Scientific Discovery Supported by the Hirshberg Foundation, at UCLA
Ductal adenocarcinoma of the pancreas, which comprises 90% of all human pancreatic cancers, is a devastating disease, with overall 5-year survival rate of only 3-5%. The incidence of this disease in the US has increased recently to ~33,000 new cases each year and is now the fourth leading cause of cancer death in both men and women. Surgery and current conventional chemotherapy offer very limited survival benefits and novel therapeutic strategies are urgently required to prevent and treat this aggressive disease.
In recent years, the incidence of obesity, metabolic syndrome, hypertension and Type II diabetes mellitus, all characterized by insulin resistance and compensatory hyperinsulinemia (i.e. an increase in the level of circulating insulin), has reached alarming rates in the developed world. In the US 65% of the adult population is overweight (BMI > 25), and 30% is considered to be obese (BMI>30). A great interest has been generated by epidemiological studies that linked hyperinsulinemia and Type II diabetes with increased risk for developing a variety of clinically aggressive cancers of several tissues, including pancreatic ductal adenocarcinoma, colon, breast and prostate cancers. The elucidation of the mechanism(s) involved is of importance because this knowledge could pave the way for new strategies for the prevention of pancreatic cancer as well as other aggressive solid cancers.
It is increasingly recognized that the communication, or crosstalk between insulin receptor and G protein-coupled receptor (GPCR) signaling is critical for the regulation of multiple physiological functions. This important mechanism of receptor crosstalk could also underlie a variety of abnormal processes. For example, excessive crosstalk between insulin and angiotensin II (ANG II) receptors leads to cardiovascular and renal abnormalities in obesity, metabolic syndrome and type II diabetes. Accordingly, the administration of angiotensin-converting enzyme (ACE) inhibitors to patients with these conditions produces important clinical benefits. The fact that administration of ACE inhibitors also protects against various cancers further confirms an important role of a crosstalk between insulin and GPCR signaling in the development and proliferation of cancers. Studies in the laboratory of Dr. Rozengurt, the incumbent of the Ronald S. Hirshberg Chair for Pancreatic Cancer Research at UCLA, have focused on GPCRs in the proliferation of normal and cancer cells for some time.
Recently Dr. Krisztina Kisfalvi, a Hirshberg fellow and Dr. Enrique Rozengurt, found a new and exciting insight concerning the link between pancreatic cancer and hyperinsulinaemia. They identified a crosstalk mechanism by which insulin enhances the biological effects of GPCR stimulation by angiotensin, bradykinin, bombesin and neurotensin in human pancreatic cancer cells. Working with Drs. Osvaldo Rey and Steven Young, the team of investigators used novel imaging techniques to visualize the earliest steps in the action of GPCRs in individual live pancreatic cancer cells in real time, especially the release of calcium (Ca2+) from stores inside the cell. The crosstalk between insulin and GPCRs not only enhances rapid responses in the cell but also leads to stimulation of the proliferation of pancreatic cancer cells. It is important to note that these experimental findings were reproduced in several cancer cell lines, increasing their relevance and generality. The results have been recently published in the Cancer section of the prestigious journal Endocrinology.
The results have important clinical implications. As they show in the paper, insulin enhances the Ca2+ release from internal stores stimulated by GPCR agonists. The magnitude, rate and duration of increases in [Ca2+]i are increasingly recognized as encoding critical information for biological processes, including gene expression and cell proliferation. Given the close relationship between the endocrine and exocrine pancreas and the local production of several GPCR stimulators (like angiotensin, neurotensin) in the pancreas, the crosstalk between insulin and GPCRs is of especial significance for the normal physiologic functions of the acinar and ductal pancreatic cells. Any imbalance in this fine regulation (like hyperinsulinaemia) leads to alteration in the normal cell functions and results in excessive proliferation. It will be of importance to determine whether the proliferation of recently identified pancreatic stem cells is increased in pancreas of obese and hyperinsulinemic animal models. It is also likely that the novel mechanism identified by Kisfalvi, Rozengurt and their collaborators is of importance for other cell types, as well. In view of the importance of gastrointestinal hormones in the function of intestinal epithelial cells and the association between hyperinsulinemia and colon cancer, it is of interest that insulin also enhanced Ca2+ signaling in response to GPCR agonists in intestinal epithelial cells.
Anti-diabetic drugs are commonly used for controlling diseases associated with hyperinsulinaemia (Type II diabetes mellitus, obesity, metabolic syndrome) and for preventing their complications (hypertension, heart failure, renal pathologies, etc). The recent work of Kisvalvi and Rozengurt, supported by the Hirshberg Foundation, raises the possibility that the use of anti-diabetic drugs could have an impact in preventing the development of pancreatic cancer in patients with Type II diabetes mellitus, obesity, metabolic syndrome, all diseases characterized by hyperinsulinemia.
The paper “Kisfalvi K, Rey O, Young SH, Sinnett-Smith J and Rozengurt R. Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq-coupled receptor agonists through an mTOR-dependent pathway. Endocrinology. 2007 Mar 22 ” can be found at http://endo.endojournals.org/search.dtl
