Cancer-associated fibroblast-derived exosome microRNA-21 promotes angiogenesis in multiple myeloma.

ABSTRACT

Multiple myeloma (MM) is the second most common hematological malignancy, and angiogenesis determines its progression. In the tumor microenvironment, normal fibroblasts (NFs) are transformed into cancer-associated fibroblasts (CAFs), which can promote angiogenesis. Microribonucleic acid-21 (miR-21) is highly expressed in various tumors. However, research on the relationship between tumor angiogenesis and miR-21 is rare. We analyzed the relationship between miR-21, CAFs, and angiogenesis in MM. NFs and CAFs were isolated from the bone marrow fluids of patients with dystrophic anemia and newly-diagnosed MM. Co-culturing of CAF exosomes with multiple myeloma endothelial cells (MMECs) showed that CAF exosomes were able to enter MMECs in a time-dependent manner and initiate angiogenesis by promoting proliferation, migration, and tubulogenesis. We found that miR-21 was abundant in CAF exosomes, entering MMECs and regulating angiogenesis in MM. By transfecting NFs with mimic NC, miR-21 mimic, inhibitor NC, and miR-21 inhibitor, we found that miR-21 significantly increased the expression of alpha-smooth muscle actin and fibroblast activation protein in NFs. Our results showed that miR-21 can transform NFs into CAFs, and that CAF exosomes promote angiogenesis by carrying miR-21 into MMECs. Therefore, CAF-derived exosomal miR-21 may serve as a novel diagnostic biomarker and therapeutic target for MM.