The tumor microenvironment (TME) plays a crucial role in virtually every aspect of
tumorigenesis of
glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant
metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as
cytokines,
proteins, and
microRNAs.
RESULTS: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (
GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of
GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells' resistance against
temozolomide (TMZ) by upregulating the prosurvival gene
programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2),
signal transducer and activator of transcription 3 (STAT3),
Nestin, and miR-21-5p and increasing the M2
cytokines interleukin 6 (IL-6) and
transforming growth factor beta 1(TGF-β1) secreted by GBM cells, promoting the M2 polarization of
GAMs. Subsequently,
pacritinib treatment suppressed GBM
tumorigenesis and stemness; more importantly,
pacritinib-treated GBM cells showed a markedly reduced ability to secret M2
cytokines and reduced miR-21-enriched exosomes secreted by
GAMs.
Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the
tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and
GAMs. Treatment with
pacritinib and the combination of
pacritinib and TMZ appeared to significantly reduce the
tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of
GAMs.
CONCLUSION: In summation, we showed the potential of
pacritinib alone or in combination with TMZ to suppress GBM
tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting
pacritinib for the treatment of TMZ-resistant GBM in clinical settings.