[Frontiers in Bioscience 2, d271-282, June 1, 1997]
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THE ROLE OF LANGERHANS ISLETS IN PANCREATIC DUCTAL ADENOCARCINOMA
Parviz M. Pour

The UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE

Received 5/6/97 Accepted 6/2/97

10. ALTERATION OF AMYLOID POLYPEPTIDE (IAPP) IN PANCREATIC CANCER PATIENTS

This question was explored by Permert et al. (80,81), who examined hormone levels in plasma and tumor tissue of pancreatic cancer patients. In many of their patients, the levels of islet hormones were abnormal, a finding that corresponded to the results of other investigators (78,79,83,84). Of particular interest were the elevated plasma levels of IAPP (islet amyloid polypeptide) which were significantly higher in patients with pancreatic cancer than with other forms of gastrointestinal malignancies (80; Fig. 16). In obese, noninsulin­dependent type II diabetics, a moderate increase in IAPP levels, to values of about 50% greater than controls, have been reported (85). In pancreatic cancer patients without diabetes, the plasma levels of IAPP are similar to those in obese diabetics but are significantly lower than those in pancreatic cancer patients with diabetes (85). In these patients, immunoreactive IAPP levels were lower in the pancreatic carcinoma than in the surrounding nontumoral tissue (85). In general, endocrine cells, staining for insulin, glucagon, somatostatin, pancreatic polypeptide, pancreastatin, serotonin, and islet amyloid polypeptide (IAPP), were found in well­poorly- differentiated areas, as well as in the invasive components of pancreatic carcinomas (85). The immunoreactivity for insulin, glucagon, somatostatin, and IAPP was lower or absent in the islets in the vicinity of pancreatic carcinoma (44,53). Moreover, unlike the normal islet cells, a variable number of cells within islets expressed tumor­associated carbohydrate antigens, including CA 19­9, DU­PAN­2, and TAG­72 (53). These findings pointed to fundamental alterations in the production, storage, or release of islet hormones by the islet cells in the vicinity of pancreatic carcinoma. They also suggested that, with differentiation toward ductal cells, islets lose their normal phenotypic pattern of expression. Another indication of this finding was that pancreatic cancer is not a localized exocrine disease, rather it involves both the endocrine and exocrine pancreas.


Fig. 16. Plasma level of IAPP in patients with cancer of various tissues

Elevated plasma IAPP levels in pancreatic cancer patients could be due to the liberation of IAPP from the islet cells surrounding the tumors by virtue of a substance(s), presumably a peptide(s) released from cancer cells. The basis for this view was the observation that, in eight of nine of these patients who underwent a subtotal pancreatectomy, the presurgically altered glucose metabolic capacity and insulin utilization rate improved postsurgically (86), and the level of plasma IAPP normalized (80,86). In three patients who required insulin before surgery, insulin was no longer needed after surgery. More strikingly, in three noninsulin dependent diabetics, blood glucose levels normalized after surgery. The results of the study by Permert et al. (81) are consistent with the study by Ishikawa et al. (84) who found that, in five out of six pancreatic cancer patients, the ratio of total proinsulin/C­peptide was high before the surgery and normalized after the surgery, whereas no such change was seen in patients with unresectable tumors. If an endocrine tissue mass was the critical factor, tumor removal should have increased the severity of diabetes and further impaired glucose metabolism rather than improve it. It should be noted that diabetes is a frequent complication of subtotal pancreatectomy for chronic pancreatitis. However, in pancreatic cancer patients, marked improvement of both whole­body and peripheral insulin sensitivity has occurred after subtotal pancreatectomy and tumor removal (80,86). These findings suggest that pancreatic cancers lead to diabetes in pancreatic cancer patients.