The inhibition of HIF-1 alpha activity in tumors from YC-1-treated mice is associated with blocked angiogenesis and an inhibition of tumor growth. YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1 alpha.
The Eyes Absent (EYA) proteins combine transactivation, tyrosine phosphatase, and threonine phosphatase activities in their function as part of a conserved regulatory cascade involved in embryonic organ development. EYA tyrosine phosphatase activity contributes to fly eye development, and vertebrate EYA is involved in promoting DNA damage repair subsequent to genotoxic stress. EYAs are known to be expressed at elevated levels in ovarian and breast cancers. Here, we show that the tyrosine phosphatase activity of the EYAs promotes tumor cell migration, invasion, and transformation. These cellular effects are accompanied by alterations of the actin cytoskeleton and increased levels of active Rac and Cdc42. The invasiveness conferred by EYA is reflected in vivo by inhibition of metastasis seen when EYA3 expression is silenced in the invasive breast cancer cell line MDA-MB-231. Together, our data directly associate the tyrosine phosphatase activity of the EYAs with the oncogenesis-associated cellular properties of motility and invasiveness.
Oncogenic targets acting in both tumor cells and tumor stromal cells may offer special therapeutic appeal. Interrogation of the Oncomine database revealed that 52/53 human breast carcinomas showed substantial upregulation WNT family ligand WNT7B. Immunolabeling of human mammary carcinoma showed that WNT7B immunoreactivity was associated with both tumor cells and with tumor associated macrophages (TAMs). In the MMTV-PymT mouse model of mammary carcinoma, we found tumor progression relied upon Wnt7b produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. In the tumor overall, there was no change in expression of Wnt/β-catenin pathway target genes, but in vascular endothelial cells (VEC) expression of these genes was reduced suggesting that VEC respond to Wnt/β-catenin signaling. Mechanistic investigations revealed that failure of the angiogenic switch could be attributed to reduced Vegfa mRNA and protein expression in VECs, a source of Vegfa mRNA in the tumor which was limiting in the absence of myeloid Wnt7b. We also noted a dramatic reduction in lung metastasis associated with decreased macrophage-mediated tumor cell invasion. Together these results illustrated the critical role of myeloid Wnt7b in tumor progression, acting at the levels of angiogenesis, invasion and metastasis. We suggest that therapeutic suppression of Wnt7b signaling might be advantageous due to targeting multiple aspects of tumor progression.
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