Secreted Non-Coding RNAs: Comparison
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NonTriple-coding RNAs comprise ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), extracellular RNAs (exRNAs), small Cajal body-specific RNAs (scaRNAs), long non-coding RNAs (lncRNA) and circular RNAs (circRNAs). These non-coding RNAs play a crucial role in many biological processes. Moreover, their aberrant expression can lead to cancer initiation, progression, and metastasis, therefore they might be considered as therapeutic targets and attractive tools for diagnosis and prognosis of cancer. Secreted non-coding RNAs play crucial roles during negative breast cancer (TNBC) is a subtype of breast carcinoma characterized by poor prognosis and high rate of metastasis. Current treatment is based on chemo- and/or radiotherapy and surgery. TNBC is devoid of estrogen, progesterone and HER2 receptors. Although precision medicine has come a long way to ameliorate breast cancer progression and strongly contribute to remodel the tumor microenvironment and the metastatic niche, to enable the formation of a supporting vasculature, the inhibition of tumor recognition by the immune system and, finally, the spreading of tumor cells and metastatization. The full comprehension of the ncRNA-guided networkdisease management, targeted therapies for the treatment of TNBC patients are still limited. Mounting evidence has shown that non-coding RNAs (ncRNAs) drive many oncogenic processes at the basis of these events is central for the development of novel effective therapies aimed at disrupincreased proliferation, invasion and angiogenesis in TNBC, strongly contributing the cross-talk between tumor cells and other cell typeso tumor progression and resistance to treatments. Many of these ncRNAs are secreted in the tumor microenvironment; such therapeutic approaches would strongly prompt the immune system to recogniz (TME) and impinge on the activity of the diverse immune and eliminate tumor cells. At the same timestromal cell types infiltrating the TME. Importantly, secreted non-coding RNAs also represent powerful biomarkers to be exploited for diagnostic in liquid biopsy and for therapeutic purposes. A comprehensive understanding of the mechanisms of action of secreted ncRNAs in TNBC represents the future challenge, which will allow the widest use of these molecules both as ncRNAs may be detected as circulating molecules in serum/plasma from cancer patients and are emerging a promising diagnostic tools and as t/therapeutic targetsools in TNBC. 

  • breast cancer
  • TNBC
  • non-coding RNA
  • ncRNA
  • exosomes
  • tumor microenvironment
  • liquid biopsy

1. Introduction

Breast cancer is the second leading cause of cancer-related mortality in women. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by significant inter- and intra-tumor molecular heterogeneity and defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor. Owing to the absence of receptors, exploited in other BC subtypes as therapeutic targets, TNBC patients often experience less favorable outcomes compared to other breast cancer subtypes [1][2]. The current standard therapies are surgical and medical treatment followed by adjuvant radiotherapy (RT) with or without chemotherapy. Compared to other subtypes of breast cancer, TNBC has the highest amount of metastasis and lowest survival rates [3]. There is a high risk of recurrence in this subtype of breast cancer also; resistance to therapy is the major obstacle to successful treatment of TNBC [4]. Consequently, there is limited progress in targeted therapies for the treatment of TNBC patients. This indicates the need to develop new TNBC treatment strategies.
Many studies have shown that non-coding RNAs make up the majority (about 90%) of the transcribed genome, and they lack the ability to code for proteins. Surprisingly, only 1–2% of the transcribed genome encodes proteins [5]. Various non-coding RNAs have been shown to regulate gene expression. Non-coding RNAs comprise ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), extracellular RNAs (exRNAs), small Cajal body-specific RNAs (scaRNAs), long non-coding RNAs (lncRNA) and circular RNAs (circRNAs). These non-coding RNAs play a crucial role in many biological processes [5][6]. Moreover, their aberrant expression can lead to cancer initiation, progression, and metastasis, therefore they might be considered as therapeutic targets and attractive tools for diagnosis and prognosis of cancer [5][6].
Although high morbidity tumor tissue biopsy is currently the most widely used procedure for cancer diagnosis and definition of prognosis, attempts to find promising non-invasive biomarkers for cancer screening, diagnosis and prognosis are generating considerable interest [7]. Of note, non-coding RNAs can circulate in the body fluids and can be detected easily in the plasma, serum, saliva, seminal, cerebrospinal fluid and urine of cancer patients including triple negative breast cancer [7][8][9]. Importantly, circulating non-coding RNAs represent a source of information about the status of malignancy and changes of circulating ncRNAs levels are correlated with the degree of tumor progression [7][8].
Among circulating non-coding RNAs, microRNAs, long non-coding RNAs and circular RNAs have been considered as a biomarker in different types of cancer including TNBC. microRNAs are the most studied group of non-coding RNAs [9]. These small non-coding RNAs (17–22 nucleotides) act as a gene expression regulator by binding to 3′UTR of target mRNAs and recruiting specific silencing proteins that form the RISC (RNA Induced Silencing Complex) [10]. Many studies have reported that microRNAs are considered not only as regulatory molecules, but also as potential therapeutic targets [11][12][13][14]. Long non-coding RNAs (lncRNAs) are transcripts of RNAs longer than 200 nucleotides, which do not encode proteins. LncRNAs can function as signaling, decoys, guided, and scaffold lncRNAs [15][16]. Circular RNAs (circRNAs) have been recently discovered and are generated by non-canonical back-splicing events, frequently linked to exon-skipping of pre-mRNA. Back-splicing leads to the production of covalently closed circular RNAs which lack 3′ end poly (A) tail and 5′ end cap [17]. Due to their structure, circRNAs are not exposed to the majority of RNases and therefore are very stable molecules. Increasing observations have indicated that they can act as sponges, which control the activity of other regulatory proteins like RNA binding proteins (RBPs) or microRNAs. Moreover, they can function as gene expression and transcription regulators [18][19][20].
Circulating non-coding RNAs can be released into body fluids, and reach distant target organs, as cell-free, non-vesicle associated molecules or otherwise as extracellular vesicle-associated molecules. In the first case, proteins like Argonaute2 (AGO), GW182, nucleophosmin 1 (NPM1) and high-density lipoproteins (HDL) may be responsible for the binding and transport of non-coding RNAs. In the second case, extracellular vesicles (EVs) surrounded by lipid bilayer can transport the non-coding RNAs. EVs can be classified into two large classes: (a) exosomes, which are produced by exocytosis from a multivesicular body (MVB) with an approximate size of 40–100 nm [21]; and (b) microvesicles (MVs), which derive directly from the plasma membrane through outward budding with dimensions in the range of 100–1000 nm [8][22].
Extracellular vesicles containing a variety of macromolecules, included non-coding RNAs, are released in the tumor microenvironment (TME), where they actively participate in cancer progression (Figure 1).
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Figure 1.
Crosstalk of circulating non-coding RNAs and tumor microenvironment. (
A
) The tumor microenvironment (TME) includes a cellular and an extracellular component. The cellular component consists of tumor cells, immune cells (TAMs, T cells, B cells, NK cells, DCs, and MDSCs) and cancer-associated fibroblasts (CAFs). The extracellular component of TME is composed by ECM proteins and signaling molecules (like cytokines, chemokines, growth factors, hormones, etc.), which are secreted by the cellular component. (
B
) ncRNAs are processed and released in body fluids. Circulating ncRNAs can be released in two ways: (1) as cell-free RNAs, complexed with protein such as AGO, NPM1 or HDL; or (2) in extracellular vesicles (exosomes and microvesicles). Both tumor cells and stromal cells may release exosomes in the TME. Through body fluids, ncRNAs can reach distant sites in the body and act as molecular mediators. (
C) Circulating ncRNAs are stable and easily detectable and can be used as non-invasive biomarkers in liquid biopsy. TME: tumor microenvironment, TAM: Tumor-associated macrophage, NK: Natural killer cell, DC: Dendritic cell, MDSC: Myeloid-derived suppressor cell, CAF: cancer-associated fibroblast, ECM: extracellular matrix, SDE: Stromal-derived exosome, CDE: Cancer-derived exosome, AGO: Argonaute2, NPM1: Nucleophosmin 1, HDL: High-density lipoprotein, MVB: Multivesicular body, MV: Microvesicle, CTC: Circulating tumor cell.
) Circulating ncRNAs are stable and easily detectable and can be used as non-invasive biomarkers in liquid biopsy. TME: tumor microenvironment, TAM: Tumor-associated macrophage, NK: Natural killer cell, DC: Dendritic cell, MDSC: Myeloid-derived suppressor cell, CAF: cancer-associated fibroblast, ECM: extracellular matrix, SDE: Stromal-derived exosome, CDE: Cancer-derived exosome, AGO: Argonaute2, NPM1: Nucleophosmin 1, HDL: High-density lipoprotein, MVB: Multivesicular body, MV: Microvesicle, CTC: Circulating tumor cell.
The tumor microenvironment (TME) is a complex environment composed of a variety of cell types including tumor cells, tumor stromal cells like fibroblasts, endothelial and immune cells [23]. In general, there is a crosstalk between cancer cells and the TME, therefore the TME affects the development and progression of cancer [24][25]. Exosomes have been now recognized as major mediators of the communication between tumor cells and the other cell types in the TME. Additionally, they have the ability to modulate the behavior of cells populating the TME and to cooperate in immune response and tumor metastasis [24]. Therefore, exosomes containing non-coding RNAs could be exploited for liquid biopsy and used as promising non-invasive biomarkers for the diagnosis and the definition of prognosis in cancer. In this rentry, the authors view, we provide an overview of the recent literature on the role of circulating non-coding RNAs in the cross-talk between TNBC cells and the TME, as well as on the possible use of these ncRNAs as biomarkers and indicators of tumor progression.

2. Functional Impact of Secreted ncRNAs on Surrounding Stromal Cells and at Metastatic Sites in TNBC

It is well recognized that cancer cells communicate, directly by cell–cell contact or through paracrine mechanisms, with each other and with the other cells of the TME, causing a gene expression reprogramming that enables protumoral functions, such as neoangiogenesis and immune escape. Extracellular vesicles, in particular, have been shown to exert a pivotal role in the transport of non-coding RNAs from cancer cells to neighboring cancer and stromal cells, contributing to the functional reshaping of the TME [26].
The majority of the studies have focused on the identification of microRNAs secreted by cancer cells and targeting a variety of cell types in the TME. It has been extensively reported that the miRNA profiles of EVs are distinct from the matched cellular profiles. Of note, cancer cells are able to actively secrete high amounts of specific miRNAs that are usually retained in normal untransformed cells [27]. Moreover, metastatic breast cancer cells have been shown to secrete exosomes that are enriched in miRNAs compared to non-metastatic breast cancer cells [28]. EVs isolated from cancer cells or from the blood of cancer patients enclose not only miRNAs, but also protein components of the RISC complex, thus displaying a cell-independent capacity to process pre-miRNAs into mature miRNAs and an immediately active miRNA-RISC complex in the recipient cell [28].
One major function of miRNA-containing EVs secreted by metastatic TNBC cells is to confer metastatic capability to the non-metastatic cancer cell population. It has been reported, for example, that miR-200 is secreted in EVs from TNBC cells and is detectable in the serum of metastatic breast cancer patients [29][30]. Transfer of miR-200 from metastatic to non-metastatic cells impinges on these last by inducing mesenchymal-to-epithelial transition. Mechanistically, miR-200 not only enhances epithelial traits, facilitating engraftment in the metastatic niche, but also suppresses the secretion of anti-metastatic factors in recipient cells [31]. A similar pro-invasive activity of recipient cells has been reported for EVs-associated miR-10b in TNBC [32] (Figure 2).
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Figure 2. Examples of miRNAs secreted in EVs by TNBC cells and their functional impact in the primary tumor and at metastatic site. microRNAs are secreted by TNBC cells into extracellular vesicles (EVs). These reach recipient cells both in the tumor microenvironment (TME) and, through the bloodstream, in the metastatic niche. miRNAs enclosed in the EVs contribute to tumor progression by affecting motility and metabolism of tumor cells and fibroblasts (CAFs), permeability of the vasculature and stiffness of the TME.
Examples of miRNAs secreted in EVs by TNBC cells and their functional impact in the primary tumor and at metastatic site. microRNAs are secreted by TNBC cells into extracellular vesicles (EVs). These reach recipient cells both in the tumor microenvironment (TME) and, through the bloodstream, in the metastatic niche. miRNAs enclosed in the EVs contribute to tumor progression by affecting motility and metabolism of tumor cells and fibroblasts (CAFs), permeability of the vasculature and stiffness of the TME.
As already mentioned, non-tumor cell types in the tumor stroma may also be targeted by cancer-derived EVs. A cell type that is strongly reprogrammed in the TME of primary tumors and at metastatic sites is the cancer-associated fibroblast (CAF), which contributes to cancer progression through its ability to affect extracellular matrix composition, T-cell function and growth factors secretion (reviewed in [33]).
A pivotal role in CAF reprogramming is exerted in TNBC by miR-9. The oncoprotein MYC is responsible for the induction of miR-9 in TNBC cells, where miR-9 targets E-cadherin (CDH1) 3’-UTR thus favoring EMT, motility and metastasization [34]. Of note, analysis of CAFs isolated from TNBC patients evidenced that miR-9 is expressed in these cells at higher levels, compared to matched normal fibroblasts. miR-9 is indeed secreted in exosomes by cancer cells and transferred to recipient fibroblasts in the TME, resulting in enhanced cell motility of CAFs. Expression of miR-9 in CAFs causes the modulation of genes mainly involved in cell motility and extracellular matrix remodeling pathways [35]. Further study from the same group also showed that miR-9 directly targets the ECM glycoprotein fibulin-3 (EFEMP1) in CAFs and EFEMP1 down-regulation is responsible for the observed increased CAFs motility upon miR-9 induction. Moreover, the supernatant of EFEMP1-depleted CAFs is able to confer resistance to cisplatin to TNBC cells, highlighting a two-way paracrine communication between these two cell types [36].
Another miRNA able to impact on CAFs behavior in the TME is miR-105. Similarly to miR-9, miR-105 is also induced by the oncoprotein MYC in TNBC cells; this miRNA is subsequently encapsulated in extracellular vesicles and secreted by the tumor cell, then transferred in paracrine manner to CAFs, also causing activation of MYC pathway in these recipient cells. Specifically, CAFs undergo a reprogramming whereby, in the presence of nutrients, they enhance glucose and glutamine metabolism to fuel adjacent cancer cells, while, upon nutrients’ deprivation, these CAFs detoxify metabolic wastes by converting lactic acid and ammonium into energy-rich metabolites [37]. miR-105-dependent reprogramming of CAFs thus influences the composition of the shared metabolic environment to promote cancer cells’ growth. Interestingly, secreted miR-105 not only affects CAFs behavior, but also strongly impacts on endothelial cells. Indeed, in endothelial monolayers, the transfer of cancer-secreted miR-105 causes down-regulation of tight junction protein ZO-1 and a consequent destruction of tight junctions allowing metastasization of breast cancer cells [38]. Permeability of the endothelial monolayer is also enhanced by the EVs-associated miR-939, targeting VE-cadherin [39].
The endothelial function is strongly affected by the EVs of breast cancer cell derivation also at metastatic sites. Breast cancer cells metastasizing to the brain may indeed promote the destruction of the blood–brain barrier (BBB) through the secretion of EV-associated miR-181c, which in turn down-regulates 3-phosphoinositide-dependent protein kinase-1 (PDPK1). PDPK1 reduction then leads to activated cofilin-induced modulation of actin dynamics responsible for the BBB modification facilitating the metastatic process [40].
In the context of metastatic breast cancer, another recipient cell type of cancer-derived EVs is the osteoblast. Bone represents one of the most frequent metastatic sites of advanced breast cancer. Wang and colleagues reported that breast cancer-derived miR-218 is present in the blood of breast cancer patients with bone metastases. Functionally, cancer-secreted miR-218 directly down-regulates type I collagen (COL1A1) expression in osteoblasts, inhibiting its deposition in the bone [41]. Reprogramming of CAF by cancer-derived EVs has been also reported to occur in the lung, another frequently targeted organ in TNBC. Specifically, EV-associated miR-122, secreted by breast cancer cells, is able to reprogram lung fibroblasts and astrocytes to suppress glucose metabolism by modulating the expression of pyruvate kinase (PKM); this network down-regulates glucose consumption in niche cells to allow metastasized cancer cells to have more glucose available [42].
In addition to the above-mentioned miRNAs, lncRNAs have also been identified as secreted in exosomes and functionally relevant in the TME (summarized in Figure 3). One such example is represented by SNHG16, a breast cancer-derived exosomal lncRNA, which may reach the Tregs population in the TME and cause immunosuppression. Functionally, SNHG16 is able to sponge miR-16-5p leading to activation of SMAD5 expression; activated SMAD5, in turn, upregulates the expression of CD73 in Tregs, a feature associated to the immunosuppressive function [43]. Another lncRNA secreted in exosomes from breast cancer cells, included TNBC cells, is BCRT1. BCRT1, transferred in exosomes, reaches the TAM population in the TME, causing their M2 polarization, which in turn accelerates cancer progression [44]. In addition to cancer-secreted lncRNAs, it has been shown that lncRNAs may be secreted also by other cell types in the TME and may have functional relevance on cancer cells’ behavior. RN7SL1 and HISLA are two relevant lncRNAs, secreted, respectively, by CAFs and TAMs, involved in chemoresistance through different mechanisms. RN7SL1 causes the activation of an anti-viral signaling in the cancer cell, then leading to tumor growth and therapy resistance [45], while exosomal HISLA causes the activation of HIF1A, which favors glycolysis and chemoresistance in the targeted cancer cells [46]. Recently, the presence of lncRNA MALAT1 has also been detected in exosomes from various cancer cell lines, included TNBC cells, and it was shown that exosomal MALAT1 exerts an autocrine pro-proliferative role on MDA-MB-231 breast cancer cells [47]. The function of lncRNA MALAT1, upregulated and oncogenic in a variety of malignancies, included TNBC [48][49][50], has been extensively studied in cancer cells; however, its role in the cross-talk between different cell types in the TME still has to be revealed, and the identification of exosomal MALAT1 now opens up an extremely fascinating and unexplored area of research.
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Figure 3. Examples of lncRNAs secreted in exosomes by cells in the TME and their functional output in TNBC. LncRNAs (BCRT1 and SNHG16) may be secreted by cancer cells and impinge on the activity of other cell types in the TME, such as TAMs and Tregs, enhancing their pro-tumoral behavior. At the same time, various cells in the TME may release lncRNAs, such as HISLA and RN7SL1, in exosomes and reach tumor cells to increase their resistance to treatments.

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