Tumor microenvironment plays a central role in the development and dissemination of cancer cells. In addition to study each specific cellular component of the microenvironment, it has become clear that it is the type and amount of information that cells exchange that ultimately affects cancer phenotype. Recently, it has been discovered that intercellular communication occurs through the release of microvesicles and exosomes, whose cargo represents the information released by one cell to a recipient cell. A key component of this cargo is represented by microRNAs (miRNAs), small non-coding RNAs with gene regulatory functions. We discovered that miRNAs released by cancer cells within microvesicles can reach and bind to Toll-like receptors (TLRs) in surrounding immune cells, and activate them in a paracrine loop. As a result, immune cells produce cytokines that increase cell proliferation and metastatic potential. This discovery provides the rationale for the development of new drugs that might be used in the treatment of cancer as well as other inflammation-related diseases.

Cancer cachexia (CC) is a multifactorial syndrome characterized by systemic inflammation, uncontrolled weight loss and dramatic metabolic alterations. This includes myofibrillar protein breakdown, increased lipolysis, insulin resistance, elevated energy expediture, and reduced food intake, hence impairing the patient's response to anti-cancer therapies and quality of life. While a decade ago the syndrome was considered incurable, over the most recent years much efforts have been put into the study of such disease, leading to the development of potential therapeutic strategies. Several important improvements have been reached in the management of CC from both the diagnostic-prognostic and the pharmacological viewpoint. However, given the heterogeneity of the disease, it is impossible to rely only on single variables to properly treat patients presenting this metabolic syndrome. Moreover, the cachexia symptoms are strictly dependent on the type of tumor, stage and the specific patient's response to cancer therapy. Thus, the attempt to translate experimentally effective therapies into the clinical practice results in a great challenge. For this reason, it is of crucial importance to further improve our understanding on the interplay of molecular mechanisms implicated in the onset and progression of CC, giving the opportunity to develop new effective, safe pharmacological treatments. In this review we outline the recent knowledge regarding cachexia mediators and pathways involved in skeletal muscle (SM) and adipose tissue (AT) loss, mainly from the experimental cachexia standpoint, then retracing the unimodal treatment options that have been developed to the present day.

The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential.

Cancer-associated cachexia is a heterogeneous, multifactorial syndrome characterized by systemic inflammation, unintentional weight loss, and profound alteration in body composition. The main feature of cancer cachexia is represented by the loss of skeletal muscle tissue, which may or may not be accompanied by significant adipose tissue wasting. Such phenotypic alteration occurs as the result of concomitant increased myofibril breakdown and reduced muscle protein synthesis, actively contributing to fatigue, worsening of quality of life, and refractoriness to chemotherapy. According to the classical view, this condition is primarily triggered by interactions between specific tumor-induced pro-inflammatory cytokines and their cognate receptors expressed on the myocyte membrane. This causes a shift in gene expression of muscle cells, eventually leading to a pronounced catabolic condition and cell death. More recent studies, however, have shown the involvement of regulatory non-coding RNAs in the outbreak of cancer cachexia. In particular, the role exerted by microRNAs is being widely addressed, and several mechanistic studies are in progress. In this review, we discuss the most recent findings concerning the role of microRNAs in triggering or exacerbating muscle wasting in cancer cachexia, while mentioning about possible roles played by long non-coding RNAs and ADAR-mediated miRNA modifications.

Background: Dedifferentiated liposarcoma is a formidable sarcoma subtype due to its high local recurrence rate and resistance to medical treatment. While 2D cell cultures are still commonly used, 3D cell culture systems have emerged as a promising alternative, particularly scaffold-based techniques that enable the creation of 3D models with more accurate cell-stroma interactions.Objective: To investigate how 3D structures with or without the scaffold existence would affect liposarcoma cell lines growth morphologically and biologically.Methods: Lipo246 and Lipo863 cell lines were cultured in 3D using four different methods; Matrigel^® ECM scaffold method, Collagen ECM scaffold method, ULA plate method and Hanging drop method, in addition to conventional 2D cell culture methods. All samples were processed for histopathological analysis (HE, IHC and DNAscope™), Western blot, and qPCR; moreover, 3D collagen-based models were treated with different doses of SAR405838, a well-known inhibitor of MDM2, and cell viability was assessed in comparison to 2D model drug response.Results: Regarding morphology, cell lines behaved differently comparing the scaffold-based and scaffold-free methods. Lipo863 formed spheroids in Matrigel^® but not in collagen, while Lipo246 did not form spheroids in either collagen or Matrigel^®. On the other hand, both cell lines formed spheroids using scaffold-free methods. All samples retained liposarcoma characteristic, such as high level of MDM2 protein expression and MDM2 DNA amplification after being cultivated in 3D. 3D collagen samples showed higher cell viability after SAR40538 treatment than 2D models, while cells sensitive to the drug died by apoptosis or necrosis.Conclusion: Our results prompt us to extend our investigation by applying our 3D models to further oncological relevant applications, which may help address unresolved questions about dedifferentiated liposarcoma biology.

Lung and breast cancer are the two most common causes of malignant pleural effusion (MPE). MPE diagnosis plays a crucial role in determining staging and therapeutic interventions in these cancers. However, our understanding of the pathogenesis and progression of MPE at the molecular level is limited. Extracellular Vesicles (EVs) and their contents, including microRNAs (miRNAs), can be isolated from all bodily fluids, including pleural fluid. This study aims to compare EV-miRNA patterns of expression in MPE caused by breast (BA-MPE) and lung (LA-MPE) adenocarcinomas compared to the control group of heart-failure-induced effusions (HF-PE). We conducted an analysis of 24 pleural fluid samples (8 LA-MPE, 8 BA-MPE, and 8 HF-PE). Using NanoString technology, we profiled miRNAs within EVs isolated from 12 cases. Bioinformatic analysis demonstrated differential expression of miR-1246 in the MPE group vs. HF-PE group and miR-150-5p and miR-1246 in the BA-MPE vs. LA-MPE group, respectively. This difference was demonstrated and validated in an independent cohort using real-time PCR (RT-PCR). miRNA-1246 demonstrated 4-fold increased expression (OR: 3.87, 95% CI: 0.43, 35) in the MPE vs. HF-PE group, resulting in an area under the curve of 0.80 (95% CI: 0.60, 0.99). The highest accuracy for differentiating MPE vs. HF-PE was seen with a combination of miRNAs compared to each miRNA alone. Consistent with prior studies, this study demonstrates dysregulation of specific EV-based miRNAs in breast and lung cancer; pleural fluid provides direct access for the analysis of these EV-miRNAs as biomarkers and potential targets and may provide insight into the underlying pathogenesis of tumor progression. These findings should be explored in large prospective studies.