Onco

A complex interaction occurs between cancer cells and the extracellular matrix (ECM) in the tumour microenvironment (TME). In this study, the expressions and mutational profiles of 964 ECM-related genes and their correlations with patient overall survival (OS) in neuroblastoma, an aggressive paediatric malignancy, were investigated using cBioPortal and PCAT databases. Furthermore, extended networks comprising protein-protein, protein-long non-coding RNA (lncRNA), and protein-miRNA of 12 selected ECM-related genes were established. The higher expressions of 12 ECM-related genes, AMBN, COLQ, ELFN1, HAS3, HSPE1, LMAN1, LRP5, MUC6, RAMP2, RUVBL2, SSBP1 and UMOD in neuroblastoma patients displayed a significant correlation with patient OS, while similar associations with neuroblastoma patient risk groups, histology and MYCN amplification were obtained. Furthermore, extended gene networks formed by these 12 ECM-related genes were established using Cytoscape, STRING, MSigDB/BioGRID, GeneMANIA and Omicsnet. Finally, the implications of the 12 ECM-related genes in other cancers were revealed using GEPIA2 and the Human Pathology Atlas databases. This meta-analysis showed the significance of these 12 ECM-related genes as putative prognostic predictors in neuroblastoma and other cancers. Full article

Purpose: To study the production of angiodrastic chemokines by colonic cancer cell lines. Methods: A pro-angiogenic factor (VEGF), two angiogenic chemokines (CXCL8, CXCL6), and one angiostatic (CXCL4) chemokine were measured by ELISA in the supernatants of the colon cancer cell lines HT-29 and Caco-2. Cells were cultured for 24 h in the presence of serum from cancer patients or healthy individuals. Results were analyzed by one-way ANOVA and the General Linear Model for repeated measures. Results: Colonic epithelial cells are potent producers of angiodrastic chemokines. HT-29 and Caco-2 cells produce all four chemokines under basal conditions and 24 h after incubation with human serum. The secretion response, however, was completely different. HT-29 cells produce more CXCL8 and VEGF irrespective of culture conditions, while Caco-2 cells seem unresponsive with respect to CXCL6 and CXCL4. Moreover, HT-29 cells produce more CXCL8 and VEGF when incubated with cancer serum, contrary to Caco-2 cells which produce more CXCL4 under the same conditions. Conclusions: The two colon cancer cell lines were producers of all chemokines studied, but their responses were not uniform under similar culture conditions. CXCL8 and VEGF are differently regulated compared to CXCL4 and CXCL6 in these two cell lines Full article

Background and Objective: This paper aimed to differentiate primary cancer types from primary tumor samples on the basis of somatic point mutations (SPMs). Primary cancer site identification is necessary to perform site-specific and potentially targeted treatment. Current methods such as histopathology and lab tests cannot accurately determine cancer origin, which results in empirical patient treatment and poor survival rates. The availability of large deoxyribonucleic acid sequencing datasets has allowed scientists to examine the ability of somatic mutations to classify primary cancer sites. These datasets are highly sparse since most genes will not be mutated, have a low signal-to-noise ratio, and are often imbalanced since rare cancers have fewer samples. Methods: To overcome these limitations a sparse-input neural network (SPINN) is suggested that projects the input data in a lower-dimensional space, where the more informative genes are used for learning. To train and evaluate SPINN, an extensive dataset for SPM was collected from the cancer genome atlas containing 7624 samples spanning 32 cancer types. Different sampling strategies were performed to balance the dataset. SPINN was further validated on an independent ICGC dataset that contained 226 samples spanning four cancer types. Results and Conclusions: SPINN consistently outperformed classification algorithms such as extreme gradient boosting, deep neural networks, and support vector machines, achieving an accuracy up to 73% on independent testing data. Certain primary cancer types/subtypes (e.g., lung, brain, colon, esophagus, skin, and thyroid) were classified with an F-score > 0.80. Full article

The high incidence and modest therapeutic outcomes of lung cancer have prompted the identification of cell molecular targets/biomarkers within the complex networks of interactions involved in cell malignancy. Most of the EMT-related regulatory mediators underline patients’ biologic variations, therapeutic refractory events, and tumor cell heterogeneity. Patient stratification based on the understanding of the relevant pathways, such as the PI3K/Akt axis crucial in EMT initiation, could favorably alter disease management. Significant clinical advantage could be expected when overexpressed Akt tyrosine kinase (Akt2) is addressed as a malignant biomarker to guide clinical management decisions, improving prognosis in lung cancer patients. Moreover, one should not miss the opportunity of using it as a druggable target aiming at the inhibition of the downstream complexity that underlies cell proliferation and survival, expression of stemness markers and drug resistance. The value of mTOR, as a downstream target of Akt, and the further activation of EMT transcription factors Twist, Snail and Zeb1 are revisited in this review. An in-depth state-of-the-art assessment provides evidence of its role in the mechanistic inhibition of epithelial markers, such as E-cadherin and miR-200, while inducing the expression of the mesenchymal ones, such as vimentin, N-cadherin, and miR-21. Lastly, evidence suggesting another transcription factor, FOXM1, as the link between the PI3K/Akt and Wnt/β-catenin pathways, prompting cell metabolism through the regulation of p70S6K, is analyzed. A more realistic approach is advised to address unmet clinical needs and support decision making at a clinical level. Taking into consideration several complex intracellular interactions might further improve patient stratification and result in better outcomes. Full article

Photodynamic therapy (PDT) is a cancer treatment that relies on the remote-controlled activation of photocatalytic dyes (photosensitizers) in cancer tissues. To effectively treat cancer, a variety of pharmacological and optical parameters require optimization, which are dependent on the photosensitizer type. As most photosensitizers are hydrophobic molecules, nanoliposomes are frequently used to increase the biocompatibility of these therapeutics. However, as nanoliposomes can influence the therapeutic performance of photosensitizers, the most suitable treatment parameters need to be elucidated. Here, we evaluate the efficacy of PDT on spheroid cultures of PANC-1 and MIA PaCa-2 pancreatic cancer cells. Two strategies to photosensitize the pancreatic microtumors were selected, based on either nanoliposomal benzoporphyrin derivative (BPD), or non-liposomal methylene blue (MB). Using a comprehensive image-based assay, our findings show that the PDT efficacy manifests in distinct manners for each photosensitizer. Moreover, the efficacy of each photosensitizer is differentially influenced by the photosensitizer dose, the light dose (radiant exposure or fluence in J/cm²), and the dose rate (fluence rate in mW/cm²). Taken together, our findings illustrate that the most suitable light dosimetry for PDT strongly depends on the selected photosensitization strategy. The PDT dose parameters should therefore always be carefully optimized for different models of cancer. Full article

The use of core needle biopsy (CNB) as a means to verify malignancy preoperatively is a paradigm in current breast cancer care, and the risk of enhancing tumor development by this procedure has been considered insignificant. Experimental work in mice has shown preoperative biopsies to increase tumor supportive elements in the microenvironment, whereas, in humans, the impact of CNB on the host’s immunologic response has not been investigated. In this pilot study, we compared the expression of CCL2/CCR2 pathway components at the protein level in samples from CNBs to those from the corresponding resected tumors from 52 patients with primary breast cancer. We found an increased expression of CD163, CD14 and CCR2 in monocytes/macrophages and a slight decrease of CCL2 in the malignant epithelium in the tumors after the biopsy. The increased infiltration of immunosuppressive monocytes/macrophages and the decreased tumor cell CCL2 expression, presumably due to the CCR2 availability-dependent CCL2 internalization, suggest that CNB enhances the activity of the CCL2/CCR2 pathway, and this finding warrants confirmatory examination. The switch in the context-dependent role of CCL2 on the polarization of macrophages may lead to increased tumor supportive function both locally and in the peripheral immune machinery. The future directions in breast cancer should include early interventions to support the tumor surveillance of the host. Full article

Supporting data sharing is paramount to making progress in cancer research. This includes the search for more precise targeted therapies and the search for novel biomarkers, through cluster and classification analysis, and extends to learning details in signal transduction pathways or intra- and intercellular interactions in cancer, through network analysis and network simulation. Our work aims to support and promote the use of publicly available resources in cancer research and demonstrates artificial intelligence (AI) methods to find answers to detailed questions. For example, how targeted therapies can be developed based on precision medicine or how to investigate cell-level phenomena with the help of bioinformatical methods. In our paper, we illustrate the current state of the art with examples from glioma research, in particular, how open data can be used for cancer research in general, and point out several resources and tools that are readily available. Presently, cancer researchers are often not aware of these important resources. Full article

About 70% of patients with metastatic colorectal carcinoma (mCRC) have liver metastases. Hepatic failure accounts for most mCRC-related deaths. Therefore, controlling liver metastases may improve outcomes. A data overview of liver-directed treatment using yttrium-90 selective internal radiation therapy (SIRT) is provided as part of a multimodality treatment. SIRT in mCRC is discussed, and the prognostic factors for patient selection are defined. Pooled analyses of three recent trials incorporating SIRT plus chemotherapy revealed subsets of patients with mCRC who might benefit from SIRT. A multidisciplinary treatment for most mCRC patients is proposed to achieve long-term survival in this cohort of patients. Full article

Cancer is one of the leading causes of death worldwide. Multifactorial etiology of cancer and tumor heterogeneity are the two most acute challenges in existing diagnostic and therapeutic strategies for cancer. An effective precision cancer medicine strategy to overcome these challenges requires a clear understanding of the transcriptomic landscape of cancer cells. Recent innovative breakthroughs in high-throughput sequencing technologies have identified the oncogenic or tumor-suppressor role of several long non-coding RNAs (lncRNAs). LncRNAs have been characterized as regulating various signaling cascades which are involved in the pathobiology of cancer. They modulate cancer cell survival, proliferation, metabolism, invasive metastasis, stemness, and therapy-resistance through their interactions with specific sets of proteins, miRNAs and other non-coding RNAs, mRNAs, or DNAs in cells. By virtue of their ability to regulate multiple sets of genes and their cognate signaling pathways, lncRNAs are emerging as potential candidates for diagnostic, prognostic, and therapeutic targets. This review is focused on providing insight into the mechanisms by which different lncRNAs play a critical role in cancer growth, and their potential role in cancer diagnosis, prognosis, and therapy. Full article

Increasing knowledge of cancer immunology has led to the design of therapies using immune cells directly or manipulating their activity, collectively termed immunotherapy. In the field of immuno-oncology, research on adaptive immune T cells has led to the development of CAR-T cells. Innate immune cells such as NK cells can also eliminate oncogenically transformed cells and regulate cells of the immune system. Considering NK cells as a live drug, numerous methods for the isolation and activation of NK cells have been shown to be clinically and therapeutically relevant. In such processes, various cytokines and antibodies present a source of stimulation of NK cells and enhance the efficacy of such treatments. The ex vivo expansion and activation of NK cells, along with genetic modification with CAR, enhance their antitumor activity. Recent preclinical studies have shown an antitumor effect through extracellular vesicles (EVs) derived from NK cells. Work with autologous NK cells has provided insights for clinical applications. In this review, we outline the recent advances of NK-cell-based immunotherapies, summarizing CAR-NK cells, BiKEs, and TriKEs as treatment options against cancer. This review also discusses the challenges of NK cell immunotherapy. Full article

Gastric cancer is one of the most common cancers and the third cause of cancer-related death worldwide. The treatment of GC patients improved due to advancements in surgery, radiotherapy and chemotherapy. However, the long-term survival rate of patients with gastric cancer remains around 20%. Thus, development of novel therapeutic approaches is of great interest, in order to reduce the need for mutilating surgeries and morbid adjuvant therapies. For many years, it was believed that the RNA was a mere intermediate molecule in the genetic information flow. However, during the past decades, with the advent of new sequencing technologies, it was revealed that non-coding RNAs play important roles in many different biological processes. The Wnt/β-catenin signaling pathway has been reported to regulate crucial events during neoplasic development, such as cell differentiation, proliferation, invasion, migration, apoptosis, and angiogenesis. In this review, we will focus on microRNAs and long non-coding RNAs that have been implicated in gastric cancer tumorigenesis via modulation of the Wnt/β-catenin signaling pathway, which provided some biomarkers to prognosis, diagnosis, and therapy. Full article

Neuroblastoma (NB) represents the most common extracranial tumor of childhood. Prognosis is quite variable, ranging from spontaneous regression to aggressive behavior with wide metastatization, high mortality, and limited therapeutic options. Radiotheranostics combines a radiopharmaceutical pair in a unique approach, suitable both for diagnosis and therapy. For many years, metaiodobenzylguanidine (MIBG), labeled with ¹²³I for imaging or ¹³¹I for therapy, has represented the main theranostic agent in NB, since up to 90% of NB incorporates the aforementioned radiopharmaceutical. In recent years, novel theranostic agents hold promise in moving the field of NB radiotheranostics forward. In particular, SarTATE, consisting of octreotate targeting somatostatin receptors, has been applied with encouraging results, with ⁶⁴Cu-SARTATE being used for disease detection and with ⁶⁷Cu-SARTATE being used for therapy. Furthermore, recent evidence has highlighted the potential of targeted alpha therapy (TAT) for treating cancer by virtue of alpha particles’ high ionizing density and high probability of killing cells along their track. On this path, ²¹¹At-astatobenzylguanidine (MABG) has been developed as a potential agent for TAT and is actually under evaluation in preclinical NB models. In this review, we performed a web-based and desktop literature research concerning radiotheranostic approaches in NB, covering both the radiopharmaceuticals already implemented in clinical practice (i.e.,¹²³/¹³¹1-MIBG) and those still in a preliminary or preclinical phase. Full article

Improved prognostication of small cell lung cancer (SCLC) patients could strengthen the treatment strategy and, thereby, potentially improve the overall survival (OS) of these patients. C-reactive protein (CRP) has been proposed as a prognostic indicator of inferior survival, although so far, only based on data from smaller studies. Data on SCLC patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and the clinical laboratory information system. CRP measurements were divided at the clinical cut-off value of 8 mg/L or 75 nmol/L) and stratified into quartiles. Cox proportional hazards model assessed the prognostic value of the CRP level. C-statistics further evaluated the biomarker’s prognostic value. In total, 923 patients were included. A pre-treatment CRP level above the clinical cut-off significantly correlated to inferior OS (adjusted hazard ratio (HR) = 1.25 (95% confidence interval (CI): 1.08–1.46). When divided into quartiles, a level-dependent correlation was observed with only the highest quartiles significantly associated with OS (3rd quartile: adjusted HR = 1.26 (95% CI: 1.03–1.55) 4th quartile: adjusted HR = 1.44 (95% CI: 1.17–1.77)). Adding CRP level to already well-established prognostic factors improved the prognostication of SCLC patients. In conclusion, high pre-treatment CRP level is an independent prognostic factor in SCLC patients. Full article

Tumor cells regulate their progression not only by the factors within their cell bodies but also by the secretome they produce and secrete. While their secretome significantly alters the fate of tumor cells themselves, they also regulate the growth of surrounding cells including both companion cancer and non-cancer cells. Tumor cell secretome consists of varying molecules that have been reported mostly tumor-promotive. Furthermore, their pro-tumor capability is enhanced by the application of chemotherapeutic agents. However, multiple lines of emerging evidence suggest that the tumor cell secretome can be tumor-suppressive in response to paracrine and endocrine signaling. This review introduces both tumor-promotive and tumor-suppressive secretomes, focusing on multi-tasking proteins in the intracellular and extracellular domains. We describe tumorigenic signaling that governs the nature of the tumor cell secretome and discuss the possibility of inducing tumor-suppressive proteomes as a novel option for cancer treatment. We evaluated the counterintuitive procedure to generate tumor-suppressive proteomes from a unique type of tumor-modifying cells, which are named “induced tumor-suppressing cells” (iTSCs). Full article

Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities. Full article

Objective: The combination of docetaxel (DTX) with Laser-Activated NanoTherapy (LANT), as a treatment for head and neck cancer (HNC), may enhance the therapeutic efficacy of lower doses of DTX, thereby minimizing the effective dosage, side effects and treatment times. Material and methods: Three HNSCC cell lines, Detroit 562, FaDu, and CAL 27, were treated with four combinations of DTX + LANT to evaluate DTX dose reduction and cell viability. Results: The 1 nM DTX + 5 nM LANT combination was the most effective treatment, increasing cell death over its corresponding DTX monotreatment with approximately 86.6%, 80.7%, and 92.1% cell death for Detroit 562, FaDu, and CAL 27, respectively. In Detroit 562, the 1 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 84.6%; in FaDu and CAL 27, the 0.5 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 78.2% and 82.4%, respectively. Conclusion: LANT may increase the therapeutic efficacy of DTX at significantly lower doses, which could improve patient outcomes. Full article

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the lung lining that is predominantly associated with occupational exposure to asbestos. MPM is responsible for thousands of deaths worldwide every year, with the median survival of MPM of 8–14 months. There are limited biomarkers available in the clinic to effectively diagnose MPM, an invasive biopsy procedure is usually required to provide a definitive diagnosis. Due to the long latency period associated with MPM disease presentation, the cancer is usually at an advanced stage at the time of diagnosis where treatment options are largely ineffective at controlling disease progression. Previous MPM-based pre-clinical studies have made significant strides in determining the exact molecular mechanisms associated with asbestos carcinogenesis. Exploring less invasive blood-based biomarkers and treatment strategies involving targeted therapy, immunotherapy, and virotherapy is particularly important. Research in these areas is of crucial importance in relation to improving the rate of novel diagnostic biomarkers and treatment strategies progressing through to clinical trials and ultimately into the clinical setting. This review comprehensively summarises both previous and current pre-clinical research developments that have specifically contributed to an improved understanding of MPM disease biology, and the development of novel diagnostic biomarkers and treatment strategies. Full article

BACKGROUND: Glioblastoma (GBM) is driven by various genomic alterations. Next-generation sequencing (NGS) could yield targetable alterations that might impact outcomes. The goal of this study was to describe how NGS can inform targeted therapy (TT) in this patient population. METHODS: The medical records of patients with a diagnosis of GBM from 2017 to 2019 were reviewed. Records of patients with recurrent GBM and genomic alterations were evaluated. Objective response rates and disease control rates were determined. RESULTS: A total of 87 patients with GBM underwent NGS. Forty percent (n = 35) were considered to have actionable alterations. Of these 35, 40% (n = 14) had their treatment changed due to the alteration. The objective response rate (ORR) of this population was 43%. The disease control rate (DCR) was 100%. The absolute mean decrease in contrast-enhancing disease was 50.7% (95% CI 34.8–66.6). CONCLUSION: NGS for GBM, particularly in the recurrent setting, yields a high rate of actionable alterations. We observed a high ORR and DCR, reflecting the value of NGS when deciding on therapies to match genomic alterations. In conclusion, patient selection and the availability of NGS might impact outcomes in select patients with recurrent GBM. Full article