Enteroendocrine cells are specialized cells present in the mucosa of the digestive tract. They account for less than 1% of all epithelial cells in the gastrointestinal tract, but as a whole, they collectively constitute the largest endocrine “organ” in the body. Enteroendocrine cells are also found in the ducts of the pancreas, the liver, and the respiratory sys-tem, another endodermal derivative that originates by in-vagination of the epithelium of the embryonic foregut. Because enteroendocrine cells closely resemble neurose-cretory cells of the central nervous system (CNS) that se-crete many of the same hormones, signaling molecules, and regulatory agents, they are also called neuroendocrine cells. Most of these cells are not grouped as clusters in any specific part of the gastrointestinal tract. Rather, enteroen-docrine cells are distributed singly throughout the gastroin-testinal epithelium. For that reason, they are described as constituting part of a diffuse neuroendocrine system (DNES). Figure 17.13 shows the parts of the gastrointesti-nal tract from which the gastrointestinal peptides are pro-duced. One notable exception to this distribution pattern is found in the pancreas. Here, enteroendocrine cells, derived from pancreatic buds that also arise from the em-bryonic foregut, form specialized accumulations called en-docrine islets of Langerhans (see page 649). In the current view, the DNES includes both neurons and endocrine cells that share common characteristics, including the expression of specific markers (e.g., neu-ropeptides, chromogranins, and neuropeptide processing enzymes) and the presence of dense-core secretory gran-ules. Secretory products of enteroendocrine cells derive from a variety of genes; they are expressed in different forms because of alternative splicing and differential pro-cessing. Secretion of enteroendocrine cells is regulated by G protein–coupled receptors and tyrosine-kinase activity. There is evidence that chromogranin-A regulates biosyn-thesis of dense-core secretory granules, whereas chromo-granin-B controls sorting and packaging of produced peptides into secretory vesicles. Table 17.1 lists important gastrointestinal hormones, their sites of origin, and their major functions. Neoplastic transformations of DNES cells are responsi-ble for development of gastroenteropancreatic (GEP) neuroendocrine tumors. These tumors represent rare neoplasms of the gastrointestinal tract and pancreas that often secrete hormonally active agents, causing distinct clinical syndromes. The appendix is the most common gastrointestinal site of origin for neuroendocrine tumors. The classical example is the carcinoid syndrome caused by the release of a variety of hormonally active substances by tumor cells. Symptoms include diarrhea (case by sero-tonin), episodic flushing, bronchoconstriction, and right-sided cardiac valve disease. Some enteroendocrine cells may be classifiable func-tionally as amine precursor uptake and decarboxylation (APUD) cells. They should not, however, be confused with the APUD cells that are derived from the embryonic neural crest and migrate to other sites in the body. APUD cells se-crete a variety of regulator substances in tissues and or-gans including the respiratory epithelium, adrenal medulla, islets of Langerhans, thyroid gland (parafollicular cells), and pituitary gland. The enteroendocrine cells differentiate from the progeny of the same stem cells as all of the other epithelial cells of the digestive tract. The fact that two dif-ferent cells may produce similar products should not imply that they have the same origin. Enteroendocrine cells produce not only gastrointestinal hormones such as gastrin, ghrelin, secretin, cholecys-tokinin (CCK), gastric inhibitory peptide (GIP), and motilin, but also paracrine hormones. A paracrine hormone dif-fers from an endocrine hormone in that it diffuses locally to its target cell instead of being carried by the bloodstream to a target cell. A well-known substance that appears to act as a paracrine hormone within the gastrointestinal tract and pancreas is somatostatin, which inhibits other gas-trointestinal and pancreatic islet endocrine cells. In addition to the established gastrointestinal hormones, several gastrointestinal peptides have not been definitely classified as hormones or paracrine hormones. These pep-tides are designated candidate or putative hormones. Other locally active agents isolated from the gastroin-testinal mucosa are neurotransmitters. These agents are released from nerve endings close to the target cell, usu-ally the smooth muscle of the muscularis mucosae, the muscularis externa, or the tunica media of a blood vessel. Enteroendocrine cells can also secrete neurotransmitters that activate afferent neurons, sending signals to the CNS and enteric division of autonomic nervous system. In addi-tion to acetylcholine (not a peptide), peptides found in nerve fibers of the gastrointestinal tract are vasoactive in-testinal peptide (VIP), bombesin, and enkephalins. Thus, a particular peptide may be produced by endocrine and paracrine cells and also be localized in nerve fibers.