Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha
Aim: To estimate the effect of long-term IFN treatment of human non-small-cell lung cancer cell line A-549 on their karyotype characteristics and on the clonal structure of cell population. Methods: Cytogenetic research was performed by standard methods using routine and differential staining. Cytog...
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| Zitieren: | Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha / O.A. Kovaleva, N.O. Bezdenezhnykh, T.T. Glazko, A.L. Vorontsova, Yu.I. Kudryavets // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 19-22. — Бібліогр.: 32 назв. — англ. |
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irk-123456789-1385942018-06-20T03:04:16Z Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha Kovaleva, O.A. Bezdenezhnykh, N.O. Glazko, T.T. Vorontsova, A.L. Kudryavets, Yu.I. Original contributions Aim: To estimate the effect of long-term IFN treatment of human non-small-cell lung cancer cell line A-549 on their karyotype characteristics and on the clonal structure of cell population. Methods: Cytogenetic research was performed by standard methods using routine and differential staining. Cytogenetic characteristics were estimated per 1000 cells (ppm, (‰)). Results: Cytogenetic analysis of IFN-modified A-549 human lung cancer cells had demonstrated far-going changes in their population structure. It was shown that long term cultivation with IFN altered the chromosome modal class of A-549 cells, induced the domination of hromosomes with certain molecular markers: the number of metaphases with der (6) t (6; 1) chromosomal rearrangement increased significantly (from 6% to 80%, p < 0.001) and the cells with der (2) t (2; 1) markers almost disappeared. Thus, under the effect of IFN the cell clonal selection takes place. Decrease of the cell division rate and pseudometaphase occurrence, increase of the number of cells containing micronuclei are the typical characteristics of IFN-modified А-549 cell subline A-549IFN. Conclusion: Long-term IFN effect results in alterations of cytogenetic properties of A-549 human lung cancer cells. 2010 Article Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha / O.A. Kovaleva, N.O. Bezdenezhnykh, T.T. Glazko, A.L. Vorontsova, Yu.I. Kudryavets // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 19-22. — Бібліогр.: 32 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138594 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Kovaleva, O.A. Bezdenezhnykh, N.O. Glazko, T.T. Vorontsova, A.L. Kudryavets, Yu.I. Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha Experimental Oncology |
| description |
Aim: To estimate the effect of long-term IFN treatment of human non-small-cell lung cancer cell line A-549 on their karyotype characteristics and on the clonal structure of cell population. Methods: Cytogenetic research was performed by standard methods using routine and differential staining. Cytogenetic characteristics were estimated per 1000 cells (ppm, (‰)). Results: Cytogenetic analysis of IFN-modified A-549 human lung cancer cells had demonstrated far-going changes in their population structure. It was shown that long term cultivation with IFN altered the chromosome modal class of A-549 cells, induced the domination of hromosomes with certain molecular markers: the number of metaphases with der (6) t (6; 1) chromosomal rearrangement increased significantly (from 6% to 80%, p < 0.001) and the cells with der (2) t (2; 1) markers almost disappeared. Thus, under the effect of IFN the cell clonal selection takes place. Decrease of the cell division rate and pseudometaphase occurrence, increase of the number of cells containing micronuclei are the typical characteristics of IFN-modified А-549 cell subline A-549IFN. Conclusion: Long-term IFN effect results in alterations of cytogenetic properties of A-549 human lung cancer cells. |
| format |
Article |
| author |
Kovaleva, O.A. Bezdenezhnykh, N.O. Glazko, T.T. Vorontsova, A.L. Kudryavets, Yu.I. |
| author_facet |
Kovaleva, O.A. Bezdenezhnykh, N.O. Glazko, T.T. Vorontsova, A.L. Kudryavets, Yu.I. |
| author_sort |
Kovaleva, O.A. |
| title |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| title_short |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| title_full |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| title_fullStr |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| title_full_unstemmed |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| title_sort |
karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2010 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/138594 |
| citation_txt |
Karyotype alterations in human lung adenocarcinoma cells after long-term action of interferon-alpha / O.A. Kovaleva, N.O. Bezdenezhnykh, T.T. Glazko, A.L. Vorontsova, Yu.I. Kudryavets // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 19-22. — Бібліогр.: 32 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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| first_indexed |
2025-07-10T06:08:20Z |
| last_indexed |
2025-07-10T06:08:20Z |
| _version_ |
1837239057248157696 |
| fulltext |
Experimental Oncology 32, 19–22, 2010 (March) 19
It is well-known that carcinogenesis and further
tumor progression are based on cell genetic damage
and genome instability. Structural chromosome altera-
tions play a major role in tumor progression. Among
the huge variety of chromosome anomalies in tumor
cells, the specific or primary karyotype alterations
are defined which are specific for certain tumor and
leukemia types, and without any doubt are related
to pathogenesis of these diseases. Structural mal-
functions (translocations, deletions, inversions and
amplifications) of oncogenes coding growth factors,
cell receptors and other proteins, which control cell
division and differentiation, are referred as primary
chromosome alterations. Oncogene activation, tumor
suppressor gene transfer, loss or damage, and also
occurrence of structural DNA recombination due to
translocation, which lead to forming of chimeric pro-
teins, play the significant role in the neoplastic trans-
formation and processes of tumor progression [1, 2].
Interferons (IFN) are typical representatives of so-
called “biological reaction modifiers” which are incorpo-
rated into interaction between the tumor and the orga-
nism, providing non-specific anti-tumor defenses and
enhancing specific organism-to-tumor response [3–5].
It is known that many IFN-induced genes belong
to tumor suppressors [6–12]. On the other hand, inte-
gration of oncogenic virus DNA or cell transformation
could be accompanied by damage of intracellular
components of IFN system [10, 13–15]. IFNs can be
referred to considerably small group of endogenous
bioregulators, which can protect cells and their ge-
nome from various lesions. First of all, IFN is a classic
anti-virus agent that prevents the replication of onco-
genic virus and the integration of viral/proviral DNA into
the cellular genome [16, 17]. In addition, previously it
was demonstrated that IFN possesses apparent anti-
mutagenic activity, and these studies derived a con-
cept that “IFN is a cell genome guardian” [4, 18, 19].
However, those studies were not properly conducted,
and the mechanisms of mentioned IFN effects and
their role in carcinogenesis had not been studied yet.
Two main aspects of the problem of IFN participa-
tion in cell genetic consistence control can be derived.
One of them, as have been mentioned previously, is
related to the IFN’s ability of direct participation in the
control of cell genetic consistence. The other aspect
is related to the genome stability asserted by IFN on a
cell population level. That aspect is also insufficiently
studied, while it is clearly demonstrated phenomenon
in the clinical research of efficacy of IFN therapy in
chronic myeloid leukemia (CML) patients.
It is shown in multiple studies that IFN therapy
application results in complete hematologic as well
as cytogenetic remission in about 70–80% of CML
patients. An apparent alteration in cell population
structure is detected in the blood of 30–40% of such
patients [20]. This made possible to search for a new
CML treatment tactics, switching from hematologic
onset control to tumor clone suppression. That op-
portunity is confirmed by diminishing the levels of
Ph+ cells and restoration of normal hemopoiesis if the
IFN is used. While therapeutic efficacy of IFN in CML
treatment is proven [20, 21], the precise mechanism of
IFN-mediated tumor growth suppression remains un-
known. So far, there was only one in vitro study, which
demonstrated the unique ability of IFN to selectively
inhibit the reproduction of Ph+ stem leukemic cells.
IFN did not prevent the proliferation of normal bone
marrow hematopoietic precursor cells. Probably, the
mechanism of cytogenetic remission in CML patients
during IFN therapy is in precise genetic selection of cell
population [22]. Unfortunately, besides the wide use
of IFN for the treatment of patients with solid tumors,
these IFN-mediated effects have not been studied
KARYOTYPE ALTERATIONS IN HUMAN LUNG ADENOCARCINOMA
CELLS AFTER LONG-TERM ACTION OF INTERFERON-ALPHA
O.A. Kovaleva, N.O. Bezdenezhnykh, T.T. Glazko, A.L. Vorontsova, Yu.I. Kudryavets*
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kiev 03022, Ukraine
Aim: To estimate the effect of long-term IFN treatment of human non-small-cell lung cancer cell line A-549 on their karyotype
characteristics and on the clonal structure of cell population. Methods: Cytogenetic research was performed by standard methods
using routine and differential staining. Cytogenetic characteristics were estimated per 1000 cells (ppm, (‰)). Results: Cytogenetic
analysis of IFN-modified A-549 human lung cancer cells had demonstrated far-going changes in their population structure. It was
shown that long term cultivation with IFN altered the chromosome modal class of A-549 cells, induced the domination of chro-
mosomes with certain molecular markers: the number of metaphases with der (6) t (6; 1) chromosomal rearrangement increased
significantly (from 6% to 80%, p < 0.001) and the cells with der (2) t (2; 1) markers almost disappeared. Thus, under the effect
of IFN the cell clonal selection takes place. Decrease of the cell division rate and pseudometaphase occurrence, increase of the
number of cells containing micronuclei are the typical characteristics of IFN-modified А-549 cell subline A-549IFN. Conclusion:
Long-term IFN effect results in alterations of cytogenetic properties of A-549 human lung cancer cells.
Key Words: interferon-alpha, human lung cancer, cell culture, chromosomes.
Received: January 24, 2010.
*Correspondence: Fax: +38 (044) 258-16-56
E-mail: kudryavets@mail.ru
Abbreviatons used: CML — chronic myeloid leukemia; IFN — interferon.
Exp Oncol 2010
32, 1, 19–22
20 Experimental Oncology 32, 19–22, 2010 (March)
in the cells of solid tumors, in particular in the cells
of non-small lung cancer.
At the time, if cells that occur spontaneously during
neoplastic transformation loose sensitivity to various
cytokines, this may lead to the accumulation of more
aggressive tumor clones. For example, a deletion of chro-
mosome I short arm is often found in solid tumors, and
its presence is associated with tumor progression [23].
In current study we have performed a comparative
analysis of A-549 cells and its subline A-549IFN that was
modified by long-term action of IFN in vitro, to evaluate
the ability of IFN to influence on karyotype characteristics
of tumor cells and on the structure of cell population.
MATERIALS AND METHODS
Non-small cell lung cancer cell line (NSCLC)
A-549 obtained from the Collection of Cell Lines of IEPOR
NASU (Kiev, Ukraine) was cultured in complete RPMI
1640 medium supplemented with 4 mM L-glutamine,
10% fetal bovine serum, 40 μg/ml of gentamycine and
50 g/ml of amphotericin B (Sigma, USA) in humidified
atmosphere containing 5% CO2, 37 °C. The concentra-
tion of IFN in A-549IFN cells media is 10 000 U/ml. The
medium was replaced each two days, and cell passages
were performed each four days with trypsin-versen
solution. To study the long-term effect of IFN, the cells
were cultivated for 1 year in the presence of recombinant
IFN-alpha-2b (BioPharma, Ukraine) at increasing con-
centrations (from 100 to 10 000 U/ml) of INF. As a result,
A-549 subline was obtained (A-549IFN) [7].
For a morphologic investigation, cytospin speci-
mens were dried and Papenheim-stained. The levels
of dividing cells, binuclear cells, cells containing micro-
nuclei and apoptotic cells occurrence were calculated
per 1000 cells and figured in per miles (‰). Chromo-
some specimens were prepared as it was described
earlier [24].
Stained specimens were analyzed using Axiostar
Plus microscope (Carl Zeiss, Germany) at x400–
1000 magnification. Specimens of live and stained
cells were photographed using Canon PowerShot
G5 digital photo camera (Canon, Great Britain).
The statistical significance of the differences be-
tween mean values was assessed by the Student’s
t-test.
RESULTS AND DISCUSSION
An amount of chromosomes in the metaphase
plates of A-549 cell culture varied from 15 to 63. Modal
class in these cells comprised of 54–59 chromosomes;
the majority of cells (28%) contained 56 chromosomes
(Fig. 1). The characteristic feature of A-549 cell line is
a giant submetacentric chromosome, which has been
detected in more than 60% of observed metaphases
(Fig. 2). Differential staining showed the marker chro-
mosome as a result of translocation of a short arm
chromosome 2 fragment onto a short arm of chromo-
some 1 (Fig. 3). This observation is consistent with the
results of other studies of A-549 cell populations [25].
Nestor A.L. et al. [25] described among the marker
chromosomes the most frequent translocations der (3)
t (3, 20), der (6) t (6; 1), der (19) t (15; 19), + der (19)
t (15; 19), del (2), der (11) t (8; 11). In current study we
observed the presence of rearranged chromosomes
previously described among the marker chromosomes
of this line, as der (6) t (6; 1), der (11) t (8; 11), der (2)
t (2, 1) in the metaphase plate of A-549 cells prior IFN
treatment. Relatively low frequency (6% — 25%) of re-
built chromosome der (6) t (6; 1) in the initial population
cells A-549 should be noted.
0
5
10
15
20
25
30
15 19 23 27 31 35 39 43 47 51 55 59 63
Chromosomes in metaphases, n
M
et
ap
ha
se
s,
%
Fig. 1. Characteristics of modal class of chromosomes
of A-549 cells
a b
Fig. 2. Typical metaphase plates of A-549 cells with giant sub-
metacentric chromosomes (arrows)
1
2
Fig. 3. Differential staining of marker chromosome with trans-
location t (1; 2) in the cell clones dominated in the parental cell
line A-549
Studies conducted using the method of fluores-
cence in situ hybridisation of DNA probes to different
chromosomes showed a high initial heterogeneity of
A-549 cell population on the marker chromosomes
[26]. It is estimated that about 25% of chromosomes
of this line are involved in various chromosomal re-
arrangements. It was shown previously that such
rearrangements results in marked increase of chro-
mosome 1 copies compared to other autosomes
(5.8 ± 1.4 copies of chromosome 1 in the karyotype)
Experimental Oncology 32, 19–22, 2010 (March) 21
[26]. The high degree of heterogeneity of rearranged
marker chromosomes in A-549 cell population makes
it difficult to allocate some marker chromosomes or
chromosome combinations among them [25, 26].
At the same time, translocation of the long arm of
chromosome 1, which is most easily identified by dif-
ferential staining, allows to track the impact of various
external factors on the structure of the cell population.
The experiments performed earlier described the
data of incorporation of chromosome 1 in intra- and
interchromosomal recombination in the tumor cells
of various origins. Thus, for example, patients with
germinogenic tumors often have normal karyotype,
but an aberration in chromosome 1 occurs frequently,
for example, the short arm of chromosome 1 can be
doubled or lost [27]. The most frequent chromosomal
aberration in neuroblastoma patients is a deletion of
chromosome 1 short arm — del (1p) [23].
Translocation 1; 2 (q25; p23) is detected in some
anaplastic giant cell lymphoma patients [28]. Au-
thors suggest that the Tmp3 gene on the chromo-
some 1 (q25) and anaplastic lymphoma kinase (ALK)
gene on 2p23 arm are incorporated in this transloca-
tion [29], and the translocation is accompanied by the
expression 104 kDa chimera protein TMP3-ALK [28].
The A-549IFN cell line was derived from original
A-549 cell line by long-term cultivation in the pres-
ence of IFN. Previously we have shown that prolonged
treatment of A-549 cells with IFN leads to significant
changes in their phenotypic properties, many of which
persist for a long time (up to two months) even in the
absence of IFN [30]. Therefore, we proposed that this
could not be the result of constant induction of genes
expression by IFN: new features of A-549IFN cells could
be explaned by stable genetic and epigenetic changes
due to IFN-induced selection of cell population.
Cytogenetic analysis of IFN-modified cells
(A-549IFN), held in the dynamics at different stages of
new subline formation, showed profound changes in the
clonal composition of these cells. It was shown that in
new cell population modal class of chromosomes varies:
an amount of chromosomes in the metaphase plates of
A-549IFN cell culture varied mostly from 48 to 66, modal
class in these cells included 58–62 chromosomes
(Fig. 4). A majority of these cells contained 62 chro-
mosomes. In the cells dominating in the population
changes occured with a specific marker chromosomes:
the number of metaphases with chromosomal rear-
rangement der (6) t (6, 1) greatly increased (from 6%
to 80%, p < 0.001), and cells with marker der (2) t (2, 1)
almost disappeared from population (see Fig. 3; Fig. 5).
Thus, these data demonstrate the process of clonal se-
lection in A-549 cells under the long-term action of IFN,
like that of described earlier for CML cells [22]. A typical
feature of the A-549IFN subline is a significant decrease
in frequency of cell division and pseudometaphases
formation (p < 0.001), and small increase of number
of cells with micronuclei (Table). The higher sensitivity
of these cells to apoptosis demonstrated in previous
studies [30] could explain current observations. It was
found that cultivation of IFN-modified A-549IFN cells
in the absence of IFN for 45 days was accompanied by
further cytogenetic and phenotypic unification of the
population — the dominance of clones with markers
der (6) t (6, 1), modal number of 54–59 chromosomes
in 80% of cells. Observed characteristics of chromo-
some modal class indicate the decrease of aneuploidy
in the new cell population of A-549IFN line. This is in
line with previous data on the decrease of indices of
malignant phenotype of these cells compared with
parental A-549 line [30].
0
5
10
15
20
25
30
35 39 43 47 51 55 59
Chromosomes in metaphases, n
M
et
ap
ha
se
s,
%
Fig. 4. Characteristic of modal class chromosomes in A-549IFN
cells
1
6
Fig. 5. Differential staining of marker chromosome with trans-
location t (6, 1) in the cell clones dominated in A-549IFN subline
Table. The frequency of occurrence of cell division, pseudometaphases and
cells with micronuclei and apoptotic cells in A-549 and A-549IFN cell line
Cell line
Number
of studied
cells
Frequency of occurrence (‰)
Pseudometa-
phases Mitosis Micronuclei Apoptosis
A-549 8000 5.6 ± 1.0 12.2 ± 1.9 2.6 ± 0.8 4.5 ± 1.5
A-549IFN 7000 1.4 ± 0.9* 3.6 ± 0.8* 5.7 ± 1.4 1.9 ± 0.5
*p < 0.001.
Thus, obtained results directly demonstrate that in
the presence of IFN clonal selection take place in the
original cell population and gives rise to a new sub-
line, which differs from the original line by a number
of biological and phenotypic parameters describe
earlier [30]. Karyological changes that we identified
in A-549IFN cells, as well as continuous changes in
the expression level of several protein markers indi-
cate the presence of both the adaptive and selective
mechanism in the reaction of cells in response to IFN
[31, 32]. The cell system, which was developed, could
be perspective to reveal the role of adaptive and se-
lective mechanisms in the emergence of a new, less
malignant cell clones under long-term action of IFN.
22 Experimental Oncology 32, 19–22, 2010 (March)
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