Can Colorectal Cancer be Prevented or Treated by Oral Hormone Replacement Therapy?

Abstract

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...

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

“…GCC knockout animals have a similar phenotype with hyperplastic crypts and reduced differentiation of secretory lineage cells (20). The suppressive effect of cGMP signaling on proliferation in the colon has highlighted the potential therapeutic value of this pathway for intestinal malignancies (21)(22)(23)40).…”

Guanylyl Cyclase C in Colorectal Cancer: Susceptibility Gene and Potential Therapeutic Target

“…Of significance, while paracrine hormones are lost in tumorigenesis, there is compensatory over-expression of the receptor GCC in almost all primary and metastatic tumors examined [139, 140]. Persistence of receptors in the face of hormone loss suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy [60, 65, 66, 70]. …”

“…Ligand activation of GCC, or cGMP, inhibited glycolysis by reducing rate-limiting enzymes including GLUT1, HKII, and PK, associated with a decrease in glucose uptake and lactate production, limiting bioenergetic support for rapid proliferation. Moreover, activation of GCC promoted mitochondrial biogenesis, increasing mitochondrial expression and function, and reconstituting oxidative metabolism in normal colonocytes and cancer cells [59, 60, 65, 66, 70]. …”

The uroguanylin system and human disease

“…Collectively, these observations suggest a role for the GC-C receptor as an intestinal tumour suppressor the dysregulation of which, reflecting the loss of paracrine hormones, is important in the initial stages of the pathophysiology of colorectal tumorigenesis [66]. This raises the possibility of using oral GC-C receptor ligands as a treatment for colon carcinoma, one of the most common malignancies [67]. Indeed, the oral administration of uroguanylin to mice suppressed intestinal tumorigenesis through inducing apoptosis in human colon carcinoma cells in vitro and inhibiting the formation of polyps in the Min/ + mouse animal model of colorectal cancer in vivo [68].…”