Link between p53 isoforms and angiogenesis: Current prospects.

Dear Editor,

Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation finally leading to an aggressive metastatic phenotype. Between many genetic lesions, mutational inactivation of p53, a tumor-suppressor gene, is the most frequent event found in 50% of human cancers. Choudhury et al. have nicely demonstrated the differential expression pattern of p53 by IHC to differentiate malignant and benign ovarian tumors.[1] p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis in various cancers including ovarian cancer. TP53, TP63, and TP73 genes are the p53 family members. p53, p63, and p73 have similar features in their gene structures and functions but have also diverged evolutionarily. The p53 family members play a very important role in the control of many critical cellular functions.[2] The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53β and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumors. However, its role in tumor progression is still unknown. A recent study examined the involvement of Δ133p53 isoforms in tumoral angiogenesis and growth in human glioblastoma. Their data showed that conditioned media from U87 glioblastoma cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Their in vivo data suggested that angiogenesis and growth of glioblastoma U87 tumors are inhibited upon depletion of Δ133p53 isoforms.[3] Although mice engineered with knocked down or total loss of expression of deltaNp63 revealed no tumor phenotype, which has been suggested loss of p63 increased cell migration and metastasis[45] indicating the role of deltaNp63 in tumor angiogenesis. It has been also shown that deltaNp63-α activates STAT3 phosphorylation, a key signaling pathway regulate angiogenesis in tumors, leading to transcriptional activation of the deltaNp63 gene through STAT3 demonstrating a positive auto regulation of deltaNp63 transcription.[6] These data summarize our current knowledge on the angiogenesis potential of P53 family members: DeltaP63/133 might be good candidates for therapeutic approaches targeting angiogenesis in various endocrine cancers e.g., ovarian cancer. These findings also offer opportunities to greatly improve current anti-angiogenic treatment for cancer.