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Morgan et al. HOX genes and the tumor microenvironment

the remainder of this review. the enhancer region , and HOXC11 is expressed in
[57]
multiple prostate cancer cell types [Table 1]. MMP-9
[25]
HOX TRANSCRIPTION FACTORS AND expression has also been shown to be activated by
[58]
METASTASIS HOXB7 in breast cancer cells , and both MMP-9 and
HOXB7 are over expressed in prostate cancer [25,53] .
Metastasis is a complex, multi stage process and the The most frequently used prostate cancer-derived
tumor microenvironment plays a key role both at the cell lines are LNCaP, DU145 and PC3, of which PC3
earliest stages, in facilitating the movement of cells has by far the higher capacity for invasion in vitro and
away from the primary tumor, and in the final stages in shows a significantly higher level of MMP-9 expression
[59]
allowing metastatic cells to generate a new tumor at compared to the other cell lines . Correspondingly,
a distant site. One of the most important mechanisms the invasive capacity of LNCaP increased significantly
by which tumors can modify the microenvironment when MMP-9 was experimentally over-expressed in
[60]
is through the release of matrix metalloproteinases these cells , and invasion by DU145 and PC3 was
(MMPs), a family of zinc-dependent endopeptidases reduced after MMP-9 expression was knocked-down
that can modify the extra cellular matrix (ECM) . Two using siRNA .
[61]
[53]
of the most extensively studied of these enzymes with
respect to prostate cancer are MMP-2 and MMP-9, In addition to the gelatinase class MMPs, the
both of which are members of the gelatinase subgroup expression of two other MMPs, MMP-3 and MMP-14,
of MMPs characterized by a fibronectin-like, gelatin- is activated by HOX transcription factors [62,63] . MMP-
binding domain . MMP-2 expression is higher in 14 differs from other MMPs as it is membrane bound
[54]
prostate tumors compared to normal prostate tissue, through a transmembrane domain with its catalytic
and has also been shown to be secreted by the former , center on the outside of the cell . Its expression in
[55]
[64]
and reducing its expression in mouse melanoma prostate cancer cells is associated with androgen
B16F10 cells resulted in significantly fewer lung independence and aggressiveness . Prostate
[66]
[65]
metastases . Both MMP-9 and MMP-2 expression is tumors primarily metastasize to bone, and MMP-14
[56]
directly activated by the binding of HOXC11 protein to has a particularly important role in this process due to

Figure 2: HOX transcription factors regulate genes in prostate cancer cells that modify the tumor microenvironment, as well genes in
stromal cells that support tumor growth. HOX transcription factors have multiple roles in regulating genes that drive angiogenesis and
metastasis. HOX targets with a key role in metastases include MMPs 2, 3, 9, and 14, as well as genes such as Snail and E-cadherin that
are involved in the epithelial to mesenchymal transition. Genes involved in angiogenesis are also regulated by HOX transcription factors
both in tumor cells and in endothelial cells. HOXD3 drives the expression of integrin alpha 5 beta 1 in endothelial cells which in turn leads
to immature, leaky vessels. A number of HOX transcription factors can also drive the expression of proangiogenic secretory factors,
including HOXB7, which regulates the transcription of FGF2, VEGFA, CXCL1, and IL8. An additional proangiogenic gene upregulated by
HOXB7 is angiopoietin-1, the product of which plays a crucial role in stabilizing newly formed vasculature. Other proangiogenic genes that
are regulated by HOX transcription factors include eNOs and uPA. HOXA9 expression in progenitor endothelial cells is necessary for their
commitment to an endothelial lineage as it directly regulates endothelial specific genes such as eNOs, VE cadherin, and VEGFR2. HOXD3
has also been shown to have a role in vessel formation by endothelial cells through the activation of uPA transcription. In addition to an
extracellular activity, a scuPA can be taken up by cancer cells in which it binds directly to HOXA5. MMP: matrix metalloproteinase; FGF2:
fibroblast growth factor 2; VEGFA: vascular endothelial growth factor A; CXCL1: C-X-C motif ligand 1; IL8: interleukin 8; eNOs: endothelial
nitric oxide synthase; uPA: urokinase plasminogen activator; scuPA: single chain form of uPA
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 281