Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article.
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.
Background: Oral cancer is one of the most prevalent cancers worldwide. Despite that the oral cavity is easily accessible for clinical examinations, oral cancers are often not promptly diagnosed. Furthermore, to date no effective biomarkers are available for oral cancer. Therefore, there is an urgent need to identify novel biomarkers able to improve both diagnostic and prognostic strategies. In this context, the development of innovative high-throughput technologies for molecular and epigenetics analyses has generated a huge amount of data that may be used for the identification of new cancer biomarkers. Methods: In the present study, GEO DataSets and TCGA miRNA profiling datasets were analyzed in order to identify miRNAs with diagnostic and prognostic significance. Furthermore, several computational approaches were adopted to establish the functional roles of these miRNAs. Results: The analysis of datasets allowed for the identification of 11 miRNAs with a potential diagnostic role for oral cancer. Additionally, eight miRNAs associated with patients' prognosis were also identified; six miRNAs predictive of patients' overall survival (OS) and one, hsa-miR-let.7i-3p, associated with tumor recurrence. Conclusion: The integrated analysis of different miRNA expression datasets allows for the identification of a set of miRNAs that, after validation, may be used for the early detection of oral cancers.
The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.
Rodent models of liver tumorigenesis have reproducibly shown that dietary sugar intake is a powerful driver of liver tumor initiation and growth. In contrast, dietary sugar restriction with ketogenic diets or calorie restriction generally prevents liver tumor formation. Ketogenic diet is viewed positively as a therapeutic adjuvant; however, most ketogenic diet studies described to date have been performed in prevention mode rather than treatment mode. Therefore, it remains unclear whether a ketogenic diet can be administered in late stages of disease to stall or reverse liver tumor growth. To model the clinically relevant treatment mode, we administered a ketogenic diet to mice after liver tumor initiation and monitored tumor growth by magnetic resonance imaging (MRI). Male C57BL/6 mice were injected with diethylnitrosamine (DEN) at 2 weeks of age and fed a chow diet until 39 weeks of age, when they underwent MRI imaging to detect liver tumors. Mice were then randomised into two groups and fed either a chow diet or switched to a ketogenic diet from 40⁻48 weeks of age. Serial MRIs were performed at 44 and 48 weeks of age. All mice had tumors at study completion and there were no differences in total tumor burden between diet groups. Although a ketogenic diet has marked protective effects against DEN-induced liver tumourigenesis in this mouse model, these data demonstrate that ketogenic diet cannot stop the progression of established liver tumors.
Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC.
The tumor suppressor p53 as the “guardian of the genome” plays an essential role in numerous signaling pathways that control the cell cycle, cell death and in maintaining the integrity of the human genome. p53, depending on the intracellular localization, contributes to the regulation of various cell death pathways, including apoptosis, autophagy and necroptosis. Accumulated evidence suggests that this function of p53 is closely involved in the process of cancer development. Here, present knowledge concerning a p53-autophagy-metastasis link, as well as therapeutic approaches that influence this link, are discussed.
The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer.
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.
Brain tumor glioblastoma has no clear molecular signature and there is no effective therapy. In rodents, the intracellular distribution of the cyclic AMP (cAMP)-dependent protein kinase (Protein kinase A, PKA) R2Alpha subunit was previously shown to differentiate tumor cells from healthy brain cells. Now, we aim to validate this observation in human tumors. The distribution of regulatory (R1 and R2) and catalytic subunits of PKA was examined via immunohistochemistry and Western blot in primary cell cultures and biopsies from 11 glioblastoma patients. Data were compared with information obtained from 17 other different tumor samples. The R1 subunit was clearly detectable only in some samples. The catalytic subunit was variably distributed in the different tumors. Similar to rodent tumors, all human glioblastoma specimens showed perinuclear R2 distribution in the Golgi area, while it was undetectable outside the tumor. To test the effect of targeting PKA as a therapeutic strategy, the intracellular cyclic AMP concentration was modulated with different agents in four human glioblastoma cell lines. A significant increase in cell death was detected after increasing cAMP levels or modulating PKA activity. These data raise the possibility of targeting the PKA intracellular pathway for the development of diagnostic and/or therapeutic tools for human glioblastoma.