Role of hypoxia and PARP1 in the regulation of vasculogenic mimicry
Metadatos
Mostrar el registro completo del ítemAutor
Fernández Cortés, MónicaEditorial
Universidad de Granada
Director
Oliver Pozo, Francisco JavierDepartamento
Universidad de Granada. Programa de Doctorado en BiomedicinaMateria
Hypoxia Vasculogenic mimicry PARP-1
Fecha
2021Fecha lectura
2021-07-05Referencia bibliográfica
Fernández Cortés, Mónica. Role of hypoxia and PARP1 in the regulation of vasculogenic mimicry. Granada: Universidad de Granada, 2021. [http://hdl.handle.net/10481/69671]
Patrocinador
Tesis Univ. Granada.Resumen
Melanomas represent a variety of neoplastic diseases that derive from the
malignant transformation of melanocytic cells. Cutaneous and uveal
melanoma are the most common presentations of this cancer type.
Unfortunately, current therapies have proved insufficient in the
management of melanoma, highlighting the need for further research.
Solid tumors usually present a state of low oxygenation known as hypoxia.
Hypoxic microenvironments trigger adaptive responses that contribute to
the malignization of tumors. For instance, the hypoxia response plays a key
role in tumor neovascularization. Angiogenesis consists in the sprouting of
new blood vessels from pre-existing vasculature and it is the best known
form of tumor neovascularization. However, alternative
neovascularization mechanisms, such as vasculogenic mimicry, have been
gaining attention in recent years. Vasculogenic mimicry describes the
ability of highly aggressive tumor cells to acquire endothelial traits and
develop vessel-like structures capable of carrying blood without the
participation of endothelial cells. It is correlated with metastasis, shorter
survival and poor prognosis in cancer patients. Unfortunately, there are
currently no available drugs to target vasculogenic mimicry in clinical
settings, and its treatment remains a major biomedical challenge.
Poly-(ADP-ribose) polymerase (PARP) 1 catalyzes the synthesis and
transfer of poly-(ADP-ribose) to target proteins. PARP inhibitors cause
synthetic lethality in cells with genetic deficiencies in the homologous
recombination DNA repair pathway, inducing the selective elimination of
cancer cells with these defects. As a result, four PARP inhibitors have been
approved so far for their clinical use against tumors displaying
characteristics of “BRCAness”. Furthermore, PARP1 has been implicated
in multiple physiological and pathological processes. For instance, PARP1
can promote the stability and function of hypoxia-inducible factors, which
raises PARP1 as an attractive druggable target for the control of hypoxiaderived
tumor processes, like vasculogenic mimicry.
The purpose of the present thesis was to explore the consequences of PARP
inhibition in the context of melanoma vasculogenic mimicry, which could expand the therapeutic benefit of PARP inhibitors while potentially
targeting a malignant trait which so far remains untreatable.
Our study shows that PARP inhibition and hypoxia can modulate the
expression of hundreds of genes during melanoma tube formation on
matrigel. The profound impact of PARP inhibition was partly due to the
modulation of long non-coding RNA, a class of RNA transcripts that do
not encode any protein products but can regulate gene expression in a
variety of ways. PARP inhibition during hypoxia significantly modulated
the expression of numerous genes implicated in vascular biology, resulting
in the global modulation of a number of vasculature-related signaling
pathways and seemingly enhancing the endothelial-like characteristics of
melanoma cells.
Consistent with previous results, PARP1 chemical inhibition or genetic
knockdown could reduce the phosphorylation of vascular endothelial
cadherin on tyrosine 658 in normoxia and hypoxia. Previous publications
have proved the crucial role of this cadherin and this specific
phosphorylation in vasculogenic mimicry. Moreover, this phosphorylation
is reportedly correlated with increased endothelial vessel permeability,
which can favor metastatic spread. Our study also found that PARP
inhibition can upregulate the expression and secretion of the plateletderived
growth factor β in vasculogenic melanoma cells. This cytokine is
involved in the recruitment of pericytes to blood vessels. In endothelial
vessels, low permeability and high pericyte coverage are markers of
vascular normalization, which is considered a sign of good prognosis in
tumors. In addition, melanoma tubular networks on matrigel seemed to
undergo a structural normalization after treatment with PARP inhibitors.
Finally, studies with human uveal melanoma xenografts showed that
treatment with PARP inhibitor olaparib improved pericyte coverage
specifically of vasculogenic mimicry pseudovessels in vivo, which was
concomitant with a decrease in metastasis in tumors with the ability to
develop vasculogenic mimicry.
In conclusion, the results of this thesis indicate that PARP inhibitors may
reduce the metastatic spread of melanoma tumors capable of vasculogenic
mimicry by normalizing vasculogenic mimicry pseudovessels.