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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