(CANCER RESEARCH 51. 282-287. January I, 1991)
Karyotypic Changes Associated with Loss of Prolactin Dependency of Rat Nb2
Node Lymphoma Cell Cultures'
Douglas E. Horsman, Sharon Masui, and Peter VV.Gout2
The Cytogenetic Laboratory ¡I).E. HJ and Department of Cancer Endocrinolog)' /S. M., P. W. GJ, British Columbia Cancer Agency, Vancouver, British Columbia,
Canada VSZ 4E6
ABSTRACT
The parent line of cultured "Nb2 node" lymphoma cells is dependent
on the hormone prolactin (l'lÃ-l) for growth and is widely used for the in
vitro bioassay of lactogenic hormones. As reported previously, I'RI independent sublines have been developed in vitro from the parental line
by lactogen deprivation. The present study describes the G-bandcd karyotypes of the Noble (Nb) strain of rat (in which the original lymphoma
developed), the PRI.-dependent cell line (157th generation), and two of
its PRI.-independent sublines (1220th and 2372nd generations). The
karyotype of the Nb rat was determined to be the same as that of Rattus
norvegicus. The stemline karyotype of the PRL-dependent cells contains
a number of well-defined chromosomal abnormalities. The PRL-independent sublines examined have the same chromosomal abnormalities as
the PRL-dependent cells plus a few additional changes indicative of
clonal evolution from the PRL-dependent stemline. The development of
PRL independence (as seen in the 1220th generation) was associated
with only two karyotypic changes, i.e., loss of the Y chromosome and a
translocation involving chromosomes 14 and 17. The recently reported
mapping of the rat PRL gene and other PRL-related genes to chromosome
17 suggests that rearrangement of chromosome 17 could be involved in
the development of the PRL independence. The PRL-dependent and
PRL-independent Nb2 cell lines provide a useful system for studying
chromosomal and molecular genetic events associated with the malignant
progression of polypeptide hormone-dependent cancers.
INTRODUCTION
Tumor progression is a characteristic feature of malignant
cancers and is manifested by alterations in phenotypic behavior
such as increases in virulence, loss of dependence on growth
factors, development of drug resistance, tissue invasiveness, and
metastatic ability (1, 2). The progression proceeds in a stepwise
manner (3) and involves the clonal development in the cancers
of variant sublines which arise, at least in part, from enhanced
genetic instability (1, 2). Cytogenetic studies of human leukemias and lymphomas have demonstrated that progression of
these diseases is associated with the sequential acquisition of
nonrandom chromosomal changes (4). There is evidence that
such changes are critical steps in the development and progres
sion of many other types of cancer (5, 6).
Hormone-dependent
cancers such as may originate in the
breast, prostate, and endometrium are commonly treated with
hormone withdrawal therapy to take advantage of their depend
ency on specific hormones for growth. While this type of
therapy may produce long-lasting remissions, disease relapse
frequently occurs in a more malignant form which is not hor
mone dependent and hence fails to respond to further endocrine
treatment. Such tumor progression is a major problem in the
clinical management of these cancers (7).
The PRL'-dependent rat "Nb2 node" lymphoma cell line has
provided a useful system for studying the in vivo and in vitro
growth characteristics of polypeptide hormone-dependent can
cers and their progression toward hormonal independence (for
reviews see Refs. 8-10). The cell line was established in culture
from a transplant of a malignant lymphoma that arose in an
estrogenized male Nb rat (8, 11). It has been determined to
have the phenotypic characteristics of an early thymocyte (11,
12). The cultured cell line has retained principal properties of
the parent tumor, including a specific requirement for PRL (or
other lactogens) for growth and the ability to give rise to PRLdependent tumors when injected s.c. into Nb rats (9). The
specific growth requirement of the cultures for PRL has led to
their extensive use for the in vitro bioassay of lactogenic hor
mones (8-10). When subcultured in medium which is deficient
in lactogens. most of the cells die within a few days; some cells
survive, however, and give rise to sublines which no longer
require exogenous PRL for growth (13). These PRL-independ
ent cells are cytologically very similar to the parent cells but
have a higher proliferation rate; they are also tumorigenic (13).
We have initiated a cytogenetic investigation to determine if
there are karyotypic differences between PRL-dependent and
PRL-independent Nb2 node lymphoma cell lines which can be
correlated with their difference in PRL dependency. In this
study karyotypes have been established of the parent PRLdependent cell line and of two PRL-independent sublines pre
viously derived from the parent line by continuous lactogen
deprivation (Fig. 1; Ref. 13). Evidence has been obtained that
the PRL-independent lines have clonally evolved from the PRLdependent stemline with only minor chromosomal changes
which may be nonrandom and potentially important in deter
mining the chromosomal regions and genes involved in the
development of PRL independence.
MATERIALS
AND METHODS
Animals
Male Nb rats (weight ca 200 g) were used as a source of normal Nb
rat cells. The animals were obtained from the colony of Nb rats which
is maintained by random littermate breeding ( 14) at the British Colum
bia Cancer Research Centre.
M>- Node Lymphoma Cell Lines
Received 6/7/90; accepted 9/25/90.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1Supported by grants from the National Cancer Institute of C'anada (P. W.
Cultured PRL-dependent and PRL-independent Nb2 node lym
phoma cell lines were revived from liquid nitrogen storage for chro
mosome analysis. Fig. 1 shows how the three lines are related and gives
an indication of their age expressed in generations (i.e., the number of
population doublings that have occurred in vitro since the parent line
was established in culture). The cell lines are designated: (a) Nb2-U17,
the parent noncloned PRL-dependent cell line (157th generation); (b)
G.) and the British Columbia Health Care Research Foundation (P. W. G.. D. E.
H.).
2To whom requests for reprints should be addressed.
*The abbreviations used are: PRL. prolactin: Nb, Noble; FBS, fetal bovine
serum.
282
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Nb2 NODE LYMPHOMA CELL KARYOTYPES
described above. Metaphases were analyzed and photographed, and
karyotypes were prepared. The chromosome assignments and deter
minations of breakpoint locations of structural rearrangements were
made at a 300-400-band resolution level according to the established
nomenclature for G-banded rat chromosomes (16, 17).
generation
Ut 7 line
(PRL-dependent)1,PRAkaryotypedjf633rd
generationcelts
RESULTS
tränictogen-frjsferred
to
medium"-1220th
3e
Chromosome Analysis of Normal Nb Rat Fibroblasts. The
karyotype of normal male Nb rat fibroblasts (42,XY) was
determined to be the same as that of Rattus norvegicus (Refs.
16 and 17; Fig. 2).
Chromosome Analysis of Nb2 Node Lymphoma Cell Lines.
The karyotype of each lymphoma cell line was determined by
analysis of 45-50 metaphases/line. The stemline karyotype of
the PRL-dependent U17 cells was pseudodiploid, i.e., 42,XY,
-17,t(2;4)(q22;q24),t( 10; 11)(q 12;q 12), +der( 15)t( 15;?)(p 12;?),
-18,+der(18)t(18;?)(pl2;?)
(Fig. 3). The origin of the extra
chromosomal material on the two derivative chromosomes
[der(15) and der(18)] could not be identified. Occasional nonclonal single cell alterations were observed; definitive sublines
could not be demonstrated.
The karyotype of the PRL-independent PRA cells was hypodiploid with a modal number of 41. It had the same abnor
malities present in the U17 stemline with two additional
changes, i.e., loss of the Y chromosome and a t( 14; 17)(p22;p 14)
(Fig. 4). A PRA subline with three additional changes, i.e.,
—Y,t(14;17)(p22;pl4) and a translocation
between the
der(4)t(2;4) and one chromosome 6 was also identified.
The karyotype of the cloned, PRL-independent SFJCD1
subline had the same changes found in the main PRA subline,
plus ?inv(lq), der(ll), der(13), and —15,resulting in a modal
number of 40 (see Fig. 5 and Table 1). All metaphases of the
SFJCD1 line had the same karyotype, reflecting the cloned
nature of this cell line. The karyotypes and progressive changes
of the three Nb2 cell lines are shown in Table 1.
subline
generation
(PRL-independent)jr157th
karyotyped|1
756th
generationr~cloned
1SFJCD1
generation
subline
(PRL-independent)2372nd(karyotyped)
Fig. 1. Relationship of the cultured, PRL-dependent Nb2 node lymphoma cell
line, designated U17, and two of its PRL-independent sublines. i.e.. Nb2-PRA
and cloned Nb2-SFJCDl. Karyotyping of the various lines was done at the
generations indicated.
Nb2-PRA, a noncloned PRL-independent line (1220th generation);
and (c) Nb2-SFJCDl, a cloned PRL-independent cell line (2372nd
generation). Both the PRA and SFJCD1 lines, as distinct from the
parental U17 line, can proliferate readily in lactogen-free, chemically
defined medium (13).
Cell Culturing
Normal Nb Rat Fibroblasts. Cultures of normal rat fibroblasts were
established from finely minced pieces of fascia, lung, or peritoneum
isolated from healthy male Nb rats and incubated at 37°Cin N-2hydroxyethylpiperazine-JV-2-ethanesulfonic acid-buffered RPMI sup
plemented with FBS (20%), L-glutamine (20 ^M), and antibiotics. For
subculturing, the fibroblasts were detached by incubation with 0.05%
trypsin plus 0.02% EDTA for 2 min at 37°C.
DISCUSSION
Nb2 Node Lymphoma Cells. Cells, resurrected from liquid nitrogen
storage, were maintained in suspension culture following procedures
described previously (13). Briefly, the PRL-dependent cells were incu
bated in Fischer's medium supplemented with 10% FBS (a source of
lactogens), lactogen-deficient horse (gelding) serum (10%), 2-mercaptoethanol (0.1 mM), penicillin (50 units/ml), and streptomycin (50 ¿ig/
ml) at 37°Cin an atmosphere of 5% CO2-95% air. The PRL-independ
Cultures of Nb2 node lymphoma cells are widely used for the
in vitro bioassay of lactogenic hormones and also as tools for
studying various aspects of polypeptide hormone-dependent
cancer growth (8-10). The present report is, as far as we are
aware, the first documented karyotypic study of Nb2 cell lines.
The cytogenetic information obtained should be useful in the
characterization and identification of the original PRL-depend
ent cell lines were maintained under similar conditions except for the
omission of FBS. The horse serum was obtained from the National
ent Nb2 line and its various sublines. The finding that the
Biological Laboratory, Ltd. (Dugald, Manitoba. Canada).
parental Nb rat karyotype (Fig. 2) was the same as that of
Rattus norvegicus (16) was to be expected since the Nb rat
Chromosome Preparations
originated from the Long-Evans strain (14), itself derived from
the Norway rat (18).
Normal Nb rat fibroblasts (1st or 2nd passage) were subcultured
onto Petri dishes and incubated for 24 h at 37°C.Metaphases were
The number of chromosomal abnormalities present in the
PRL-dependent Nb2-U17 stemline was relatively low (i.e., five;
harvested in situ by a 30-h incubation with Colcemid (0.01 ng/ml;
Gioco), a 30-min hypotonie treatment (1% sodium citrate), and fixation
Table 1). At the 300-400-band resolution level it was possible
with methanoliacetic acid (3:1). The dishes were air dried and stored
to determine the chromosomal rearrangements and the break
overnight at 56°C.Metaphases were banded by a 30-60-s exposure to
point sites quite precisely. The chromosomal changes may have
0.25% trypsin (Difco) and stained for 1-2 min with 4% Giemsa stain
arisen in the animal during the development of the malignant
(G. T. Gurr) (15).
Nb2 node lymphoma cells in exponential growth phase (5 x IO5 lymphoma and its subsequent serial transplantation and/or in
cells/ml) were incubated with Colcemid (0.02 /¿g/ml)for 4 h at 37°C. vitro during subculturing. The extent to which the chromosomal
changes involve cancer-specific genes or are the result of ran
The cells were then centrifuged (10 min at 1000 rpm), resuspended in
hypotonie K.C1(0.075 M), for 4 min at 37°C,fixed with methanol-acetic
dom chromosome breakage or rearrangement has yet to be
determined. In this regard, however, it is of interest that at least
acid, and dispersed onto wet glass slides. Following air drying and
overnight storage at 56°C,the metaphases were Giemsa banded as three of the breakpoint sites in the Nb2-U17 cells (i.e., 2q22,
283
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Nb2 NODE LYMPHOMA CELL KARYOTYPES
11 fîil
U M
II
M
M
11
18
li
10
il
13
II
If
15
14
16
11
g;
19
17
12
I
20
Fig. 2. G-banded karyotype of normal mâleNb rat fibroblasts.
M
II
II
I»'
10
8
K
13
ti
14
ICI U
16
15
20
Fig. 3. G-banded karyotype of the PRI.-dependent
arrowheads, derivative chromosomes.
I
11
12
17
it
i
%i
19
Ã-Ã-<(
18
I
Nb2-U17 lymphoma cells (157th generation). Bars, absent chromosomes: arrows, reciprocal translocations;
least in estrogenized Nb rats (8).
The observation that all the chromosomal abnormalities of
the parental PRL-dependent Nb2-U17 stemline are also present
in the PRL-independent PR A and SFJCD1 sublines (Table 1)
indicates that these cell lines have common clonal ancestry.
The additional karyotypic changes in the sublines suggest that
the three Nb2 cell lines have developed along a common evo
lutionary pathway in which the SFJCD1 line has clonali y
4q24, and 18pl2) are identical to common fragile sites ex
pressed in the genome of the laboratory rat (19). The signifi
cance of such fragile sites in rat malignancies is uncertain, since
little or no apparent concordance has been established between
the observed common fragile sites and cancer-specific break
point sites found in spontaneous and chemically or virally
induced rat cancers (19, 20). The results of the present study,
however, do not exclude the possibility that some of the fragile
sites may be involved in the development of lymphomas, at
284
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Nb2 NODE LVMPHOMA CELL KARVOTYPES
i
1li7U13t»19Fig.
II17|Xabsent
thearrowheads,
4. G-banded karyotype of
chromosomes.ft1u7t\t»
derivative
Bars,i2U8if•
Nb2-PRA lymphoma cells (1220th generation).
chromosomes;li5-
reciprocal
translocations;K6a-/12il181
-<ffÃ-10l|165flt11/
*
/'•'11/1
P13M2S£8/||1489203M9»«!15\fi10«I16PRL-independent
«14MH3lì9(115/K4
19
l17\6ft12«P181Yarrows,
20
Fig. 5. G-banded karyotype of the cloned PRL-independent Nb2-SFJCDl lymphoma cells (2372nd generation). Bars, absent chromosomes; arrows, reciprocal
translocations; arrowheads, derivative chromosomes; bar with arrowheads adjacent to chromosome 1. region of suspected inversion.
evolved from the PRA line which in turn clonali) evolved from
the U17 stemline (Table 1).
The karyotypic changes in the examined Nb2 cell lines are
associated with progression-related phenotypic changes, i.e.,
the development of PRL independence and increased growth
rate (Table 1). In the case of the PRL-dependent U17 and PRLindependent PRA cell lines only two karyotypic differences
were found, i.e., —
Y and t(14;17), raising the question as to
whether there is a causal relationship between these karyotypic
changes and, e.g., the development of PRL independence. It is
not known if the loss of the Y chromosome plays a significant
role in the loss of the PRL dependency. [In humans, loss of the
Y chromosome has been observed in certain leukemias and
lymphomas, but there is no unequivocal evidence that it is of
285
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Nb2 NODE LYMPHOMA CELL KARYOTYPES
Table 1 Karyotype and progressive changes fount! in related ,\'/>2node lymphoma cell lines
Cell line'
Parent I'17. PRL-dependent. DT = 20 h
PRÄ.PRL-independent,
DT = 17h
Karyotype
42,XY.-!7.t(2;4)(q22;q24).
t(10:ll)(ql2;ql2).
+der(15)t(15:7)(pl2:7),
-18.+der(18)t(18;7)(pl2;7)
41,X,-Y,-17.t(2;4)(q22;q24).
Progressive
changes
-Y
t( 10; 1 1)(q 12;q 12).t( 14; 17)(p22:p 14).
SFJCDI. PRL-independent.
DT = 14 h
+dcr(15)t(15;?)(pl2;7).
-18.+der{18)t(18;?)(pl2;?(
40.X.- V.- 17.?inv( 1)(q3 1q4 1).
t(2:4)(q22;q24),
inv(lq)
13p+
-15
-l3.+der(13)t(13:?)(pl3:7).
t(14;l7)(p22;pl4).
-l5.+der(15)t(15;7)(pl2;7).
-l8,+dcr(18)t(18:?)(pl2;?)
°Phenotypic properties, including culture-doubling time (DT), as described in Ref. 13.
etiological or prognostic significance (21); there is evidence that
it may be a normal phenomenon of cell aging (22).] On the
other hand, abnormalities affecting chromosome 17 could have
a role in the development of the PRL independence in the Nb2
cell lines, since somatic cell hybridization studies have indicated
that, in the rat, chromosome 17 harbors the PRL gene (23) and
also a number of PRL-related genes, i.e., the genes for placenta!
lactogen II and PRL-like proteins A and B (24). In the PRLdependent Nb2-U17 cells there is monosomy for chromosome
17;" in the PRL-independent PRA and SFJCDI cells the re
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cers.
ACKNOWLEDGMENTS
Sai Ma is thanked for assistance in part of the study and Kelly Fox
for culturing the cells. Drs. Nicholas Bruchovsky and Charles T. Beer
of the Department of Cancer Endocrinology, British Columbia Cancer
Agency, are thanked for helpful discussions.
4 Recent studies have shown that PRL-dependent cells of the different "Nb4
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9). also have monosomy for chromosome 17.
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Karyotypic Changes Associated with Loss of Prolactin
Dependency of Rat Nb2 Node Lymphoma Cell Cultures
Douglas E. Horsman, Sharon Masui and Peter W. Gout
Cancer Res 1991;51:282-287.
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