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Morgan et al. HOX genes and the tumor microenvironment

Its proangiogenic effects are also mediated through it binds directly to HOXA5 protein and prevents it
non-VEGF pathways, including the downregulation of from activating the transcription of the key tumor
fibulin-1 in castrate resistant prostate cancer . It is suppressor gene p53 [21] . Taken together, these studies
[93]
targeted by the tumor-suppressor microRNA (miR)- imply the existence of a HOX-mediated feedback
200 that blocks angiogenesis and inhibits metastasis mechanism from the developing neovasculature to
in multiple tumor types . the tumor whereby HOXD3 promotes uPA expression
[94]
in the endothelial cells, and this in turn blocks p53
An additional proangiogenic gene upregulated by expression in the tumor, promoting cell proliferation
HOXB7 is angiopoietin-1 (Ang-1) [58] , the product of and survival.
which plays a crucial role in stabilizing newly formed
vasculature. The binding of Ang-1 protein to its receptor CONCLUSION
on endothelial cells promotes their adherence to mural
cells such as pericytes and smooth muscle cells [95-97] . The evidence from previous studies indicates that
Correspondingly, Ang1 secretion by prostate cancer the expression of HOX genes in the prostate tumor
cells in a xenograft model was shown to enhance modifies the microenvironment in a manner that
tumor growth through an increased level of branching supports metastasis through degradation of the
in the neovasculature [98] . ECM, and angiogenesis through the secretion of
proangiogenic cytokines. This is complemented by the
Additional proangiogenic genes that are regulated by expression of HOX genes in the microenvironment,
HOX transcription factors include endothelial nitric particularly in endothelial cells, that promotes tumor-
oxide synthase (eNOs) [99] and urokinase plasminogen supportive functions including angiogenesis and
activator (uPA) [100] . HOXA9 expression in progenitor the secretion of proteins that directly influence the
endothelial cells within the tumor microenvironment malignant phenotype. Thus, targeting the function of
was shown to be necessary for their commitment to an HOX proteins may not only have a direct effect on
endothelial lineage, and it was also shown to directly tumor cells, but could also help reverse changes in
regulate endothelial specific genes such as eNOs, the tumor microenvironment that would otherwise
VE cadherin, and VEGFR2 [99] . In this context HOXA9 promote cancer progression.
was identified as a key target of histone deacetylases
(HDACs), as its expression was significantly reduced DECLARATIONS
after HDAC inhibitor treatment and this in turn blocked
angiogenesis both in mice [99] and in a clinical trial of Authors’ contributions
combined HDAC and VEGF inhibitors for multiple Performed the literature search and drafted the
cancers including advanced prostate cancer [101] . manuscript: R. Morgan
HOXD3 has also been shown to have a role in vessel Helped write the manuscript and provided further
formation by endothelial cells through the activation interpretation of the referenced studies: H.S. Pandha
of uPA transcription [100] . uPA is involved at all stages
of angiogenesis, including endothelial cell division, Financial support and sponsorship
migration, the formation of stable vessels, and the None.
regulation of vascular permeability through proteolytic
degradation of the extracellular matrix [102-104] . This is Conflicts of interest
mediated through intracellular signaling initiated The authors are shareholders in HOX Therapeutics
by its binding to receptors including uPA receptor Ltd., a company which is developing novel HOX/PBX
(uPAR; CD87), low-density lipoprotein receptor- binding antagonists, although these reagents are not
related protein receptor (LRP/α2MR), and specific discussed in this review.
integrins [105-110] . In addition, uPA converts plasminogen Patient consent
into serine protease plasmin [111,112] , which in turn Not applicable.
breaks down matrix proteins and activates a number
of MMPs [113-116] . uPAR-bound uPA has been shown Ethics approval
in a number of studies to be localized to the leading Not applicable.
edge of migrating cells [117-119] to help ensure a focused
degradation of the ECM and liberate matrix-bound REFERENCES
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Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 283