Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.Colorectal cancer is the 4th most common neoplasm and the 2nd leading cause of cancerrelated mortality, producing 10% of cancer-related deaths, in the U.S. [1][2][3] While surgery is the mainstay of treatment, occult metastases produce relapse in ~50% of patients [2,4,5] and adjuvant chemotherapy only marginally improves survival. [4,6] The poor prognosis and paucity of effective therapy underscore the clinical need for new approaches for earlier prevention and therapy. Conventionally, colon cancer is considered a genetic disease, reflecting sequential accumulation of mutations in oncogenes, tumor susceptibility genes or tumor suppressors, [7] most frequently (>80%) including sporadic or inherited alterations in the gene encoding adenomatous polyposis coli (APC). [8,9] In that context, a novel paradigm is emerging which suggests that at initiation, intestinal neoplasia evolves from a state of paracrine hormone insufficiency, [10][11][12] providing a novel therapeutic opportunity for colorectal cancer prevention by ligand supplementation to reconstitute disrupted tumorsuppressing signaling pathways. [13,14] Corresponding Author: Peng Li M.D., Ph.D., Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, JAH 364, Philade...