Identifying Molecular Pathways in Carcinoid

Daniel C. Chung, MD
Harvard Medical School
Boston, MA 02115

The underlying molecular abnormalities in carcinoid tumors are poorly understood. This is an important deficiency in the field of neuroendocrine tumors, and is in sharp contrast to what we know about many other tumors such as colon cancer, breast cancer, or pancreatic cancer. Understanding some of these alterations can provide important insights into why the tumor forms and more importantly, how to develop new therapies. Our laboratory is interested in identifying some of these molecular alterations in carcinoids and in pancreatic neuroendocrine tumors. We have taken a multi-pronged approach to examine changes at the level of DNA, RNA, and protein.

Our strategy was to examine human tumor samples, in contrast to cultured cell lines. While there is some inherent tissue heterogeneity, this approach is appealing in that the changes identified reflect what is going on in actual tumors. We are fortunate to have developed a large collection of tumor samples from our institution to work with. I’d like to share some exciting new data about one gene/protein that we have recently obtained.

This protein is a transcription factor called HoxC6. This Hox gene was of particular interest because it appears to be a target of the Menin gene that is responsible for the Multiple Endocrine Neoplasia-I syndrome. HoxC6 was dramatically upregulated in GI carcinoids. Levels were very low in normal tissues, indicating that this gene is likely to play a role in tumor pathogenesis. To establish a biological role for HoxC6, independent studies were performed in which we overexpressed Hoxc6 and also knocked-down its expression in the Bon carcinoid cell line. Carcinoid cells that expressed high levels of HoxC6 had higher levels of growth and proliferation, and those with lower levels of HoxC6 grew at significantly slower rates. Traditionally, Hox genes are thought to play an important role in embryonic development, so its specific function in tumorigenesis in the adult is uncertain. Independent studies were performed to screen a variety of oncogenic pathways, and we were able to successfully demonstrate that HoxC6 was an important regulator of the AP-1 transforming pathway. This is a novel function for the HoxC6 gene and the first description of the role of the AP-1 pathway in this tumor type. Disrupting this specific interaction between Hoxc6 and AP-1 prevented HoxC6 from activating the AP-1 pathway and stimulating cell growth. This indicates a new and specific target for therapeutic intervention. There are some established inhibitors of AP-1 signaling, and we would like to see if we can identify molecules that may specifically block the protein-protein interaction between HoxC6 and AP-1. These studies are in press in Gastroenterology.

We are grateful for the support of the Caring for Carcinoid Foundation. Through studies such as these, we hope to improve our understanding of the molecular basis of the disease, and then utilize this information to design novel, targeted therapies.