GI hormonal changes in diabetes influence pancreatic cancer growth.
Streptozotocin diabetes prevents induction of pancreatic tumors in several animal models, suggesting a pivotal role for islet cell products in the pathogenesis of pancreatic cancer. To test the hypothesis that altered gastrointestinal peptide levels in streptozotocin diabetes influence tumor growth, human pancreatic cancer cells (MIA PaCa-2) were implanted subcutaneously into streptozotocin diabetic nude mice. After 3 weeks, tumors in the control group weighed 43 mg and tumors in the diabetic group weighed 12 mg (P < 0.001). Plasma insulin and IGF-1 levels were significantly decreased in the streptozotocin-treated animals compared to those of control (insulin: 23 microU/ml vs 31 microU/ml, P < 0.001; IGF-1: 254 ng/ml vs 324 ng/ml, P < 0.001). In contrast, somatostatin and glucagon were significantly elevated in the streptozotocin diabetic group relative to control levels (somatostatin: 179 pg/ml vs 54 pg/ml, P < 0.001; glucagon: 290 pg/ml vs 134 pg/ml, P < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd = 15.5 nM), IGF-1 (Kd = 30.0 nM), and somatostatin (Kd = 2.5 nM) on the MIA PaCa-2 cells. Receptors for glucagon were absent. In an in vitro cell proliferation assay, cell division was promoted by insulin (P < 0.01, max + 11%) and IGF-1 (P < 0.01, max + 10%). Somatostatin inhibited cell division (P < 0.01, max - 18%). No effect was seen with glucagon. The growth of pancreatic cancer, particularly in diabetes, may be influenced by gut peptides in a receptor-dependent fashion.
Fisher
W E
WE
Department of Surgery, Ohio State University, Columbus 43210, USA.
Boros
L G
LG
O'Dorisio
T M
TM
O'Dorisio
M S
MS
Schirmer
W J
WJ
D000818:Animals; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000097:blood*; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology*; D013004:Somatostatin / Q000097:blood; D013311:Streptozocin; D014407:Tumor Cells, Cultured
D005768:Gastrointestinal Hormones; D007328:Insulin; D013004:Somatostatin; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D005934:Glucagon