Abstract
The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.
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Background
The last decades have revealed that the malignant properties and progression of tumors are not controlled by cancer cells exclusively [1]. The area surrounding the tumor contains various non-malignant cell types, including fibroblasts, lymphocytes, inflammatory cells, endothelial cells, adipose tissue, and mesenchymal stem cells [1]. In the early stages of tumorigenesis, the microenvironment displays anti-tumor immunity and controls tumor growth [2]. As the tumor continues to develop, the role of the microenvironment shifts over to be tumor promotive [2]. Cells found in the tumor microenvironment (TME) have been recognized as key regulators of tumor promotion by providing mitogenic growth factors, growth inhibitory signals or trophic factors [2]. The complex heterotypic interactions between tumor cells and non-cancerous cells within the TME occur through direct contact between cells or paracrine signal exchange of cytokines and growth factors [2]. The most well-recognized cell-to-cell interaction within the TME is between tumor cells and macrophages or fibroblasts [2]. Macrophages play an integral role in host innate immune response against infections [3]. Tumor cells release factors, such as vascular endothelial growth factor (VEGF), colony stimulating factor 1 (CSF1), and platelet-derived growth factor (PDGF), that aid in the recruitment of macrophages to tumors [3]. Once the macrophages are recruited to the tumor, they can promote tumor progression by enhancing tumor cell proliferation, as well as by remodeling the tumor stroma to facilitate invasion and angiogenesis [3]. Fibroblasts are responsible for the production of extracellular matrix (ECM), such as collagen and fibronectin, and facilitate remodeling in wound healing [72]. Invadopodia are dynamic actin-rich membrane protrusions that tumor cells produce to degrade and invade through the extracellular matrix [72]. It was recently proposed that invadopodia are docking sites for EVs facilitating the degradation of the extracellular matrix through a localized secretion of metalloproteinase MT-1-MMP, thus promoting cell invasion [15, 73]. Similarly, the migration of tumor cells through tissues and chemotactic gradients is also initiated by the formation and release of fibronectin-bound EVs at the leading edge of migrating cells. These fibronectin-bound EVs are proposed to promote adhesion assembly and stabilization allowing a directional and persistent tumor cell migration [74, 75]. Tumor-derived EVs are also known to influence the integrity of vascular barriers, which is frequently associated with metastatic dissemination. Proteomics analysis of tumor-associated EVs has shown that EVs release a number of proteins such as SERPINA1, SERPINF2, and MMP9, the up-regulation of which play a significant role in ECM remodeling, vascular leakiness, and invasiveness [76]. Likewise, melanoma-derived EVs have been shown to induce pulmonary vascular leakiness [77], while EVs produced by glioblastoma cells containing high levels of VEGF-A induce endothelial cell permeability and angiogenesis in vitro [78]. In addition, EVs derived from lung cancer or breast cancer cells were reported to carry miR-23a and miR-105 respectively, which both target tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration [79, 80]. An interesting feature of tumor-derived EVs is their ability to establish a pre-metastatic niche, a phenomenon where the primary tumor can promote its own metastasis by recruiting stromal cells to distant organs or by modulating gene expression of distant cells in order to establish a growth supportive environment. EVs derived from colorectal cancer cells enriched for miR-21 can be specifically targeted to liver tissue and induce liver macrophage polarization towards an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype, therefore promoting an inflammatory pre-metastatic niche supportive of liver metastasis [81]. Moreover, melanoma EVs were shown to home to lymph nodes and consequently enhance the migration of melanoma cells to sentinel lymph nodes. In addition, melanoma EVs were able to upregulate the expression of genes within the distal lymph node microenvironment related to tumor cell recruitment to sentinel nodes, extracellular matrix modifiers promoting trap** of melanoma cells, and vascular growth factors promoting melanoma growth, creating a pre-metastatic niche supportive of metastasis [82]. Melanoma-derived EVs were further reported to educate bone marrow-derived cells towards a pro-vasculogenic and pro-metastatic phenotype through the receptor tyrosine kinase MET [77]. More recently, the uptake of pancreatic ductal adenocarcinoma-derived EVs by Kupffer cells (liver macrophages) was reported to cause TGF-β secretion and upregulation of fibronectin production by hepatic stellate cells, leading to an enhanced recruitment of bone marrow-derived macrophages through macrophage migration inhibitory factor (MIF), whose association with EVs correlated with liver metastasis occurrence and disease progression [83]. Interestingly, using different tumor models, Hoshino and colleagues reported that the metastatic organotropism and establishment of a pre-metastatic niche is mediated by EVs via the secretion of different sets of integrins (for e.g. integrin- α6β4, α6β1, or αvβ5) that favor the preferential fusion of tumor cells with resident cells at their predicted destination. The authors showed that tumor-derived EVs taken-up by organ-specific cells prepared the pre-metastatic niche and that distinct integrin patterns predicted the organotropism of tumor cells, integrins α6β4, and α6β1 being associated with lung metastasis, while integrin αvβ5 was found to be associated with liver metastasis [84]. Reprogrammed glucose metabolism is a hallmark of cancer cells. Remarkably, cancer cells are also proficient in reprograming the glucose metabolism of stromal cells through the release of EVs carrying high levels of the miR-122 that target the glycolytic enzyme pyruvate kinase. This mechanism is proposed to facilitate metastasis by increasing nutrient availability in the pre-metastatic niche [70].
Extracellular vesicles as modulators of anti-cancer drug resistance
Drug resistance poses a serious challenge for the treatment of cancer and occurs when cancer cells become tolerant to anti-cancer drugs. Although many types of cancers are initially susceptible to anti-cancer drugs, tumor cells can develop resistance over time through different mechanisms that impair drug efficacy. The most common mechanisms of drug resistance include genetic or epigenetic upregulation of prosurvival signaling and inhibition of apoptotic pathways, drug inactivation or alteration of drug target molecules, overexpression of multidrug resistance proteins (MDR) and increased transport of efflux pumps, or drug export. Recently, the emergence of EVs as novel drug resistance modulators has added to the complexity of resistance mechanisms. EVs mediate intercellular communication by transferring proteins and nucleic acids to remote target cells. The development of drug resistance via EVs is articulated around mechanisms involving such cargo. EVs can mediate drug resistance by directly exporting or sequestering cytotoxic drugs, reducing their effective concentration at target sites. Recent evidence has shown that EVs play an important role not only in mediating drug resistance, but also in conferring resistance to drug-sensitive cancer cells. Indeed, EVs are capable of horizontal transfer of specific bioactive cargoes that may alter cell cycle control and apoptotic programs in recipient cells (Fig. 2). EVs can also mediate intercommunication between cancer cells and stromal cells within the tumor microenvironment, leading to the acquisition of drug resistance and tumor progression. Mastering our understanding of these resistance mechanisms will help in improving cancer treatments and subsequently patients’ outcome. Detailed mechanisms by which resistance may occur are outlined in this section.
Mechanisms of extracellular vesicles-mediated transfer of anti-cancer drug resistance. Extracellular vesicles can mediate drug resistance by directly exporting or sequestering cytotoxic drugs reducing their effective concentration at target sites. Extracellular vesicles can also compete with bona fide target cells for the binding of immunotherapeutic agents targeting cellular antigens. Extracellular vesicles also mediate transfer of drug resistance to drug-sensitive cancer cells through the horizontal transfer of specific bioactive cargoes including drug efflux pumps, prosurvival factors, inhibitors of apoptosis, and non-coding RNAs
Extracellular vesicles as a sink for immunotherapies
Cancer cells use extracellular vesicles to compromise targeted therapies. EVs carry on their surface, a plethora of cellular antigens displayed in an orientation identical to that found on the surface of cells from which they emanate. The presence, on EVs surface, of cellular antigens targeted by immunotherapy acts as a sink for monoclonal antibodies-based drugs, thereby diminishing their bioavailability to their intended target. In the case of B-cell lymphoma, the presence of CD20 on the surface of EVs protects targeted lymphoma cells from rituximab (an anti-CD20 monoclonal antibody) attack [85]. In vitro as well as in vivo studies in breast cancer point to the role of HER2-positive extracellular vesicles in modulating resistance to anti-HER2 monoclonal antibody Trastuzumab. Extracellular vesicles secreted either by HER2-positive tumor cells in vitro or found in the serum of breast cancer patients bind to Trastuzumab, and inhibit its activity in vitro [86]. More recently, EVs have been involved in another type of drug resistance mediated by cellular receptor expression. The immunotherapy breakthrough crowned by the 2018 Medicine Nobel prize consists in the use of inhibitors of immune-checkpoints to unleash the power of an immune system otherwise tamed by immune checkpoint ligand expressed on the surface of tumor cells. The disruption of the interaction of the checkpoint ligand (e.g. PD-L1) with the inhibitory checkpoint receptor (PD-1) on T cells, restores T cell function and anti-tumor immunity. However, not all patients respond to such immune checkpoint inhibitor therapy, and the presence of checkpoint ligand (PD-L1) on EVs early after therapy, classifies patients as responders or resistant to anti-PD-1 therapy in melanoma [87]. By capturing the immunotherapeutic antibody on their surface, EVs drive this antibody away from the tumor, leaving it free to engage PD-1 on oncoming tumor-specific T cells. The same mechanism has been described in the case of glioblastoma in vitro, in which tumor-derived EVs were shown to express PD-L1 and inhibit T cell proliferation as well as antigen-specific T cell responses [88].
Extracellular vesicles-mediated drug export and sequestration
Irrespective of the administration route of anti-cancer drugs, systemic, oral or subcutaneous, the main goal of the treatment is to target drugs to the tumor site, where cellular drug uptake or membrane permeability are determinant in the drug efficacy and treatment success. However, it is recognized that abnormal tumor architecture (e.g.: poor vascularization, abnormal extracellular matrix) complicates drug uptake and is associated with therapy failure and drug resistance [89]. Even in case of efficient uptake of drugs by targeted cells, cancer cells are known to export drugs in the extracellular space using specialized transporters of the multi-drug resistance (MDR)-ATP binding-cassette (ABC transporters) system [90]. These pumps reduce the intracellular accumulation of many anti-cancer drugs to sub-therapeutic levels, thus decreasing or abolishing drug efficacy. In addition, EVs can be utilized by cancer cells as drug vehicles to facilitate drug resistance through drug sequestration and expulsion. Shedden and colleagues were the first to report a positive correlation between the expression of genes associated with vesicle shedding and drug resistance in a large panel of different cancer cell lines [94]. Interestingly, ATP-transporter A3 (ABCA3) expression is crucial for EVs biogenesis and contributes to the observed drug resistance. Indeed, genetic or chemical depletion of ABCA3 enhanced intracellular retention of both drugs [94].
Cancer cells can also sequester drugs within intracellular vesicles preventing them from reaching the targeted subcellular compartment and rendering them nonfunctional. In a breast cancer cell model resistant to mitoxantrone, cells displayed increased EV-like structures at the plasma membrane containing the ATP-binding cassette ABCG2 in which mitoxantrone was significantly sequestered [95]. Subcellular drug sequestration was also shown to be mediated by ABCA3 in leukemia cells resistant to a panel of cytostatic drugs [96]. Indeed, ABCA3 localized to the limiting membranes of lysosomes and multivesicular bodies and caused cytostatic drugs to be efficiently sequestered [96].
Extracellular vesicles-mediated transfer of drug efflux pumps
In addition to drug export or sequestration, cancer cells can transmit resistance through horizontal transfer of EVs carrying drug efflux pumps. Drug efflux transporters of the multi-drug resistance (MDR)-ATP binding-cassette (ABC transporters) system have long been acknowledged as major contributors to multidrug resistance in tumor cells [90]. EVs carrying P-glycoprotein (P-gp, MDR-1 or ABCB1), one of the most well-studied drug efflux pump, have been implicated in the transfer of multidrug resistance to sensitive cells in several human cancer models, such as prostate and ovarian cancers, acute T lymphoblastic leukemia, and osteosarcoma [97,98,99,100]. Indeed, EVs from sera of patients undergoing a course of docetaxel treatment compared to matched EVs from the same patients prior to commencing docetaxel treatment, when applied to both prostate cancer drug sensitive and resistant cells, showed a correlation between cellular response to docetaxel and patients’ response to treatment with docetaxel [97]. Similarly, extracellular vesicles-mediated intercellular transfer of functional MRP1 drug efflux transporter (ABCC1) was reported in leukemia cells [101]. Other drug efflux exporters such as ABCG2 or ABCA3 have been shown to transfer horizontally through EVs and modulate drug resistance in recipient cells [85, 102]. Although tumor cells represent an abundant source of EVs, it is important to question whether the consequences of this transfer of cargo is sustainable in vivo. The presence of selective P-gp/MDR-1 mRNA in EVs released from doxorubicin-resistant osteosarcoma cells suggests that resistant tumor cells use several means to spread drug resistance to sensitive cells, either by transferring MDR proteins directly to sensitive cells or by transferring the mRNA that encodes them, contributing to the diversity of drug resistance mechanisms [100]. On the other hand, depletion of drug efflux pumps through EVs exocytosis has been shown to increase the sensitivity of tumor cells to anti-cancer drugs in vitro. In an in vivo setting, one can legitimately wonder whether this in vitro beneficial response could not result in a net drug resistance within the tumor microenvironment. Indeed, these EVs loaded with MDR transporters could be transferred to other cells within the heterogeneous tumor itself or the stromal cells within the tumor microenvironment, therefore possibly influencing their response to treatment.
Extracellular vesicles-mediated export of prosurvival cargo
EVs transfer of cargo can contribute to the heterogeneity of tumor response to anti-cancer drugs. This cargo includes prosurvival factors, which enhance cell viability and decrease apoptosis sensitivity, thus leading to resistance to anti-cancer drugs. For instance, components associated with the PI3K/AKT pathway, one of the major oncogenic signaling axis involved in cancer cell proliferation and survival, have been reported in EVs. In hepatocellular carcinoma (HCC) invasive cells lines, resistance to Sorafenib in vitro as well as in vivo was induced by delivery of hepatocyte growth factor (HGF) through EVs and subsequent activation of the HGF/c-MET/PI3K/AKT signaling pathway [103]. In addition, platelet-derived growth factor receptor-beta (PDGFR-β), which is enriched in EVs released by melanoma cells resistant to BRAF inhibitor, PLX4720, can be transferred to recipient melanoma cells, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from BRAF inhibition [104]. More recently, triple negative breast cancer cell lines resistant to Docetaxel and Doxorubicin were shown to release EVs that induced resistance to these chemotherapy drugs in recipient non-tumorigenic breast cells [105]. Indeed, these EVs caused changes in gene expression associated with cell proliferation and apoptosis including the PI3K/AKT pathway, suggesting that they may contain ligands or receptors connected to the PI3K signaling axis [105]. Likewise, EVs can also carry prosurvival molecules that modulate the immune system functions likely inducing immune tolerance and escape. Transforming growth factor-β (TGF-β) cytokines have been shown to play a critical role in establishing immunological suppression [106]. Indeed, TGF-β1 was found in tumor-derived EVs and reported to inhibit the proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 and to induce regulatory T cells [59]. Additionally, in vivo and in vitro studies on HER2-overexpressing breast cancer have reported the presence of increased amounts of the immunosuppressive cytokine TGF-β1 in EVs released from cells resistant to HER2-targeting drugs [107]. Although the patients’ cohort was too small to be conclusive, these findings suggest that the level of EVs-associated TGF-β1 in the plasma of the patients correlates with resistance to Lapatinib and Trastuzumab [107]. Resistance to apoptosis is a vital escape mechanism by which tumor cells acquire drug resistance and thus contribute to cancer progression. EVs-mediated delivery of prosurvival factors is proposed to provide tumor cells with an additional mechanism to suppress cell death induced by anti-cancer drugs. Survivin is a prosurvival protein member of the inhibitors of apoptosis (IAP) family shown to be present in EVs derived from different tumor types [108,109,110]. Survivin has been implicated in the suppression of cell death and the regulation of mitosis, and therapeutic strategies targeting survivin in cancer are intensively investigated [111]. Indeed, Khan and colleagues identified EVs as mediators of stress-induced survivin secretion from HeLa cells treated with a sublethal dose of proton irradiation [109]. More recently, Kreger and colleagues have reported that treating highly aggressive MDA-MB-231 breast cancer cells with Paclitaxel (PTX) induces the secretion of EVs enriched with survivin that significantly promote the survival of serum-starved and PTX-treated fibroblasts and SKBR3 breast cancer cells [112].
Moreover, the enrichment of microRNAs (miR) in EVs have been shown to promote anti-cancer drugs resistance in different cancers (Table 1). For example, the investigation of drug resistance in breast cancer cells or pancreatic ductal adenocarcinoma cells revealed that EVs-mediated transfer of miR-155 to sensitive cells resulted in chemoresistance spreading. Interestingly, increased accumulation of miRNA in EVs exposed to chemotherapeutic agents can also serve as a disposal mechanism aimed at decreasing the intracellular levels of miRNA with drug sensitivity promoting roles [113, 114].
Tumor microenvironment-mediated intercellular communication and drug resistance
Tumor growth and drug resistance are not only determined by cancer cells but are also supported by non-tumor cells within the tumor microenvironment. The importance of the role of EVs in the intercellular communication within the tumor microenvironment is increasingly acknowledged. The bidirectional EV-mediated transfer of cargo to and from non-tumor cells effectively influences recipient cell’s phenotype as well as their response to anti-tumor treatments, thus promoting the development of an environment hospitable towards cancer growth, invasion, and metastasis. For instance, by secreting chemoresistance-inducing EVs containing Snail and miR-146, pancreatic cancer-associated fibroblasts (CAFs), that are intrinsically resistant to the chemotherapeutic agent gemcitabine, have been shown to mediate the transfer of resistance to pancreatic cancer epithelial cells when exposed to this drug, thereby increasing their proliferation and survival [39]. Similarly, Binenbaum and colleagues have recently reported that transfer of miR-365 in macrophage-derived EVs induces resistance of pancreatic adenocarcinoma cells to gemcitabine in vitro and in vivo [115]. Moreover, CAF-derived EVs further promoted tumor growth of colorectal cancer stem cells (CSCs) upon treatment with 5-fluorouracil or oxaliplatin, even though these cells were intrinsically chemoresistant. Interestingly, the authors have also shown that inhibition of EVs secretion by CAF increased chemosensitivity of colorectal CSCs [116]. Likewise, the vesicular transfer of miR-21 from cancer-associated adipocytes and fibroblasts to ovarian cancer cells has been reported to decrease apoptosis and promote chemoresistance to paclitaxel by downregulating the expression of apoptotic peptidase activating factor (APAF1) mRNA [117]. Similarly, tumor-associated macrophages (M2 polarized macrophages)-derived secretion of miR-21 has been shown to confer cisplatin resistance in gastric cancer cells. Functional studies revealed that vesicular miR-21 can be directly transferred from macrophages to gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway through down-regulation of PTEN [ ATP binding-cassette Adaptive Dialysis-like Affinity Platform Technology AKT serine/threonine kinase Apoptosis-linked gene 2-interacting protein X Apoptotic peptidase activating factor ADP-ribosylation factor 6 ARRDC1-mediated microvesicles Arrestin 1 domain-containing protein 1 ATPase Copper Transporting alpha ATPase Copper Transporting beta Cancer-associated fibroblast Calcium/calmodulin-dependent protein kinase Cannabinol MET proto-oncogene, receptor tyrosine kinase Colony stimulating factor 1 C-X-C chemokine receptor type 4 Extracellular matrix Epidermal growth factor Epidermal growth factor receptor Epithelial-to-mesenchymal transition Extracellular signal-regulated kinase Endosomal sorting complex required for transport Fas ligand Hepatocellular carcinoma Hepatitis C virus Human epidermal growth factor receptor 2 Hes family BHLH transcription factor 1 Hes family BHLH transcription factor 5 Hepatocyte growth factor Heat shock protein 105 Heat shock protein 70 Heat shock protein 72 Inhibitors of apoptosis Inteleukin-2 Interleukin-6 Intraluminal vesicle Janus kinase Mitogen-activated protein kinase Multidrug resistance proteins Myeloid-derived suppressor cells MAPK/ERK Kinase MHC class 1 related chain ligand A Migration inhibitory factor Myosin light-chain kinase Matrix metalloproteinase 9 Multidrug resistance-associated protein 1 Mesenchymal stem cells Membrane-type-1 matrix metalloproteinase Multivesicular endosome Natural killer NKG2-D-activating natural killer receptor Neurogenic locus notch homolog protein 2 Neurogenic locus notch homolog protein 3 Neutral sphingomyelinase 2 Peptidylarginine deiminase 2 Peptidylarginine deiminase 4 Protease-activated receptor 2 Planar cell polarity Programmed cell death receptor 1 Platelet-derived growth factor Platelet-derived growth factor receptor-beta Programmed death ligand 1 Prostaglandin E2 P-glycoprotein Phosphatidylinositol-3-kinase Phospholipase D Proteolipid protein Premelanosome protein Phosphatidylserine Proline-serine-alanine-proline motif Phosphatase and tensin homolog Raf-1 proto-oncogene, serine/threonine kinase Stromal cell-derived factor 1 Serpin family A member 1 Serpin family F member 2 Suppressor of cytokine signaling 5 Signal transducer and activator of transcription Tissue factor Transforming growth factor-beta Tumor microenvironment Tumor necrosis factor alpha Tumor susceptibility gene 101 Tissue transglutaminase Vascular endothelial growth factor Vacuolar protein sorting 4 Vesicle trafficking 1 Wingless-type MMTV integration site family, member 4 WW Domain containing E3 ubiquitin protein ligase 2 Zonula occludens protein 1 Naito Y, Yoshioka Y, Yamamoto Y, Ochiya T. 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Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365. Exp Cell Res. 2018;362(2):386–93. SM, MH, and JCG are supported by Sidra Medicine institutional funding. AAB is supported by Sidra Medicine internal grant (SIRF_20046). LJ is supported by NIH F32 grant (CA217064). AR is supported by NCCCR, HMC institutional funding. SU is supported by Medical Research Center, HMC institutional grant (Grant #16354/16). The authors declare no funding support was received for this study. Not applicable, please refer to the original reference. SM, AAB, and LJ performed the scientific literature search, designed the review structure, elaborated the figures and tables, and wrote the manuscript. AR helped with the writing of the manuscript. MH and SU assisted with the design of the manuscript. JCG helped with the manuscript writing and corrected the final version of the document. All authors have read and approved the final version of the manuscript. Not applicable, neither ethics approval was required for this review nor involvement of patients. All authors consent to publication. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Maacha, S., Bhat, A.A., Jimenez, L. et al. Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance.
Mol Cancer 18, 55 (2019). https://doi.org/10.1186/s12943-019-0965-7 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12943-019-0965-7Abbreviations
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