Abstract
The concept of tumor growth being angiogenesis dependent had its origin in the observations of Judah Folkman in 1969 of a retinoblastoma in a child. Tumor angiogenesis is initiated when endothelial cells (ECs) respond to local stimuli and migrate towards the growing mass, which results in the formation of tubular structures surrounded by perivascular support cells that transport blood to the inner tumor. In turn, the neo-vasculature supports tumor development and eventual metastasis. This process is highly regulated by several signaling pathways. Central to this process is the Notch signaling pathway. Beyond the role of Notch signaling in tumor angiogenesis, a major hallmark of cancer development, it has also been implicated in the regulation of tumor cell proliferation and survival, in epithelial-to-mesenchymal transition, invasion and metastasis and in the regulation of cancer stem cells, in a variety of hematologic and solid malignancies. There is increasing evidence for the tumor vasculature being important in roles other than those linked to blood perfusion. Namely, endothelial cells act on and influence neighboring tumor cells by use of angiocrine factors to generate a unique cellular microenvironment, thereby regulating tumor stem-like cells’ homeostasis, modulating tumor progression, invasiveness, trafficking and metastasis. This review will focus on Notch signaling components that play a part in angiocrine signaling in a tumor setting.
Highlights
It was only in 1969 that Judah Folkman raised the possibility of tumor growth being angiogenesis-dependent by observing a retinoblastoma in a child, which consisted of a large tumor that protruded from the retina into the vitreous and was highly vascularized
Genetic manipulation of endothelial Jagged1 in a mouse model of prostate cancer revealed that loss of endothelial Jag1 had an inhibitory effect in the neo-angiogenic and maturation responses [70]. These results identified endothelial Jagged1 as a proangiogenic and pro-maturation regulator of tumor angiogenesis
Since cancer stem cells are known for occupying a perivascular niche in the tumor, the study of angiocrine mechanisms of Notch signaling represents a strong proposition for the scientific community [123]
Summary
The first description of the process of angiogenesis was made in 1794 by a British surgeon and anatomist, John Hunter [1]. The experimental study of new blood vessels formation, i.e., angiogenesis, began in the late 1930s and early 1940s, when several investigators studied the events of neovascularization in experimental tumors [12,13]. Prior to 1970, the prevailing belief was that tumor angiogenesis was a side-effect of dying tumor cells It was only in 1969 that Judah Folkman raised the possibility of tumor growth being angiogenesis-dependent by observing a retinoblastoma in a child, which consisted of a large tumor that protruded from the retina into the vitreous and was highly vascularized. He observed tiny metastases shed in the vitreous that were all avascular and had a necrotic center. Since Folkman’s seminal discovery, many signaling pathways have been identified as key contributors to the neo-angiogenic process, leading to the creation and application of anti- angiogenic drugs in cancer treatment, such as the anti-VEGF antibody bevacizumab and the tyrosine kinase inhibitors like sunitinib or sorafenib, among others [14,15,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
