Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues

Abstract

Guanylyl cyclase C (GCC) has been detected only in intestinal mucosa and colon carcinoma cells of placental mammals. However, this receptor has been identified in several tissues in marsupials, and its expression has been suggested in tissues other than intestine in placental mammals. Selective expression of GCC by colorectal tumor cells in extraintestinal tissues would permit this receptor to be employed as a selective marker for metastatic disease. Thus, expression of GCC was examined in human tissues and tumors, correlating receptor function with detection by PCR. GCC was detected by ligand binding and catalytic activation in normal intestine and primary and metastatic colorectal tumors, but not in extraintestinal tissues or tumors. Similarly, PCR yielded GCC-specific amplification products with specimens from normal intestine and primary and metastatic colorectal tumors, but not from extraintestinal tissues or tumors. Northern blot analysis employing GCC-specific probes revealed an Ϸ4-kb transcript, corresponding to recombinant GCC, in normal intestine and primary and metastatic colorectal tumors, but not in extraintestinal tissues. Thus, GCC is selectively expressed in intestine and colorectal tumors in humans and appears to be a relatively specific marker for metastatic cancer cells in normal tissues. Indeed, PCR of GCC detected tumor cells in blood from some patients with Dukes B colorectal cancer and all patients examined with Dukes C and D colorectal cancer, but not in that from normal subjects or patients with Dukes A colon carcinoma or other nonmalignant intestinal pathologies.

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

“…13 By both biochemical and molecular methods, expression of GC-C has been widely observed in human primary and metastatic colorectal adenocarcinomas. 14,15 In contrast, expression of both guanylin 16,17 and uroguanylin 1 is absent or markedly decreased in colorectal tumors compared to adjacent normal tissue. Thus, a breakdown in normal signaling between GC-C and its ligands may occur in transformed tissue.…”

Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells

“…Reactions were terminated with ice-cold 100% ethanol, and supernatants were separated from pellets by centrifugation (12,000 Â g, 15 minutes at 4jC) and processed for cGMP determinations (16).…”

“…The principal source of cGMP in these cells is guanylyl cyclase C (GCC; ref. 11), the receptor for the endogenous hormones, guanylin and uroguanylin, and the diarrheagenic bacterial heat-stable enterotoxins (ST), which is selectively expressed by intestinal epithelial cells in adult mammals (16,17).…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…Recently, GC-C mRNA also has been detected in all segments of the rat nephron by RT-PCR [79]. GC-C mRNA is also detected in the regenerating liver [80], and in metastatic tumors of colon cancer [81].…”