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.

Alvimopan (6 or 12 mg) accelerates GI recovery and is well tolerated in patients undergoing open laparotomy.

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Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.

Functional ST receptors are expressed in normal colonic tissue and primary and metastatic colorectal tumors but not by extraintestinal tissues in humans. Expression of ST receptors does not vary as a function of the metastatic site or grade of these tumors. Receptors expressed by colorectal tumors retain their characteristic function, with binding of ST coupled to activation of guanylyl cyclase. These studies support the suggestion that ST receptors represent a specific marker for human colorectal tumors that may have use as a target for directing diagnostics and therapeutics to these tumors in vivo.

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Reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers might be useful to more accurately assess micrometastases in lymph nodes of colorectal cancer patients undergoing disease staging.

Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.