Publication: Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies
Authors
Angara, Kartik ; Rashid, Mohammad H. ; Shankar, Adarsh ; Ara, Roxan ; Iskander, Asm ; Borin, Thaiz F. ; Jain, Meenu ; Achyut, Bhagelu R. ; Arbab, Ali S.
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Publisher
Universidad de Murcia. Departamento de Biología Celular e Histología
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DOI
DOI: 10.14670/HH-11-856
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info:eu-repo/semantics/article
Description
Abstract
Glioblastoma (GBM) is one hypervascular
and hypoxic tumor known among solid tumors.
Antiangiogenic therapeutics (AATs) have been tested as
an adjuvant to normalize blood vessels and control
abnormal vasculature. Evidence of relapse exemplified
in the progressive tumor growth following AAT reflects
development of resistance to AATs. Here, we identified
that GBM following AAT (Vatalanib) acquired an
alternate mechanism to support tumor growth, called
vascular mimicry (VM). We observed that Vatalanib
induced VM vessels are positive for periodic acid-Schiff
(PAS) matrix but devoid of any endothelium on the inner
side and lined by tumor cells on the outer-side. The
PAS+ matrix is positive for basal laminae (laminin)
indicating vascular structures. Vatalanib treated GBM
displayed various stages of VM such as initiation
(mosaic), sustenance, and full-blown VM. Mature VM
structures contain red blood cells (RBC) and bear
semblance to the functional blood vessel-like structures,
which provide all growth factors to favor tumor growth.
Vatalanib treatment significantly increased VM
especially in the core of the tumor, where HIF-1α was
highly expressed in tumor cells. VM vessels correlate
with hypoxia and are characterized by co-localized
MHC-1+ tumor and HIF-1α expression. Interestingly,
20-HETE synthesis inhibitor HET0016 significantly
decreased GBM tumors through decreasing VM
structures both at the core and at periphery of the
tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by
tumors to make functional vessels by transdifferentiation
of tumor cells into endothelial-like cells to supply
nutrients in the event of hypoxia. AAT induced VM is a
potential therapeutic target of the novel formulation of
HET0016. Our present study suggests that HET0016 has
a potential to target therapeutic resistance and can be
combined with other antitumor agents in preclinical and
clinical trials.
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