PANCREATIC BETA-CELLS CULTURED FROM INDIVIDUAL PRENEOPLASTIC FOCI IN A MULTISTAGE TUMORIGENESIS PATHWAY - A POTENTIALLY GENERAL TECHNIQUE FOR ISOLATING PHYSIOLOGICALLY REPRESENTATIVE CELL-LINES

Citation
F. Radvanyi et al., PANCREATIC BETA-CELLS CULTURED FROM INDIVIDUAL PRENEOPLASTIC FOCI IN A MULTISTAGE TUMORIGENESIS PATHWAY - A POTENTIALLY GENERAL TECHNIQUE FOR ISOLATING PHYSIOLOGICALLY REPRESENTATIVE CELL-LINES, Molecular and cellular biology, 13(7), 1993, pp. 4223-4232
Citations number
48
Categorie Soggetti
Biology
ISSN journal
02707306
Volume
13
Issue
7
Year of publication
1993
Pages
4223 - 4232
Database
ISI
SICI code
0270-7306(1993)13:7<4223:PBCFIP>2.0.ZU;2-Z
Abstract
Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, i n addition, present the opportunity to establish cell cultures more re presentative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenes is pathway can be cultured in vitro and show that they preserve distin ctive characteristics of the normal cells from which they arose, pancr eatic beta cells. In the RIP1-Tag2 line of transgenic mice, which expr ess the simian virus 40 T antigen in insulin-producing beta cells, pan creatic islets develop into vascularized tumors in a multistage pathwa y. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated betaHC, releas e insulin at physiological concentrations of glucose. In contrast to t umor-derived lines (betaTC), which are not properly regulated, the abi lity of the betaHC lines to respond correctly to glucose correlated wi th maintenance of normally depressed levels of low-K(m) hexokinases. G lutamic acid decarboxylase (GAD), an early autoantigen in type I diabe tes, was detected in most of the betaHC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly be tween the different cell lines, suggesting independent regulation. Cla ss I major histocompatibility complex antigens were detected on the be taHC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cy totoxic T-cell killing assay. The betaHC lines will be of value for st udies of beta-cell physiology, autoantigenicity, and tumor development . This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation an d to provide a source of cells that maintain important qualities of th eir normal progenitors.