Regulation of Pancreatic Cancer Growth by Gastrointestinal Hormones: A Clinically Useful Strategy?

Abstract

The concept that hormonal manipulation could be used to control the growth of cancers originating from organs normally under hormonal control was proposed over 100 years ago. In 1895, the Scottish surgeon George T. Beatson performed bilateral oophorectomy on a woman with advanced breast carcinoma, which resulted in dramatic regression of her disease and demonstrated that hormonal control of cancer was possible.1 Another surgeon, Charles B. Huggins, eventually won the Nobel prize in 1966 for demonstrating regression of cancers by endocrine manipulation. He demonstrated that antiandrogenic treatment consisting of orchiectomy or the administration of estrogens could produce long-term regression in patients with advanced disseminated prostatic carcinoma.2 Today, dramatic results are not uncommon after hormonal treatment of prostatic, breast, endometrial, and ovarian cancer, even in patients with advanced disease.3,4 A similar approach to pancreatic cancer, a malignancy that usually presents in an advanced stage, may hold great promise. The fact that many gastrointestinal hormones affect the growth of the normal exocrine pancreas suggests that these peptides could be used to slow the growth of pancreatic cancer. Gastrointestinal hormones, such as somatostatin, that normally inhibit the division of the exocrine pancreatic cells, may also slow the growth of exocrine pancreatic cancer and provide a relatively nontoxic therapeutic option. It has also been postulated that antagonists of growth-promoting hormones, such as cholecystokinin, may be beneficial in the adjuvant treatment of pancreatic cancer. Alternatively, growth-promoting hormones, by increasing tumor cell division, may increase the sensitivity of a pancreatic tumor to adjuvant cytotoxic treatment. To provide a more substantial rationale for gastrointestinal hormonal therapy for pancreatic cancer, it must be proven that these hormones can indeed affect the growth of autologous malignant cells. In the laboratory, several experimental steps are commonly taken to demonstrate the potential of a hormone in manipulating the growth of pancreatic cancer. The growth effect of the hormone must be shown in vitro using proliferation assays. The growth effect should also be demonstrated in vivo, commonly by studying the effect of the hormone on the growth of established tumor xenografts in athymic nude mice or by studying the effect of the hormone on carcinogenesis. Evidence that the tumors produce receptors for the hormone are important in clarifying the mechanism of altered growth. Finally, neutralization of the hormone or the receptor with an antibody or specific antagonist should inhibit the growth effect. By summarizing the results of many such experiments, this chapter provides a substantial rationale for further study into the use of gastrointestinal hormones as adjuvant treatment of pancreatic cancer.