The biological behavior of gastric enterochromaffin (ECL) cell tumors remains an enigma and their clinical management a source of controversy and concern. As a result, surgical management is often disparate and based upon relatively arbitrary concepts (size, primary lesions, and number of lymph nodes) and the inability to define whether the lesions are simply hyperplastic cell aggregates that are gastrin-dependent for their growth or gastrin-autonomous neoplastic cells.
The aims of this grant are to identify molecular markers that can be utilized to assess whether the ECL cell is gastrin-responsive or when the lesion has become gastrin-autonomous. A unique rodent model (Mastomys) has been developed in our laboratory to investigate ECL cell tumor biology. This rodent is unique in being the only known model of rapid (< 4 months) ECL cell tumor transformation. Numerous studies have indicated that its gastric carcinoid lesion is similar to that of human disease. Our preliminary data utilizing a number of molecular strategies in ECL cell tissue from rats, Mastomys and human demonstrate several conserved gene alterations particularly associated with AP-1 activity. Our hypothesis is that a biological rationale for surgical therapy for ECL cell carcinoids may be derived from studying and defining the evolution of ECL cell proliferation and neoplastic transformation in the Mastomys and applying these findings to humans. The most promising initial gene target pathway is AP-1 transcription.
The aims of the proposal are 1) identify whether fos/jun expression is a marker of ECL cell autonomy in Mastomys exposed to variable periods of hypergastrinemia, 2) define the gene pattern expression pathways associated with gastrin autonomy in the ECL cell using gene chip technology to examine alterations in gene expression as the ECL cell converts from normal to gastrin dependent and gastrin-autonomous neoplasia, 3) examine the human relevance of gastrin autonomous genes using tissue microarray technology. A pre-operative determination of the neoplastic ECL cell gene expression relating to gastrin responsiveness will improve the rationale for therapeutic gastric or antral resection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097050-02
Application #
6794710
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Xie, Heng
Project Start
2003-08-22
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$218,273
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Svejda, Bernhard; Kidd, Mark; Kazberouk, Alexander et al. (2011) Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT. Cancer 117:4141-54
Drozdov, Ignat; Svejda, Bernhard; Gustafsson, Bjorn I et al. (2011) Gene network inference and biochemical assessment delineates GPCR pathways and CREB targets in small intestinal neuroendocrine neoplasia. PLoS One 6:e22457
Kidd, M; Modlin, I M; Eick, G N et al. (2007) Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development. Am J Physiol Gastrointest Liver Physiol 292:G191-200
Kidd, Mark; Modlin, Irvin M; Pfragner, Roswitha et al. (2007) Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor-beta1-mediated regulatory abnormalities including up-regulation of C-Myc and MTA1. Cancer 109:2420-31
Pannala, Rahul; Gafni-Kane, Adam; Kidd, Mark et al. (2007) An ileal endometrioma: of carcinoids and cadherin. J Gastrointest Surg 11:229-32
Kidd, Mark; Eick, Geeta N; Modlin, Irvin M et al. (2007) Further delineation of the continuous human neoplastic enterochromaffin cell line, KRJ-I, and the inhibitory effects of lanreotide and rapamycin. J Mol Endocrinol 38:181-92
Modlin, Irvin M; Kidd, Mark; Pfragner, Roswitha et al. (2006) The functional characterization of normal and neoplastic human enterochromaffin cells. J Clin Endocrinol Metab 91:2340-8
Modlin, Irvin M; Latich, Igor; Kidd, Mark et al. (2006) Therapeutic options for gastrointestinal carcinoids. Clin Gastroenterol Hepatol 4:526-47
Modlin, Irvin M; Kidd, Mark; Latich, Igor et al. (2006) Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed. Ann Surg 244:52-60
Kidd, Mark; Modlin, Irvin M; Mane, Shrikant M et al. (2006) Q RT-PCR detection of chromogranin A: a new standard in the identification of neuroendocrine tumor disease. Ann Surg 243:273-80

Showing the most recent 10 out of 18 publications