−) mice months before tumor onset.ResultsHistone H3 methylation increases in Msh2−/− compared to control Msh2+/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2+/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2+/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2−/− mice left their histone methylation profiles almost unchanged.ConclusionsMMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.

Novel concept of the border niche: glioblastoma cells use oligodendrocytes progenitor cells (GAOs) and microglia to acquire stem cell-like features.

Glioblastoma (GBM) is a major malignant brain tumor developing in adult brain white matter, characterized by rapid growth and invasion. GBM cells spread into the contralateral hemisphere, even during early tumor development. However, after complete resection of tumor mass, GBM commonly recurs around the tumor removal cavity, suggesting that a microenvironment at the tumor border provides chemo-radioresistance to GBM cells. Thus, clarification of the tumor border microenvironment is critical for improving prognosis in GBM patients. MicroRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass was compared, and five miRNAs showing characteristically higher expression in the tumor border were identified, with the top three related to oligodendrocyte differentiation. Pathologically, oligodendrocyte lineage cells increased in the border, but were rare in tumors. Macrophages/microglia also colocalized in the border area. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, suggesting that OPCs and macrophages/microglia constitute a special microenvironment for GBM cells at the tumor border. The supportive function of OPCs for GBM cells has not been discussed previously. OPCs are indispensable for GBM cells to establish special niches for chemo-radioresistance outside the tumor mass.

Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice.

The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell-cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onward. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and nontransgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of nonperpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress; all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.

Antibody-Drug Conjugate-Based Therapeutics: State of the Science.

Antibody-drug conjugates (ADCs) are complex engineered therapeutics consisting of monoclonal antibodies, directed toward tumor-associated antigens, to which highly potent cytotoxic agents are attached using chemical linkers. This targeted drug delivery strategy couples the precision of the antibody targeting moiety with the cytocidal activity of the payload, which is generally too toxic on its own to be systemically administered. In this manner, ADCs confer a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload, thus broadening the potential therapeutic window compared with traditional chemotherapy. The pace of ADC development is accelerating, with the number of investigational agents in human trials having more than tripled over the past 5 years, underscoring the enthusiasm for this transformative approach to cancer treatment. Here, we review the key structural elements of ADC design (antibody, linker, and payload), highlighting critical aspects and technological advances that have affected the clinical effectiveness of this class of biopharmaceuticals. The ADC field continues to evolve, including ongoing efforts aimed at improving target selection, developing payloads with varied mechanisms of action and increased potency, designing innovative bioconjugation strategies, as well as maximizing efficacy and tolerability in patients. An overview of the current clinical trial landscape is provided, with emphasis on the clinical experience of the four ADCs to have received regulatory approval to date, as well as additional promising candidates currently in late-stage clinical development in both solid tumor and hematological malignancies.

Tumor Neovascularization and Developments in Therapeutics.

Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents.