Ribonucleases in Tumor Angiogenesis and Cancer Progression
Angiogenesis, the growth of new capillary blood vessels in the body, is an important natural process occurring both in health and in disease. Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult. In females, angiogenesis also occurs during the monthly reproductive cycle and during pregnancy. In healthy tissues, angiogenesis is precisely regulated by a balance between stimulatory and inhibitory factors. When this balance is disturbed, the result is either too much or too little angiogenesis. The list of diseases that have abnormal angiogenesis as an underlying mechanism grows longer every year, affecting more than one billion people worldwide. Abnormal blood vessel growth, either excessive or insufficient, can lead to many deadly and debilitating conditions, including cancer, skin diseases, age-related blindness, diabetic ulcers, cardiovascular disease, stroke, and many others. Restoring the body’s natural control of angiogenesis is a widespread approach to fighting these diseases.
During tumorigenesis, cancerous tumors release angiogenic factors that stimulate blood vessels to grow into the tumor, providing it with oxygen and nutrients. A key mechanism of antiangiogenic therapy interferes with the process of blood vessel growth to starve the tumor of its blood supply. In the U.S., there are currently 13 FDA-approved anti-cancer therapies with recognized antiangiogenic properties in oncology to treat many types of cancers, such as colon, kidney, lung, breast, liver, brain, ovarian, thyroid, and multiple myeloma. These agents, which interrupt critical cell signaling pathways involved in tumor angiogenesis and growth, include monoclonal antibodies directed against specific proangiogenic growth factors and/or their receptors.
Research in the Hu laboratory mainly focuses on mechanism and function of angiogenin (ANG) and ribonuclease 4 (RNASE4), two members of the vertebrate-specific, secreted ribonuclease superfamily ANG was first purified as an angiogenic molecule from the conditioned medium of human colon adenocarcinoma cell line HT-29 in 1985. ANG is up-regulated in various human cancers. It promotes cancer progression by inducing tumor angiogenesis as well as cancer cell proliferation and survival. A unique feature of ANG, which distinguishes it from the other angiogenic factors, is that it mediates ribosomal RNA (rRNA) transcription, which is essential for other angiogenic factors to stimulate angiogenesis. After several years of rigorous research in our lab, ANG binding proteins and receptor have been identified, signaling pathways characterized, and inhibitors developed for cancer therapy.
Nil Vanli, a Biochemistry PhD student in the Hu laboratory, aims to understand the function and mechanism of RNASE4, a novel angiogenic factor. RNASE4 was co-purified with ANG from HT-29 conditioned medium in 1985, but its biological activities have been overlooked ever since. RNASE4 and ANG belong to the same superfamily of enzymes, share the same promoters and are co-regulated. Extrapolating from the biological activities of ANG, we hypothesized and verified that RNASE4 has angiogenic, pro-growth, and pro-survival functions. We have found that RNASE4 is up-regulated in many types of solid cancers including prostate cancer, the focus of our laboratory. Part of Nil’s thesis project was to develop serum level of RNASE4 as a novel diagnosis marker for prostate cancer, for which she has developed a sensitive double antibody ELISA assay Her next aim is to assess the therapeutic activity of RNASE4 monoclonal antibodies in vitro and in vivo using xenograft animal models to set a strong foundation for future preclinical work. In addition, she is currently working on identifying the cell surface receptor for RNASE4 and characterizing the signaling pathways of RNASE4 in regulating cell growth and survival.
Vanli N, Guo-Fu Hu. 2015. Mechanism and function of angiogenin in prostate cancer. Chinese J Biochem Mol Biol. 31: 1261-1266.