Liquid Biopsy for Cancer Cachexia: Focus on Muscle-Derived Micrornas

International Journal of Molecular Sciences Review Liquid Biopsy for Cancer Cachexia: Focus on Muscle-Derived microRNAs Roberta Belli 1,*,†, Elisabetta Ferraro 2,†, Alessio Molfino 1, Raffaella Carletti 1, Federica Tambaro 1, Paola Costelli 3 and Maurizio Muscaritoli 1,* 1 Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; alessio.molfi[email protected] (A.M.); [email protected] (R.C.); [email protected] (F.T.) 2 Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56126 Pisa, Italy; [email protected] 3 Department of Clinical and Biological Sciences, University of Torino, 10124 Torino, Italy; [email protected] * Correspondence: [email protected] (R.B.); [email protected] (M.M.); Tel./Fax: +390-649-972-020 (M.M.) † These authors contributed equally to this work. Abstract: Cancer cachexia displays a complex nature in which systemic inflammation, impaired energy metabolism, loss of muscle and adipose tissues result in unintentional body weight loss. Cachectic patients have a poor prognosis and the presence of cachexia reduces the tolerability of chemo/radio-therapy treatments and it is frequently the primary cause of death in advanced cancer patients. Early detection of this condition could make treatments more effective. However, early diagnostic biomarkers of cachexia are currently lacking. In recent years, although solid biopsy still remains the “gold standard” for diagnosis of cancer, liquid biopsy is gaining increasing interest as a source of easily accessible potential biomarkers. Moreover, the growing interest in circulating microR- Citation: Belli, R.; Ferraro, E.; NAs (miRNAs), has made these molecules attractive for the diagnosis of several diseases, including Molfino, A.; Carletti, R.; Tambaro, F.; cancer. Some muscle-derived circulating miRNA might play a pivotal role in the onset/progression Costelli, P.; Muscaritoli, M. Liquid of cancer cachexia. This topic is of great interest since circulating miRNAs might be easily detectable Biopsy for Cancer Cachexia: Focus on by means of liquid biopsies and might allow an early diagnosis of this syndrome. We here summarize Muscle-Derived microRNAs. the current knowledge on circulating muscular miRNAs involved in muscle atrophy, since they Int. J. Mol. Sci. 2021, 22, 9007. might represent easily accessible and promising biomarkers of cachexia. https://doi.org/10.3390/ijms22169007 Keywords: cancer cachexia; liquid biopsy; miRNAs; biomarkers Academic Editor: Marta Murgia Received: 5 July 2021 Accepted: 18 August 2021 1. Introduction Published: 20 August 2021 Cachexia is a multifactorial disorder associated with chronic diseases, such as cancer, Publisher’s Note: MDPI stays neutral chronic heart failure, chronic obstructive pulmonary disease, and chronic kidney disease [1]. with regard to jurisdictional claims in Cachexia in cancer affects about half of the patients and is the direct cause of death published maps and institutional affil- in about 20% of them [2–7]. Cancer cachexia (CC) is a life-threatening disorder driven iations. by a complex interaction between tumor-and host-related factors [8–10] and its under- lying mechanisms are not completely clarified [11]. A major hallmark of cachexia is the involuntary weight loss due to low muscle mass, with or without loss of fat mass [12]. The pathophysiology of muscle wasting during cachexia is characterized by a negative protein and energy balance, caused by a variable combination of reduced food intake and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. metabolic abnormalities [13–15]. Chronic inflammation seems to be one of the major drivers This article is an open access article of muscle wasting in cancer cachexia [16–18]. Also, altered glucose metabolism and insulin distributed under the terms and resistance are associated with cancer cachexia and their contribution to the progression of conditions of the Creative Commons skeletal muscle wasting has been reviewed by Masi and collaborators [16–18]. In spite of Attribution (CC BY) license (https:// its detrimental influence on patients’ quality of life [8–10], morbidity and mortality, and the creativecommons.org/licenses/by/ wide circulation of the diagnostic criteria [17], CC is still largely unrecognized, underdiag- 4.0/). nosed and undertreated [19]. Currently no biomarkers of cancer cachexia are present [20]. Int. J. Mol. Sci. 2021, 22, 9007. https://doi.org/10.3390/ijms22169007 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 9007 2 of 20 In the last ten years, several molecules have been proposed as biomarkers of cachexia including pro-inflammatory cytokines (e.g., interleukine 6, IL-6 and tumor necrosis factor alpha, TNF-α), hormones (e.g., leptin and ghrelin) and peptides such as C-terminal agrin fragment (CAF) [21–23]. However, none of these are specific to this syndrome and none of these fully satisfy the characteristics of a good biomarker in CC [21–23]. It has been suggested that some cellular mediators, including specific microRNAs (miRNAs), released by host tissues or by tumor cells, might contribute to the development of cachexia [23–25]. Detection of muscle-derived miRNAs in the blood might allow for the recognition of muscle derangements occurring in cachexia from the early stage. In this review, we report on the most recent evidence on the modulation of circulating muscle-derived miRNAs during cancer cachexia, both in animal models and humans. We consider muscle-derived miRNAs those expressed- exclusively or not- by skeletal muscles. We hypothesize that, in the near future, the circulating forms of some of these miRNAs could be exploited as biomarkers of cancer cachexia in liquid biopsies. 2. Liquid Biopsy 2.1. Liquid Biopsy in Cancer Liquid biopsy is a technique that is gaining increasing interest, especially in the field of oncology. Although solid biopsy still remains the “gold standard” for diagnosis and treatment choice for many types of cancer [26], liquid biopsy utilizes body fluids as surrogate tissues to provide information on cancer. Originally, the liquid biopsy in the field of cancer was used to study mainly the circulating tumor cells (CTCs). Indeed, the U.S. National Cancer Institute (NCI) defined liquid biopsy as “a test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood” [27]. However, in the last few years, besides CTCs, numerous circulating elements have been identified in liquid biopsies [28], such as cell-free circulating nucleic acids (cfNAs), microvesicles, and exosomes [29]. More schematically, in a liquid biopsy, we can non-invasively detect circulating cellular (i.e., CTCs), subcellular (extracellular vesicles) and molecular (e.g., DNA, miRNA, lncRNA, mRNA, proteins) [30,31] elements deriving from a tumor, which might allow the detection of tumor-specific genetic aberration, or RNA or protein alterations [30]. The detection and isolation of these circulating particles as sources of cancer genomic and proteomic information is commonly performed using blood samples [29]. However, CTCs, cfNAs and extracellular vesicles are also present in other biological fluids such as urine, saliva and cerebrospinal-fluid [32–38]. The scientific community’s growing interest in liquid biopsy depends on the possibility to obtain relevant information on the tumor and to learn about its molecular dynamic changes with minimally invasive methods, less dangerous and less expensive compared to surgical biopsies [39–45]. Indeed, although giving direct information, tissue biopsies have some disadvantages such as lack of indications regarding the spatial and temporal heterogeneity of the tumor [46], limited accessibility to the tumor tissue which could increase the possibility of false negative results [46], and bleeding or infections as a consequence of an invasive biopsy or excisional procedure [47]. Vice versa, a liquid biopsy obtained with a routine blood draw overcomes many of these limitations [48]; liquid biopsy could be used as a rapid tool for the diagnosis and monitoring of tumor progression and, possibly, for prediction of treatment response, detection of recurrence, and traceability of tumor genome evolution over time [42,43,49,50], which would be almost impossible with solid biopsy (Table1). Int. J. Mol. Sci. 2021, 22, 9007 3 of 20 Table 1. Advantages and disadvantages of liquid biopsy. Advantages Disadvantages Needs a small volume of blood Techniques not yet standardized (usually 6–10 mL) Clinical practice rules are not yet Not invasive established It is not reliable for all types of cancer (e.g., lung cancers), the Easily repeated diagnosis and subtyping can be established by only histology Useful to reveal spatial May not be representative of the LIQUID BIOPSY and temporal tumor whole cancer heterogeneity Real time monitoring for drug response and resistance Timely search for genotyping mutations Although the potential of liquid biopsy is emerging as a diagnostic and prognostic tool, some issues need to be solved before liquid biopsy becomes part of the clinical practice [51]. One important limitation of liquid biopsy in oncology is the low specificity and sensitivity, since alterations are detected in body fluids, and not in the tumor itself [29]. 2.2. Liquid Biopsy Biomarkers vs. Classical Biomarkers in Cancer Cachexia Although liquid biopsy is commonly used and studied in cancer, it might

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