Connecting a tumor to the environment.

Tumor cells are not only susceptible to signals from the environment, but they likewise release signal substances. It is well known that tumor cells secrete angiogenic factors--most prominently the vascular endothelial growth factor--which initiate the vascularization of the tumor for its nourishment. This process has been termed neoangiogenesis. Besides this, two further processes have recently been discovered that facilitate the interaction of the tumor with the lymphatic system and the nervous system, named lymphangiogenesis and neoneurogenesis. These three "geneses" have a cognate, in part common regulation and conjointly promote metastasis development. Neoangiogenesis and lymphangiogenesis provide the structures for the two routes of tumor cell dissemination, i.e. either hematogenous or lymphatic. Neoneurogenesis accomplishes the innervation of the tumor by the ingrowth of nerve endings into the tumor and alternatively or additionally by the protection of existing nerve cells from destruction. These tumor-innervating nerve cells may release neurotransmitters which are proliferative or promigratory signals for the tumor cells. Furthermore, nerve fibers are used as routes for tumor cell dissemination, too, which is known as perineural invasion.