'Modeling' Carcinoid

Seung Kim, MD, PhD
Stanford University School of Medicine
Stanford, CA 94305

What is carcinoid? We know that it constitutes a rare, neuroendocrine tumor, but at the cellular and molecular level, we know very little about what carcinoid is. The past several decades of 'cancer research' has validated repeatedly that a detailed understanding of the basis for how cancers develop, where they come from, and how they progress can lead to development of effective treatments for specific cancers. Moreover, much of the most important work in these areas of cancer research comes from development of specific cancers in animal models, which provide powerful experimental tools for understanding the behavior and origins of cancer. Based on this successful precedent, the Caring for Carcinoid Foundation has made investments in a number of research projects that aim to use experimental animals like mice to investigate the cellular and molecular basis of 'what carcinoid is.'

In my group at Stanford University School of Medicine, we are using CFCF support in attempts to produce a mouse 'model' of carcinoid. This is a somewhat ambitious goal, since no genetic model of carcinoid yet exists. To accomplish this, we are using classical mouse genetic methods to perturb the 'growth control' of cells in the mouse intestine that are thought to be the origins of carcinoid tumors. (The origins and molecular defects leading to carcinoid tumor formation in mice are also being explored by the group led by Dr. Andrew Leiter, another recipient of CFCF support; see Wang et al 2007). In prior studies of endocrine tumors that form in organs like the prostate and pancreas, other groups have previously shown that tumor formation can be 'driven' by production of a foreign viral protein, called 'T-antigen' (Hanahan, 1985; Garabedian et al 1998). These studies led ultimately to new ways of thinking about neuroendocrine tumors in these organs (Hu et al 2004; Karnik et al 2005; Ippolito et al 2005, 2006). Our work in carcinoid, if successful, could lead to better understanding about the molecular and cellular changes that lead to formation of carcinoid tumors, and to better ways of testing and discovering new therapies for carcinoid.


Literature cited:

Garabedian, E.M., et al 1998. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci USA 95:15382-7

Hanahan, D. 1985. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115-22.

Hu, Y. et al 2004. RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci USA 101:5559-64.

Ippolito, J.E., et al 2006. Linkage between cellular communications, energy utilization, and proliferation in metastatic neuroendocrine cancers. Proc Natl Acad Sci USA 103:12505-10.

Ippolito, J.E., et al 2005. An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers. Proc Natl Acad Sci USA 102:9901-6.

Karnik, S.K. et al 2005. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 102:14659-64.

Wang, Y. et al 2007. Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active beta-catenin. Proc Natl Acad Sci USA 104:11328-33.