The paracrine hormone hypothesis of colorectal cancer.
Colorectal carcinogenesis originates in the context of dysregulated epithelial cell homeostasis, wherein hyperproliferation, hypodifferentiation, metabolic reprogramming, and mesenchymal remodeling reflect recursive mutually reinforcing mechanisms contributing to progressive genomic instability. Although genotypic and phenotypic elements characterizing the terminal integration of these pathophysiological processes defining cancer are well enumerated, events initiating, coordinating, and sustaining this hierarchical maladaptive systems evolution remain elusive for most tumors. In the intestine, guanylyl cyclase C (GCC) and its paracrine ligands organize and regulate the homeostatic integrity of the crypt-villus axis, forming a hormonal tumor suppressor signaling sequence, whose dysfunction defines the initiation of neoplastic transformation and creates a permissive niche for tumor progression.
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Giovanni.Pitari@jefferson.edu
G M
GM
Pitari
P
P
Li
J E
JE
Lin
D
D
Zuzga
A V
AV
Gibbons
A E
AE
Snook
S
S
Schulz
S A
SA
Waldman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000378:metabolism*; D006706:Homeostasis; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008871:Microvilli / Q000201:enzymology / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019899:Paracrine Communication / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006728:Hormones; D006162:Guanylate Cyclase