be excluded in tumors of any origin. Furthermore, NPY release from the sympathetic nerves is increased in conditions of tissue ischemia, which occurs during tumor growth, as well as in several systemic diseases such as hypertension or renal failure and during stress.4,5,84,85 Although the role of stress in tumor growth is still very controversial, there are animal and human studies linking it with cancer development and progression. For example, stressful life events have been associated with increased risk of breast and colon cancer.86−90 The potential effect of stress on tumor growth is usually explained by changes in the immune system.91 However, given NPY’s powerful angiogenic and growth-promoting activities and its release during stress, a potential role of NPY as a stress-induced neurogenic regulator of tumor growth demands investigation.

Taken together, NPY is an important factor in growth and development of tumors, particularly, but not solely, those of neural crest origin. The angiogenesis-dependent growth-stimulatory activities of NPY are modified by its tumorand receptor-specific direct effects on tumor cell proliferation. These bidirectional actions make NPY, its receptors and converting enzyme, DPPIV, attractive new targets in tumor therapies directed against both tumor cell proliferation and vascularization.

11. NPY-Mediated Angiogenesis and Neurogenesis

Angiogenesis and arteriogenesis are essential not only for tissue repair in ischemic and degenerative diseases but also during organ development. While the last two decades of angiogenesis research have identified many factors, which in vitro and/or in vivo are able to stimulate growth of new capillaries, stimulation of the formation of new fully matured arteries has remained a challenge. One of the reasons for our poor understanding of mechanisms of arteriogenesis may be attributed to the fact that most of our knowledge came out of tumor biology. Tumor angiogenesis, however, may not represent physiological but rather a thwarted process of vessel formation. During organogenesis and normal tissue growth, blood vessels develop in a tissue-specific well-organized pattern, and lay alongside of peripheral autonomic and sensory nerves.92,93 This association, however, had long been neglected until recently when molecular

110 J. B. Kitlinska & Z. Zukowska

signals governing angiogenesis and neurogenesis have begun to emerge. Growth factors known to be angiogenic and released by innervated tissues, such as VEGF or bFGF, were also found to possess neurogenic activity.92 For example, VEGF, derived from the Schwann cells, was shown to signal sprouting of vessels alongside of nerves93 while neurotrophins secreted by vascular smooth muscle and endothelium are both angiogenic and neurogenic.94 Coordination of vessel and nerve guidance is provided by endothelial and neuronal expression of specific attracting or repelling signaling molecules such as semaphorins and their receptors, neuropilins,95 or Eph/ephrin family of proteins.96

NPY appears to be one of the signals which are used during sprouting of both vascular as well as neuronal cells, particularly from arteries and sympathetic nerves. Recent studies have shown that the peptide, in addition to being angiogenic and arteriogenic,97 also stimulates neurogenesis. Through a series of elegant studies, Gray and Scharfman have demonstrated that the peptide increases proliferation and sprouting of neuronal stem cells in the dentate gyrus of the adult hippocampus98 and implicated NPY in recovery from epileptic seizures, depression after electroconvulsive shock therapy and some cognitive disorders.99 The neurogenic activity of NPY, however, appears to be mediated by Y1 receptors expressed by neuronal progenitor cells,12 the type of receptors different from those which induce angiogenesis (Y2). Thus, NPY’s angiogenic and neurogenic activities can be differentially regulated by expression of specific receptors on respective cells. In addition, endothelial expression of DPPIV, an enzyme which forms Y2/Y5 agonist and which is not expressed by neuronal cells, may serve as a “stop-and-go” signal for neurogenesis and angiogenesis, respectively.

Whether or not NPY-mediated angiogenesis and neurogenesis, are temporally related and how, has not been determined yet. However, one can speculate that they are interdependent, and one process can facilitate the other. For example, increased neuronal sprouting may be started by Y1 receptor activation but subsequently amplified and guided by formation of vessels, arteries in particular, which are themselves stimulated by NPY and endothelial activation of DPPIV and Y2 receptors. How these processes are executed remains to be determined, but even at the present time, one thing is certain, that proper neurogenesis is required for proper, physiological arteriogenesis, and vice versa.

Thus, the challenge of inducing formation of a new fully functional circulation for ischemic tissues will depend on our better understanding of how these two processes, neurogenesis and arteriogenesis, can be reproduced and coordinated.

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