Functional glucocorticoid receptor modulates pancreatic carcinoma growth through an autocrine loop.

Abstract

Several peptide hormones have been shown to influence growth and function in pancreatic carcinoma and have given evidence for an autocrine feedback loop governing the proliferation of these malignant cells. Conversely, steroid hormones including glucocorticoids have been shown to inhibit the growth of pancreatic cancer cells; however, the prevalence of the glucocorticoid receptor or its mechanism of growth suppression in these tumors is unknown. The ability of growth factors thought to be active in this autocrine loop to reverse the glucocorticoid-induced growth inhibition was studied in vitro in a human pancreatic adenocarcinoma (HPAC) cell line with a well-characterized glucocorticoid receptor (GR). The glucocorticoid dexamethasone (DEX) inhibited growth in a dose-dependent manner as measured by a [3H]thymidine incorporation assay as well as an MTT cell proliferation assay. Maximal effects were seen within 48 hr at a concentration of 100 nM DEX, suppressing growth to approximately 18% of control. When the maximally suppressed DEX-treated cells were exposed to exogenous growth factors, they rapidly attained or exceeded the growth rate of control cells: insulin-like growth factor = 106%, transforming growth factor-alpha = 134%, insulin = 151%, and epidermal growth factor = 187% (all P < 0.05, Student's t test). In order to determine the frequency of the GR in pancreatic cancer and the clinical relevance of our findings, immunohistochemical staining for the GR was performed on 20 human tumors. Twelve (60%) of all cancers, as well as all normal pancreatic tissues (n = 4), stained positively for cytoplasmic and/or nuclear GR with expression correlating highly with degree of tumor differentiation (Kruskal-Wallis test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: J Norman, M Franz, R Schiro, S Nicosia, J Docs, P J Fabri, W R Gower Jr
• Journal: The Journal of surgical research (J Surg Res) Vol. 57 Issue 1 Pg. 33-8 (Jul 1994) ISSN: 0022-4804 [Print] United States
• PMID: 7518883 (Publication Type: Journal Article)

Chemical References

• Growth Substances
• Receptors, Glucocorticoid
• Dexamethasone

Topics

• Carcinoma (metabolism, pathology)
• Cell Division (drug effects)
• Dexamethasone (pharmacology)
• Dose-Response Relationship, Drug
• Growth Substances (pharmacology)
• Humans
• Immunohistochemistry (methods)
• Pancreas (metabolism)
• Pancreatic Neoplasms (metabolism, pathology)
• Receptors, Glucocorticoid (physiology)
• Staining and Labeling
• Tumor Cells, Cultured