Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways

Abstract

Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemia in vitro model systems were used to investigate microvesicles as vehicles of protein-coding messages. Several leukemic cells (K562, LAMA-87, TOM-1, REH, and SHI-1), each carrying a specific chromosomal translocation, were analyzed. In the leukemic cells, these chromosomal translocations are transcribed into oncogenic fusion transcripts and the transfer of these transcripts was monitored from leukemic cells to microvesicles for each of the cell lines. Microarray gene expression profiling was performed to compare transcriptomes of K562-derived microvesicles and parental K562 cells. The data show that oncogenic BCR-ABL1 transcripts and mRNAs related to basic functions of leukemic cells were included in microvesicles. Further analysis of microvesicles cargo revealed a remarkable enrichment of transcripts related to cell membrane activity, cell surface receptors, and extracellular communication when compared with parental K562 cells. Finally, coculturing of healthy mesenchymal stem cells (MSC) with K562-derived microvesicles displayed the transfer of the oncogenic message, and confirmed the increase of target cell proliferation as a function of microvesicle dosage.Implications: This study provides novel insight into tumorderived microvesicles as carriers of oncogenic protein-coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683-95. Ó2017 AACR.

Extracellular vesicles: lipids as key components of their biogenesis and functions

“…Exosome and microvesicle functions appear to be either complementary or in opposition. Complementary, for instance, in the case of transfer of oncogenic material to recipient cells (75), but in opposition in the immune system. Indeed exosomes act positively in the immune response by extending the duration of antigen presentation in lymph nodes (74) and appear as a tool for immunotherapy against cancer (76), whereas microvesicles (ectosomes) turn off the immune response by inducing differentiation of CD4 T cells into T regulatory lymphocytes (77).…”

Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation

“…Moreover, patients with different types of cancer were reported to have high number of circulating MVs suggesting their direct involvement in modulating cell communication within the tumor microenvironment. More importantly, the hypoxic microenvironment may accelerate the release of MVs into the surrounding environment promoting tumor growth, invasion and angiogenesis [ 24 , 25 ]. Recently, Horenstein AL et al .…”

Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy

“…Several studies have suggested that, under different conditions, tumor cells produced EVs that modulated themselves, in an autocrine feedback loop [73,74,75], which is relevant for the concepts of tumor auto-sustaining and the increase of tumor aggressiveness.…”

“…Several leukemic cells, including erythromyeloblastoid, chronic myeloid leukemia (CML), and pre-B ALL cells, released their specific oncogenic fusion transcripts in MVs; interestingly, these EVs returned to leukemic cells with an autocrine loop [75]. In particular, CML-derived Exo promoted the proliferation and survival of CML cells, both in vitro and in vivo, by TGF-β1/TGF-β1 receptor engagement [77].…”

“…Moreover, Exo released by CML cells stimulate BMSCs to produce IL-8 which, in turn, promotes both in vitro and in vivo leukemic cell survival [104]. MVs containing “leukemic” transcripts from CML cells transferred these mRNA in healthy MSCs, increasing their proliferation [75]. In addition, CML-Exo were able to enhance angiogenesis in vitro; this effect was amplified when the Exo were released in hypoxic conditions [120].…”