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