Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma

Abstract

The tumor microenvironment is deeply involved in the process of tumor growth and development. In this study, we focused on cancer-associated fibroblasts (CAFs) and their derived exosomes on the lymphoma microenvironment to uncover their clinical significance. CAFs were established from primary lymphoma samples, and exosomes secreted from CAFs were obtained by standard procedures. We then investigated the roles of CAFs and their derived exosomes in the survival and drug resistance of lymphoma cells. CAFs supported the survival of lymphoma cells through increased glycolysis, and the extent differed among CAFs. Exosomes were identified as a major component of the extracellular vesicles from CAFs, and they also supported the survival of lymphoma cells. The suppression of RAB27B, which is involved in the secretion of exosomes, using a specific siRNA resulted in reduced exosome secretion and decreased survival of lymphoma cells. Moreover, anti-pyrimidine drug resistance was induced in the presence of exosomes through the suppression of the pyrimidine transporter, equilibrative nucleoside transporter 2 (ENT2), and the suppression of ENT2 was significant in in vivo experiments and clinical samples. RNA sequencing analysis of miRNAs in exosomes identified miR-4717-5p as one of the most abundant miRNAs in the exosome, which suppressed the expression of ENT2 and induced anti-pyrimidine drug resistance in vitro. Our results suggest that exosomes including miR-4717-5p secreted from CAFs play a pivotal role in the lymphoma microenvironment, indicating that they are a promising therapeutic target.

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

“…Folicular lymphoma-associated CAFs, isolated from malignant lymphoma patients, were shown to protect tumor cells from apoptosis in response to cytotoxic drugs [218]. These CAFs do not alter proliferation rate of cancer cells but markedly upregulate the expression of the anti-apoptotic BCL2L1 gene in folicular lymphoma cells [219][220][221].…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…This is a base for the formation of metastases and resistance to chemo/actinotherapy. CAF-derived exosome efficiency mainly depends on the specific miRNAs in their cargo [73,122,136,[148][149][150][151][152][153][154][155][156][157][158][159][160] (summarised in Table 4). Cancer wasting and cachexia are present in many patients in the terminal phase of malignant disease [161].…”

Extracellular Vesicles and Cell Pathways Involved in Cancer Chemoresistance

“…The role of SLCs in mediating cancer chemoresistance is well acknowledged due to their ability to mediate drug transport, besides their physiological substrates [ 113 , 114 , 115 , 116 ]. Several SLCs can be found in the dedicated database of exosome cargos, named Exocarta [ 117 ], which also collects the rough proteomic data about exosomes released by cancer cells; however, only little information is currently available on the function of these proteins as exosome cargo(s) [ 35 , 100 , 101 , 118 ].…”

“…However, some information that links SLCs to drug resistance induced by extracellular vesicles is available ( Figure 2 ). An eminent example is the case of the equilibrative nucleoside transporter 2 (ENT2) [ 35 , 119 ]. It belongs to the SLC29 family and is responsible for the uptake of purine and pyrimidine nucleosides [ 120 ].…”