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From the Tumor Biology Program, Mayo Foundation, Rochester, Minnesota
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The centrosome is the major microtubule-organizing center in mammalian cells; it regulates the number, stability, polarity, and spatial arrangement of microtubules in interphase cells.19,20 Thereby, the centrosome and microtubules play a role in maintaining overall cell polarity, provide an architectural framework for directed organelle transport, and participate in cell shape and movement.
The interphase centrosome consists of a pair of orthogonally oriented centrioles surrounded by a pericentriolar matrix. Duplication of the centrosome begins during S phase of the cell cycle when the two centrioles lose their orthogonal arrangement before the formation of a procentriole (or bud) closely associated with the proximal end of each of the original centrioles. The procentrioles lengthen during S and G2, so that by prophase the cell contains two diplosomes, that is, two orthogonal pairs of full-length centrioles.21-24 At the onset of prophase, the diplosomes, along with associated pericentriolar material, move to opposite sides of the nucleus and establish the bipolar mitotic spindle.25
We recently have shown that the centrosomes of high-grade breast cancers do not follow this program of events.14 In breast tumor cells, centrosome duplication is uncoupled from the cell cycle, resulting in cells with numerous centrosomes, many of which are larger than normal. Tumor centrosomes typically show inappropriate levels of phosphorylated proteins, in contrast to normal centrosomes, which contain increased levels of phosphorylated proteins during mitosis.
Here we compare the ultrastructure of centrosomes of normal breast epithelial tissues and breast adenocarcinomas. These studies reveal dramatic abnormalities in the centrioles and centrosomes of breast tumor cells. These abnormalities include 1) supernumerary centrioles, 2) excess pericentriolar material, 3) disrupted centriole barrel structure, 4) unincorporated microtubule complexes, 5) centrioles of unusual length, 6) centrioles functioning as ciliary basal bodies, and 7) mispositioned centrosomes. Structural centrosome abnormalities, most notably excess pericentriolar material, were associated with an increased frequency of abnormal mitoses as assessed by Ki-67-immunolabeled paraffin sections of the same tumors. The relevance of centrosome structure with regard to cell polarity, differentiation, bipolar and multipolar mitosis, and tumor progression is discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissues from 45 consecutive mastectomy and lumpectomy surgeries were collected according to an Institutional Review Board-approved protocol. Tissues were omitted from the analysis if patients had received previous chemotherapy or radiation therapy (n= 6), did not include primary invasive tumor (n = 4), were poorly preserved (n = 3), or were from male patients (n = 1). The remaining 31 tumors, which included two grade 2, nine grade 3, and twenty grade 4 specimens (Mayo histological grading scale), were analyzed. Six normal tissues from breast reduction surgeries were also analyzed.
Transmission Electron Microscopy Processing and Observation
Tissues were cut into small pieces and placed in fixative (4% formaldehyde, 1% glutaraldehyde in sodium phosphate buffer, pH 7.2) at 4°C for up to 36 hours. Tissues were further processed by postfixation in osmium tetroxide, en bloc staining with uranyl acetate, dehydration in ethanol, and embedding in epoxy resin. Thin sections were poststained with lead citrate and examined using a Philips CM10 Biotwin transmission electron microscope (Philips Electronic Instruments, Mahwah, NJ). Tissues were categorized according to centrosome location, number of centrioles in thin section, qualitative level of pericentriolar material, presence and arrangement of centriolar appendages, presence of primary cilia, variations on centriolar structure, and multipolar mitotic figures.
Light Microscopy and Mitotic Index Determination
Portions of tissues also were formalin-fixed and paraffin-embedded
for light microscopy. Sections were immunostained using MIB-1 antibody
against Ki-67 (Dako Corp., Carpinteria, CA). Ki-67 is a nuclear antigen
that is present in late G1, S, G2, and mitotic cells, but is lacking in
G0 and early G1 cells. Condensed chromosomes are stained intensely with
this antibody, allowing for easy quantification of proliferative and
mitotic cells and identification of abnormal mitotic figures.
Proliferative index (PI) was calculated as the percentage of
Ki67-positive cells out of the total number of epithelial cells. A
minimum of 200 cells was counted in defined fields of view using a 40x
objective. Likewise, mitotic index (MI) was calculated as the
percentage of mitotic cells in the same fields of view. When no mitotic
cells were observed, the MI was calculated as <1 mitotic cell per the
total number of cells observed. Because the frequency of abnormal
mitotic figures is very low in most tissues, the abnormal mitotic index
(AMI) was determined by scanning the entire section and counting the
total number of mitotic cells and the total number of abnormal mitotic
figures. The ratio of abnormal to total mitoses was then multiplied by
the mitotic index to yield the AMI. These data are summarized in Figure 7
. All tissues were scored blindly. Photographs were made using a Nikon
FXA photomicroscope.
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A subset of tissues was selected for immunofluorescence studies. These tissues included one tumor with normal centrosome ultrastructure, one tumor with clusters of extra centrioles, two tumors with extra pericentriolar material, and two tumors with inverted polarity. Normal tissue used for immunofluorescence was from a different patient than that used in the ultrastructure studies. All tissues were frozen in liquid nitrogen within 30 minutes of surgical removal and stored at -70°C until use. Cryosections were immunostained with a monoclonal antibody against centrin, a centrosomal protein, as previously described.14 Sections were examined and photographed using a Nikon FXA epifluorescence microscope.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal breast epithelial tissues were organized with a high
cuboidal layer of luminal cells separated at intervals from the
basement membrane by a discontinuous layer of myoepithelial cells
(Figure 1, A and B)
. The nuclei of the
luminal epithelial cells tended to be basal and the centrioles
apical. Although apical, most often the position of the centrioles was
eccentric; that is, they were located near the lateral junctional
complexes of adjacent cells (Figure 1B)
. Although centrioles usually
did not maintain an orthogonal orientation, they were typically close
to each other (Figure 1, A and C)
. Occasionally, an extremely short
primary cilium extended from the distal end of the mature centriole
(Figure 1C)
. Fine striated rootlets infrequently were observed
extending from the proximal ends of centrioles toward the base of the
cell (Figure 1D)
. The striated rootlets were quite variable in extent
and were not observed with most centrioles. Other than distal and
subdistal appendages on the mature centriole and fine fibrillar
material along the outer walls of the centriole barrels, little
pericentriolar material was noted with the centrioles of normal luminal
epithelial cells (Figure 1, A
-D). Subdistal appendages were slightly
more developed on the centrioles of the myoepithelial cells, and their
primary cilia were longer than those of luminal epithelial cells
(Figure 1, B and E)
. Unlike luminal epithelial cells, diplosomes of
myoepithelial cells were located close to the nuclei. Filaments
extended from the myoepithelial diplosome to the nucleus (Figure 1E)
;
this was never observed in luminal epithelial cells. No centrosome
abnormalities were observed in normal epithelial cells of the four
reduction mammoplasties examined by electron microscopy.
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Twenty-four of 31 invasive tumors contained centrosomes and that
differed from those of normal breast cells in a variety of ways. Eleven
tumors were characterized by centrosomes with more than two centrioles
(Figures 2 and 3
, A-C). In thin sections, these
supernumerary centrioles ranged from a pair of centrioles with a single
extra procentriole to a field of 9 centriole profiles (Figure 2, A
-F).
Often the extra centrioles were arranged in a group and were closely
linked by fine fibers extending between subdistal appendages (Figure 2, C, E, and F)
. Appendages normally associated with only the mature
centriole were seen frequently with more than one centriole in these
groups (Figure 2, C
-F, and Figure 3A
). Centrosomes with extra
centrioles were most often located adjacent to the nucleus (Figure 2, B, E, and F)
, in contrast to normal luminal epithelial cells, in which
the centrioles tended to be closer to the apical plasma membrane
(Figure 1, A and B)
.
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-F), to moderate (Figure 2A)
and
excessive levels (Figure 3)
. In all, nine tumors had excess
pericentriolar material, often in addition to extra centrioles. In some
tumors this pericentriolar material had a distinct fibrogranular
appearance (Figures 2A and 3)
reminiscent of material associated with
basal body formation in ciliated cells. Large granular masses, similar
to generative complexes involved in ciliary basal body formation, were
also observed in the pericentriolar material in some tumor cells
(Figure 3E)
. Many centrioles were encased in electron opaque material
pressed directly to the barrel of the centriole (Figure 3, B and C)
.
In addition to excessive pericentriolar material, two tumors had
centrioles that were structurally defective in various aspects (Figure 4)
. Normal centrioles are composed of
nine sets of triplet microtubules in which the A microtubule is
complete and the B and C microtubules share protofilaments with A and
B, respectively.26
Unusual microtubule complexes were
observed near complete centrioles in some tumors (Figure 4A)
. These
microtubule complexes were not assembled into normal triplets nor
arranged in a barrel shape; rather they were an assortment that
included five or more microtubules with shared protofilaments embedded
in amorphous electron-opaque material (Figure 4A)
. In one instance a
centriolar microtubule triplet was displaced away from the centriole
barrel, resulting in what has been termed an open ring centriole
(Figure 4B)
. Unusually long centrioles (Figure 4D)
were observed in one
tumor. Primary cilia ranged from very short to well developed (Figure 4C)
.
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. The beaks were bordered by the
apical plasma membrane that protruded well past the junctional
complexes that mark the apical limit of the lateral plasma membrane.
Beak cytoplasm contained numerous secretory vesicles, endoplasmic
reticulum, and mitochondria. The centrosomes in these cells were near
the junctional complexes and just apical to the nucleus, but not
adjacent to the lumen as in normal luminal epithelial cells (Figure 5A)
. In one well differentiated grade 2 tumor with apocrine metaplasia,
the beaked apocrine cells were mixed with ciliated cells. The ciliated
cells also maintained apical/basal polarity, but along their apical
membrane were numerous cilia with centrioles functioning as ciliary
basal bodies (Figure 5B)
. These cilia and basal bodies were similar in
location and appearance to those of normally ciliated cells such as
ciliated respiratory epithelium. Microvilli also were located along the
apical membranes of the ciliated cells (Figure 5B)
. The apical
membranes of the ciliated cells did not protrude into the lumen as did
the nonciliated beaked cells (Figure 5A)
. Both the ciliated and the
beaked cells were in regions of tumors that were well differentiated.
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. The apical and lateral
membranes were identified by their location relative to junctional
complexes and the presence of microvilli on the apical membrane. In
these instances, the cell apices often did not face a lumen, but
instead faced collagen fibrils of the stromal connective tissue (Figure 5C)
. The centrosomes of these cells were normal in structure and were
located next to the junctional complexes near the apical plasma
membrane, but, because the apices face the stroma, the cell polarity
was inverted. Mitosis in Tumor Cells
Although mitotic figures were not observed in normal breast
tissues, there were numerous mitotic figures present in four of the
tumors examined transmission electron microscopy. Some mitotic figures
appeared normal in thin section, having a typical metaphase plate and
bipolar spindle (not shown), whereas others had significant
abnormalities (Figure 6)
. A tripolar
mitosis is shown in Figure 6A
. Tracings of microtubules, spindle poles,
and condensed chromosomes from six nonadjacent serial sections through
the cell in Figure 6A
are presented in Figure 6B
. Analysis of the
reconstruction in three dimensions revealed that one spindle pole was
composed of two distinct but adjacent foci of microtubules, which
perhaps resulted from their coalescence in prometaphase. Each spindle
pole had at least two centrioles recognizable as distinct structures in
these six nonadjacent thin sections. Many division figures were too
bizarre for analysis in thin section.
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As previously described,14
normal breast tissues have
an apically positioned pair of immunolabeled spots that correspond to
the centrioles (Figure 6E)
. Pairs of spots also were observed in cells
of the tumor with normal centrosome ultrastructure, although the tissue
was anaplastic and centriole location appeared random (Figure 6F)
. Many
cells in the tumor with numerous centrioles closely linked by fine
fibers contained clusters of spots the size and shape of centrioles
(Figure 6G)
, whereas spots of various sizes and shapes were present in
cells of the tumors characterized by extra pericentriolar material
(Figure 6H)
.
Proliferation and Mitotic Indices
Indices of proliferation, mitosis, and abnormal mitosis are
summarized in Figure 7
. Tissues were
placed in one of four categories on the basis of tissue type and
centriole/centrosome structure. Category I is comprised of all normal
tissues from reduction mammoplasty. All six of these tissues had normal
centrosome structure as assessed by immunofluorescence and/or electron
microscopy. Category II consists of the nine tumors that have normal
centriole/centrosome structure as assessed by immunofluorescence and
electron microscopy. Category III contains twelve tumors with abnormal
centriole/centrosome structure such as supernumerary centrioles or
structurally defective centrioles. Tumors with excess pericentriolar
material in addition to centriole abnormalities are excluded from this
category and placed in Category IV. Category IV contains seven tumors
with excess pericentriolar material, regardless of other
centriole/centrosome characteristics.
The six normal breast tissues (Category I, Figure 7
) examined by light
microscopy had a median PI of 5.3% as determined by Ki67
immunostaining. These normal tissues had a median MI of 0.00% (mean
mitotic index = 0.03%) based on the total of 4238 epithelial
cells observed. On examination of entire histological sections from all
six tissues, only two contained identifiable mitotic figures, and no
abnormal mitotic figures were observed. Of the nine tumors with normal
centriole/centrosome ultrastructure (Category II, Figure 7
), five
contained no abnormal mitotic figures and four did, yielding a
median AMI of 0.00% (mean = 0.16%). The median PI, MI, and
AMI of Category II tumors were not significantly different from
Category III tumors.
The Category IV tumors, characterized by the presence of excess pericentriolar material, had the highest median frequencies of proliferation, mitosis, and abnormal mitosis (28.2%, 0.71%, and 0.46%, respectively). Category IV values, with the exception of the PI relative to Category III, were significantly different from the values of all other categories.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Only by selecting breast biopsy tissue from premenopausal women in the luteal phase of the menstrual cycle was Ferguson28 able to investigate mitosis in normal breast parenchyma. In these normal cells, very little pericentriolar material was associated with the spindle poles. The normal tissues in the present study were not selected according to the phase of menstrual cycle, and no mitoses were observed by transmission electron microscopy or by light microscopy. However, normal breast epithelium does maintain a population of proliferating cells that immunostain with antibodies to Ki67; our median PI value of 5.3% in normal breast epithelium is within the range of published values.29 In agreement with our observations on interphase cells by immunofluorescence and by transmission electron microscopy, Ferguson28 noted that centrioles of normal interphase cells were apical and not associated with the basal nuclei. Likewise, primary cilia have previously been noted in myoepithelial cells.30
Centrosomes undergo changes throughout the cell cycle.21-24 The nuclear and centrosome cycles are synchronized by checkpoints that prevent DNA reduplication before karyokinesis and prevent centrosome reduplication before anaphase. In certain normal cell types such as binuclear mouse hepatocytes31 and human megakaryocytes,32 synchrony between the nuclear and centrosome cycles is maintained even in the absence of cytokinesis, resulting in polyploid cells with centrosome numbers appropriate for the level of ploidy. Due to the numerous centrosomes arranged around the polyploid nucleus, megakaryocytes lack apical/basal polarity, although they do have a radial organization. In contrast, cancer cells have asynchronous nuclear and centrosome cycles, often resulting in multicentrosomal aneuploid cells that lack apical/basal polarity and appear disorganized.
We have shown that centrosomes and centrioles of most human breast tumors (24 of 31 analyzed) display a range of significant structural and functional abnormalities. Breast tissues can be divided into four categories: normal tissue with structurally normal centriole/centrosomes (Category I), tumors with structurally normal centriole/centrosomes (Category II), tumors with centriole-based abnormalities (Category III), and tumors with excess pericentriolar material (Category IV). Category IV tumors are associated with significantly increased frequencies of both normal and abnormal mitoses. Cells having no visible centrosome abnormality are also present in all tumors. Some abnormalities may be related to loss of synchrony between the centrosome cycle and nuclear cycle.
Tumor cells that become ciliated retain apical/basal polarity and tend to be well differentiated. These tumors are included in Category III. Ciliated cells have been described infrequently in breast carcinomas.33 These multiple centrioles probably arise through the same acentriolar basal body neogenesis that occurs in normal ciliated epithelial cells.34-37 In effect, these cells differentiate into the wrong cell type, resulting in metaplasia rather than anaplasia. These ciliated breast tumors have PI and MI of 20% and 0.2%, respectively, similar to normal breast epithelium. The ciliated cells, like normal ciliated epithelial cells, probably are terminally differentiated and remain in G0 of the cell cycle. Therefore, the production of centrioles that function as ciliary basal bodies may be a relatively harmless structural alteration with no adverse implications for genetic stability.
Open-ring centrioles and centrioles missing triplet microtubles (MTs) occur in some Category III tumors. Although these structures are similar to those present during basal body formation in hamster ciliogenesis,38 no cilia are present in these tumors. Disrupted centriole barrels similar to open-ring centrioles have also been observed as a consequence of infection with and treatment with DNA-binding dyes,39 and DNA-binding dyes have been shown to induce multipolar mitoses in cultured cells.39 However, in the present study, open ring centrioles are not associated with an increase in the frequency of multipolar mitoses.
Unusual microtubule complexes embedded in dark amorphous material were also noted in one Category III tumor. The PI, MI, and AMI of this tumor are not significantly different from those of tumors with normal centrosome structure. These novel structures have not been described previously, and their importance is not understood. They may be a further indication that the mechanics, as well as timing, of centriole formation is not well regulated in tumors.
Some tumors (11 of 31 studied) produce extra centrioles that do not serve as ciliary basal bodies. In some cells of these Category III tumors, centrioles often appear linked closely together by fine fibers and remain near the nucleus. These tumors are anaplastic; ie, they are not as differentiated as tumors that produce cilia and do not retain apical/basal cell polarity. The presence of procentrioles along the proximal walls of mature centrioles indicates that these extra centrioles arose through template driven duplication rather than through acentriolar neogenesis typical of basal body production in ciliated cells.35 Fine fibers linking the centrioles in tumors are similar to those described linking the pair of centrioles of a diplosome,40 further supporting the idea that they originate as procentrioles associated with a mature centriole. Because template-driven centriole duplication normally occurs only once per nuclear cycle, these cells have lost the synchrony between the nuclear cycle and the centrosome cycle. As long as the centrioles remain linked together, they may function as one large centrosome in an interphase cell. However, if these large centrosomes separate into more than two spindle poles at the onset of mitosis, it is likely that chromosomal missegregation will occur, resulting in aneuploidy. Indeed, the frequency of abnormal mitoses is quite variable among these tumors, indicating that most cells with extra centrioles are capable of forming bipolar spindles.
Other tumors (9 of 31 studied, 7 of which were available for
proliferation and mitotic index determination) accumulate excess
pericentriolar material with their centrosomes and variable numbers of
extra centrioles (Category IV tumors). The nature of the pericentriolar
material is reminiscent of fibrogranular material and generative
complexes associated with acentriolar as well as centriolar basal body
formation.34-37,41
However, no cilia are observed and the
randomly positioned centrioles are not located near the plasma
membrane. This accumulation of excess pericentriolar material may be
the result of overexpression of centrosomal proteins or the
reorganization of material that is normally dispersed within the
cytoplasm.14,42,43
Increased levels of
-tubulin,14,17
pericentrin,15
and
centrin14
have been demonstrated in abnormal centrosomes
in human tumors, and it is likely that other centrosomal proteins are
present in increased levels as well. -tubulin-containing complexes
located in the pericentriolar material are the site of microtubule
nucleation, and as such are key to centrosome function.44
We have shown that tumors with excess pericentriolar material are
highly anaplastic and have lost cell polarity. These Category IV tumors
tend to have higher median frequency of abnormal mitoses (0.46%)
compared to tumors with other centrosome abnormalities (0.09%). This
higher frequency of abnormal mitoses in tumors with extra
pericentriolar material suggests that the regulation of accumulation of
centrosomal proteins is more critical than regulation of centriole
duplication for proper centrosome function during the cell cycle.
Some cells have more than two centrosomes that can function as spindle poles, yielding atypical multipolar mitoses. Atypical mitoses have been observed in breast tumors and other pathological specimens such as ulcerative colitis7 and a mouse model of pancreatic cancer.3 Multipolar mitoses were observed in several breast tumors in the present study. Aberrant mitoses such as these may arrest in metaphase, with the cells eventually undergoing apoptosis. In some instances, however, a selective advantage may be conferred to one of the daughter cells, leading to a clone of cells with chromosome gains and/or losses.
Serial sectioning through mitotic tumor cells showed that spindle poles are sometimes composed of more than one focus of microtubules. These spindle poles likely resulted from the coalescence of two or more centrosomes before metaphase. Coalescence of centrosomes could allow the formation of a bipolar spindle in a cell having extra centrosomes. Coalescence of extra centrosomes may be a mechanism by which cells can minimize the rate at which aneuploidy develops in tumors. Because compounded aneuploidy ultimately would be a self-limiting characteristic of tumors, a proportion of bipolar mitoses must be maintained for tumor growth.
The centrosomal abnormalities described here in breast tumor cells reflect changes in the status of cell and tissue differentiation of the tumors. Differentiated tumors have centrosomes of more normal appearance that are either mislocated, as in the tumors with inverted cell polarity, or perform a normal function not typical of mammary epithelial cells, such as producing ciliary basal bodies in tumors displaying apocrine metaplasia. Centrosome abnormalities are characteristic of poorly differentiated anaplastic tumors that have lost checkpoint synchronization of nuclear and centrosome cycles. This loss is reflected in centrosome defects and multipolar mitoses. As recognized by Boveri2 earlier in this century, defective centrosomes may decrease the fidelity of chromosome segregation during multipolar mitoses. Consequently, centrosome abnormalities such as those described here may confer a mutator phenotype to tumor cells. As is the case for the molecular mutator phenotype, most mutated progeny will not be viable, but occasionally progeny with a selective advantage will emerge and thrive, and thus the tumor progresses to a more aggressive state.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Cancer Institute (CA72836 and CA09441) and the Department of Defense (DAMD17-98-1-8122) and by the Mayo Clinic Foundation.
Accepted for publication August 24, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-tubulin ring complex to Drosophila salt-stripped centrosome scaffolds. J Cell Biol 1998, 142:775-786This article has been cited by other articles:
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