Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age‐related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.

Cancer cachexia or wasting is a paraneoplastic syndrome characterized by systemic inflammation and an involuntary loss of body mass that cannot be reversed by normal nutritional support. This syndrome affects 50%–80% of cancer patients, depending on the tumor type and patient characteristics, and it is responsible for up to 20% of cancer deaths. MicroRNAs are a class of non-coding RNAs (ncRNAs) with 19 to 24 nucleotides in length of which the function is to regulate gene expression. In the last years, microRNAs and other ncRNAs have been demonstrated to have a crucial role in the pathogenesis of several diseases and clinical potential. Recently, ncRNAs have begun to be associated with cancer cachexia by modulating essential functions like the turnover of skeletal muscle and adipose tissue. Additionally, circulating microRNAs have been suggested as potential biomarkers for patients at risk of developing cancer cachexia. In this review article, we present recent data concerning the role of microRNAs and other ncRNAs in cancer cachexia pathogenesis and their possible clinical relevance.

High-risk human papillomavirus (HPV)-driven cancers represent a major health concern worldwide. Despite the constant effort to develop and promote vaccination against HPVs, there is still a high percentage of non-vaccinated population. Furthermore, secondary prevention programs are not ubiquitous worldwide and not widely followed. Metastatic disease is the cause of the great majority of cancer-associated deaths, making it essential to determine its underlying mechanisms and to identify actionable anti-metastatic targets. Within certain types of cancer (e.g., head and neck), HPV-positive tumors show different dissemination patterns when compared with their HPV-negative counterparts, implicating HPV-related factors in the metastatic process. Among the many groups of biomolecules dysregulated by HPV, microRNAs have recently emerged as key regulators of carcinogenesis, able to control complex processes like cancer metastization. In this review, we present recent data on the role of microRNAs in the metastization of HPV-related cancers and on their possible clinical relevance as biomarkers of metastatic disease and/or as therapeutic targets.

The nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) has been implicated in the progression of cancers induced by high‐risk human papillomaviruses (HPV). In cancer patients, NF‐κB is also thought to drive a chronic systemic inflammatory status, leading to cachexia. This study addressed the ability of dimethylaminoparthenolide (DMAPT), a water‐soluble NF‐κB inhibitor, to block the development of HPV‐induced lesions and wasting syndrome in HPV16‐transgenic mice. Mice received DMAPT orally (100 mg/kg/day), once a day, for 6 consecutive weeks. Body weight was monitored weekly along with food and water intake. After 6 weeks the animals were submitted to a grip strength test and sacrificed for specimen collection. Skin samples were analyzed histologically and for expression of NF‐κB‐regulated genes Bcl2 and Bcl2l1. Gastrocnemius muscles were weighted and analyzed for expression of NF‐κB subunits p50, p52, p65, and Rel‐B. DMAPT reduced the incidence of epidermal dysplasia (18.2% versus 33.3% in HPV16+/− untreated mice). This was associated with reduced expression of Bcl2 and Bcl2l1 (p = .0003 and p = .0014, respectively) and reduced neutrophilic infiltration (p = .0339). Treated mice also showed partially preserved bodyweight and strength, which were independent of the expression levels of NF‐κB subunits in skeletal muscle.These results suggest that NF‐κB inhibition may be a valid strategy against HPV‐induced lesions in vivo and warrant further preclinical tests particularly in the set of combination therapies. In addition, the data may support the use of DMAPT to prevent wasting syndrome.

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Cancer cachexia is a multifactorial syndrome characterized by general inflammation, weight loss and muscle wasting, partly mediated by ubiquitin ligases such as atrogin-1, encoded by Fbxo32. Cancers induced by high-risk human papillomavirus (HPV) include anogenital cancers and some head-and-neck cancers and are often associated with cachexia. The aim of this study was to assess the presence of cancer cachexia in HPV16-transgenic mice with or without exposure to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Male mice expressing the HPV16 early region under the control of the cytokeratin 14 gene promoter (K14-HPV16; HPV+) and matched wild-type mice (HPV−) received DMBA (or vehicle) topically over 17 weeks of the experiment. Food intake and body weight were assessed weekly. The gastrocnemius weights and Fbxo32 expression levels were quantified at sacrifice time. HPV-16-associated lesions in different anatomic regions were classified histologically. Although unexposed HPV+ mice showed higher food intake than wild-type matched group (p < 0.01), they presented lower body weights (p < 0.05). This body weight trend was more pronounced when comparing DMBA-exposed groups (p < 0.01). The same pattern was observed in the gastrocnemius weights (between the unexposed groups: p < 0.05; between the exposed groups: p < 0.001). Importantly, DMBA reduced body and gastrocnemius weights (p < 0.01) when comparing the HPV+ groups. Moreover, the Fbxo32 gene was overexpressed in DMBA-exposed HPV+ compared to control mice (p < 0.05). These results show that K14-HPV16 mice closely reproduce the anatomic and molecular changes associated with cancer cachexia and may be a good model for preclinical studies concerning the pathogenesis of this syndrome.

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Monitoring measurable residual disease (MRD) is crucial to assess treatment response in Multiple Myeloma (MM). Detection of MRD in peripheral blood (PB) by exploring Extracellular Vesicles (EVs), and their cargo, would allow frequent and minimally invasive monitoring of MM. This work aims to detect biomarkers of MRD in EVs isolated from MM patient samples at diagnosis and remission and compare the MRD-associated content between BM and PB EVs. EVs were isolated by size-exclusion chromatography, concentrated by ultrafiltration, and characterized according to their size and concentration, morphology, protein concentration, and the presence of EV-associated protein markers. EVs from healthy blood donors were used as controls. It was possible to isolate EVs from PB and BM carrying MM markers. Diagnostic samples had different levels of MM markers between PB and BM paired samples, but no differences between PB and BM were found at remission. EVs concentration was lower in the PB of healthy controls than of patients, and MM markers were mostly not detected in EVs from controls. This study pinpoints the potential of PB EVs from MM remission patients as a source of MM biomarkers and as a non-invasive approach for monitoring MRD.