(CANCER RESEARCH .14. 1385-1394, June 1974]
A Scanning Microscope Study of the Topography of HeLa Cells1
Keith R. Porter, Virginia Fonte, and Gary Weiss
The Department of Molecular, Cellular, and Developmental Biology. University of Colorado. Boulder. Colorado 80302
SUMMARY
This report describes a scanning electron microscope
study of the surface features of HeLa S3 cells, a line
established by George Gey from a human cervical carci
noma. The cells, maintained in spinner culture and grown in
monolayer on coverglasses, were fixed and subsequently
dried by the critical-point method. Micrographs show the
exposed surfaces of the cells to be covered prominently by
slender microvilli which, in their form and distribution,
display many abnormal features. These surface characteris
tics are found to persist through various stages of growth
and confluency. They depart strikingly in most respects
from those displayed by the normal columnar cells of the
cervix from which the tumor originated.
INTRODUCTION
In one of his earliest reports on the structure and behavior
of HeLa cells. Gey (8) called attention to numerous
"microfibrils"
which extend from the surfaces of these cells.
He found them to be just at the limits of light resolution and
commented that the "microfibrils" are "in constant motion,
many bending over and disappearing in some regions with
new ones being produced simultaneously
in other regions
close by." Electron micrographs reproduced in the same
paper, although not in those days improving greatly on
phase contrast images of living cells, leave no doubt that
Gey was observing what have subsequently been called
microvilli and/or filopodia.
In the nearly 20-year interval since Gey's Harvey Lecture,
many images of thin sections of HeLa cells have been
published, and they consistently show microvilli extending
from the cell surface, especially the free surfaces (6, 7).
Since the thin section represents only a small sample of the
cell and since the microvilli are seldom straight, rod-like
structures (at least after fixation), it is infrequent that a
transmission micrograph includes more than a fragment of
a single microvillus, and measurements
of length and
observations on the overall number and distribution per cell
are difficult to make from such images. Even in the few
instances in which replicas of these surfaces have been
examined (7, 18), the artifact introduced by drying detracts
from the value of the observations.
1This work was supported in part by a contract from the Special Virus
Cancer Program. National Cancer Institute, and in part by a Biomedicai
Research Support Grant from the American Cancer Society.
Received December 4. 1973: accepted February 14. 1974.
JUNE
The development of techniques for examining cultured
cells and soft tissues by scanning electron microscopy has
greatly enhanced our ability to explore the topography of
cell surfaces. While the resolution improves only 10- to
15-fold on that of the light microscope, the large depth of
focus and the 3-dimensional impression provided by the
mode of image formation yields a wealth of information
important to an appreciation of malignant transformation
and the general behavior of these and other tumor cells ( 15,
16).
In this paper we describe some of the surface features of
HeLa cells as revealed by scanning microscopy.
MATERIALS
AND METHODS
The HeLa S3 cells were maintained in a spinner culture in
Eagle's minimal essential medium supplemented with 5%
fetal calf serum and antibiotics [penicillin, 50 units/ml;
streptomycin,
50 ng/m\ (Grand Island Biological Co.,
Grand Island, N. Y.) and Fungizone, 2.5 Mg/ml (E. R.
Squibb & Sons, New Brunswick, N. J.)]. Approximately 2
x 10* cells were transferred to 22- x 22-mm coverglasses in
30-mm Petri dishes containing 2 ml of Dulbecco's modified
Eagle's medium, 10% fetal calf serum, and antibiotics. The
dishes were incubated at 37°in a high-humidity incubator in
an atmosphere
of 5% CU2-95% air. The cultures were
examined and fixed at intervals between 24 and 96 hr of
incubation. Living and fixed cultures were observed and
photographed through phase optics on a Reichert inverted
microscope.
Micrographs
of liver cells were taken with
Zeiss-Nomarski
differential
interference
equipment
for
transmitted light microscopy (Figs. 1 and 2).
In preparation for scanning electron microscopy, the cells
were fixed for 20 min at 37°in 3% glutaraldehyde
(Taab
Laboratories,
Reading, England) buffered to pH 7.4 with
0.05 M cacodylate and 50% Puck's saline G, followed by a
postfixation of 10 min with 1% OsO4 (pH 7.2) buffered with
0.2 M cacodylate. They were then rapidly dehydrated with
acetone. In order to avoid the distortions caused by changes
in surface tension when progressing from the liquid to the
gas phase, the cells were processed through the Sorvall
critical-point drying apparatus (Ivan Sorvall, Inc., Newtown, Conn.) according to the technique described by Porter
et al.2 (16). Thin layers of carbon and gold (200 A) were
evaporated
onto the cells which were then viewed with a
2This clever and extraordinarily effective technique for avoiding drying
artifacts was introduced to electron microscopy by Anderson in 1951 (2).
1974
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1385
K. R. Porter et al.
Cambridge Stereoscan S-4 electron microscope operated at
20 kV.
Human cervical tissue was surgically removed from 2
patients, aged 28 and 40. The customary methods of
colposcopy involving acetic acid and Schiller's iodine were
avoided. The biopsies were washed in warm Puck's saline G
As expected, the micrographs from scanning microscopy
are valuable in providing clear views of the concentration,
distribution, and forms of the microvilli (Figs. 5, 6, and 7, a
and b). The population density on cells that are relatively
spread is of the order of 1.7/sq urn. This means that, on the
whole exposed surface of a 600-sq. firn cell, there are
to remove surface mucus and. within 5 min of removal,
approximately 1100 microvilli. On the spherical HeLa cells,
were fixed in 3% glutaraldehyde buffered with 0.05 M the microvilli are present over a greater proportion of the
cacodylate. The fixative was made isotonic with Puck's entire surface. Where attached to a substrate, they are
saline G. After 3 hr in glutaraldehyde, the tissue was reported by Fisher and Cooper (7) to have microvilli on the
washed in Puck's saline and postfixed for 30 min in 1% free surfaces only, i.e., on about three-fifths of the cell
OsO«. Thereafter, dehydration was accomplished with surface.
acetone, and the small tissue blocks were carried through
On the surfaces possessing microvilli. we have detected no
critical-point drying by methods described previously (16). pattern or unevenness in their distribution. They are not, in
Following drying, the surfaces were coated with 100 to 200 other words, more numerous over the cell center than along
the margins of extended units, as is the case in rat sarcoma
A of gold.
A Cambridge Stereoscan S-4 scanning microscope was 4337 cells cultured under similar conditions (16). It is also
evident that the microvilli persist during most of the phases
used at 20 kV for all microscopy.
of mitosis and are not displaced at this time by other surface
structures such as blebs or ruffles (Fig. 8). They seem,
OBSERVATIONS
during this phase (mitosis) of the cycle, to be supplemented
HeLa cells in culture appear generally in 2 forms, either by a population of filopodia which appear to attach the
dividing cells to the substrate (Fig. 8). These latter differ
as spheres or as slightly flattened, epithelioid cells adherent
to the substrate. Occasionally, they remain confluent to from microvilli in being longer and in tapering toward their
tip ends, where they frequently bifurcate and end in small
form small epithelial sheets (Fig. 3). In nonsynchronized
populations of growing cells such as that shown in Fig. 3, attachment discs. Late in cytokinesis and early in Gì,the
some cells are in division (arrows) and others are in Gì,
S. or microvilli are replaced briefly by blebs and an inflated or
G2. Assuming that HeLa cells repeat roughly the behavior swollen version of the filopodia (Fig. 10) (5). This is
of CHO cells grown under similar conditions ( 17), one can apparently a very brief transitory event, because cells with
decide that the spherical forms are in mitosis or in early G, this surface morphology are encountered very infrequently.
The Microvilli. The microvilli on HeLa cells vary greatly
and that the attached and spread cells, especially those in
contact with one another and/or the substrate, are in late in length and, to a lesser extent, in diameter and contour.
Gì,S, or 62. This interpretation is supported by studies of Our length measurements range all the way from 0.2 to 6.0
Erlandson and deHarven (6) on synchronized populations of urn. Their diameter, which is minimal at ~0.1 ßm, is
HeLa cells which they examined by using thin sections and increased slightly by the coating of carbon and gold
evaporated on their surfaces for the purposes of scanning
transmission electron microscopy.
Where the population of cells is sparse (Fig. 3), it is microscopy. On some cells, most of the microvilli stand
characteristic, as mentioned above, for these cells to spread erect, are fairly straight, and have a uniform diameter (Fig.
out and to associate in small sheets during what is presumed 7, a and b). On others, they adopt tortuous forms which
to be the S phase of the cycle. This behavior can be taken as include local swellings and elbow-like bends (Figs. 6, 9, and
some evidence of contact inhibition but not inhibition of II). Occasionally, also, on these latter cells the microvilli
enduring tenure (1). Any junctions established between occur in clusters of 2 or more emerging from a single base or
these cells are in no sense permanent: rather, they seem to location in the cell cortex. Whether this variation from cell
be labile and readily broken. It appears that the cells shrink to cell bears any relation to different phases of the cell cycle
and pull apart some during preparation for microscopy. As has not been determined, but the question is being investi
the population becomes more dense, the cells pile up on one gated through studies on synchronized populations. Of this
another and all contact effects disappear. Under these we are certain, the morphology shown is in many respects a
conditions they fail to show any tendency to spread and dramatic departure from that of microvilli on normal cells
(Figs. 13 and 14) and represents 1 phenotypic characteristic
appear to remain spherical throughout the cycle (Fig. 4).
The Cell Surfaces. The presence of numerous microvilli of HeLa cells. Conceivably, it is pathognomonic of the
malignant transformation for microvilli to display these
on the surfaces of HeLa cells is evident in all micrographs,
including those of living cells taken with Nomarski optics several abnormalities.
The Internal Structure. The internal structure of the
(Figs. 1 and 2). Whether, in the light microscope, images of
the individual microvilli are resolved or whether one is HeLa cell cortex and microvilli has been depicted previously
seeing several microvilli overlapping in the depth of the field (7, 20). The major features are shown in Fig. II. The cell
cannot be definitely determined. The limitations of light surface is very irregular in profile, as one would expect. The
resolution also make it difficult to decide definitely whether cortex just under the plasma membrane is a dense lattice of
the villi are constantly merging with and emerging from the fine (60 A) filaments. This extends into the bases of the
microvilli where, in microvilli of the smallest diameter, the
cell surface as proposed by Gey (8).
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Scanning
randomness of the cortical lattice gives way to a parallel
arrangement of the filamentous components.
Microtubules are common in the cortex and just beneath
it. These seem randomly oriented and without obvious
relation to other structural elements of the cortex. The
mitochondria, which appear abnormal, polysomes, profiles
of elements of the endoplasmic reticulum, and residual
bodies of lysosomal activity are all present (Fig. II). We
have encountered no virus-like particles or exogenous
pathogens of any kind.
The extraordinary irregularities in the form of microvilli,
especially those involving diameter variations and contour
changes (Fig. 6), are clearly evident in micrographs of
sections (Fig. 11). It is obvious that a section cut normal to
the surface, as in Fig. 6, might very reasonably appear in
transmission image as in Fig. 11. Presumably, these rela
tively gross features of the microvilli have some counterpart
in the arrangement and structure of microfilaments within
the microvilli, but the scope of the present study has not
been adequate to determine this.
Other Surface Features. The surfaces of most of these
cells, except for the microvilli, are relatively unadorned. The
membrane surface between the microvilli is smooth and
structureless except for a few dark spots which probably
represent pits or openings in cortical vesicles (Fig. 6,
arrows). These measure about 200 A in diameter.
It is apparent, however, that some cells in every popula
tion show a few blebs. As mentioned above, these are small
spherical excrescences of the surface which vary in diameter
from 1 to 5 urn. They have smooth surfaces and remain
attached to the cell by a pedicle. There is some evidence that
these may be shed and have a temporary existence in the
immediate environment of the cell (18).
Epithelial Cells of the Normal Cervix. The diagnosis of
the original HeLa cell tumor as an epidermoid carcinoma
(9) has recently been revised to adenocarcinoma of the
cervix (12). This is apparently a fairly rare form of cervical
carcinoma, involving mucous gland ducts of the internal os.
This revised diagnosis indicates that HeLa is more closely
related to the columnar cells of the cervix than to the
squamous cells of the external os (11). We have examined
the surfaces of both cell types in normal tissue by scanning
microscopy and find microvilli on the columnar cells only.
The squamous (epidermoid) cells are covered with finger
print-like patterns of ridges (Fig. 12), as reported by other
investigators of this tissue (13, 21). The ridges are about
0.15 ¿imwide and are separated by ~0.7 ^m spaces and,
toward the margins of the cell, they tend to orient parallel to
the junctions with adjacent cells (21).
Surfaces of columnar cells are depicted in Figs. 13 and 14.
It is obvious even at low magnifications that the free
surfaces of these cells are covered with microvilli that are
much more closely packed (9/sq ^m) than are the micro
villi on HeLa cells grown in vitro. They clearly vary in
length but seem never to exceed 2.0 urn. Their diameters
are uniform at ~0.1 urn. In places (Fig. 14, arrows), a
few tiny strands connecting the microvilli can be seen;
these we interpret as being residual strands of mucus.
Ciliated cells have been seen occasionally in our prepara
Microscope
Study of HeLa Ceux
tions (Fig. 14) as, also, in those of Jordan and Williams (13).
The individual cilia are all of 1 length and are the typical 0.2
urn in diameter. Except for a few microvilli, they seem to be
the only occupants of the free surface of the cell.
DISCUSSION
Scanning microscopy provides an image of the cultured
HeLa cell that conforms in major respects to that provided
earlier by transmission studies of thin sections (5 7, 19, 20).
The striking feature is that the cells are covered with long
slender microvilli. This appears to have been the character
istic phenotype from the time the cells were first isolated
and described (8, 9). Fisher and Cooper (7) have reported
that, where the cell is spread over a substrate, the underside
is devoid of microvilli. None of the scanning observations
we have been able to make have been adequate to confirm
this, and all we have from side views of the cells is some
evidence of intimacy of contact between cell and substrate
which would be unlikely if the undersurface were covered
with microvilli. Where the cell is growing in vivo and
invading normal tissue, microvilli are evident extending
from all surfaces (20). Under these circumstances and also
where the cells are off the substrate in vitro, it appears that
the free surfaces of HeLa cells, in their entirety, normally
and characteristically produce microvilli.
There are only 2 periods in the cell cycle when these
slender extensions are much less prominent than usual. One
is during late cytokinesis and early Gìwhen, as noted
originally by Byers and Abramson (5), the daughter cells
undergo a brief period of blebbing. These authors have
correlated the blebbing with events in the intercellular
bridge which, until the end of cytokinesis, connects the 2
daughter cells. During this time, the cell achieves the
appearance shown in Fig. 10. A few microvilli persist, but
mostly the surface is covered by blebs. Even the filopodia,
which at metaphase are slender and normally connect the
cell to the substrate, adopt, very curiously, a swollen
appearance.
The other period when blebbing is a prominent feature of
the surface is during anaphase (5, 6, 14, 19), when blebbing
is confined to the poles of the cells. From these observa
tions, the suggestion that blebs replace microvilli is difficult
to avoid, but we have in fact no other evidence of any
transformation of one into the other. The swollen character
of the filopodia at cytokinesis (Fig. 10) implies that these
structures are responding to a general tendency of cell
extensions, including microvilli. to adopt a more massive
(less slender) form during this brief phase of the cell cycle.
Microvilli. It is customary for microvilli occurring on
normal cells to be straight and uniform in diameter and
more or less uniform in length. This is certainly true of those
found on adsorptive cells of the intestine and the serosal
surfaces of the body cavity (3). It is of greater pertinence
here that the microvilli on the free surfaces of columnar cells
of the cervix are also uniform and straight. This consistency
in form of normal cell microvilli makes more impressive the
gross irregularities shown by the microvilli of HeLa cells. In
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K. R. Porter et al.
all aspects they are abnormal. Instead of being straight they
are crooked. Their diameters and cross-sectional cylindrical
forms vary enormously. They even branch (Figs. 6 and 11).
Instead of being more or less uniform in length, they vary
from mere bumps on the cell surface to slender hairs several
/¿min length. This latter variation may reflect a constant
extension and withdrawal, a certain dynamism of microvilli,
as suggested by the early observations of Gey (8). The other
form abnormalities are less readily accounted for. Presum
ably, they have their basis in some defect in structural
proteins of the finely fibrous core or conceivably reflect
some local dysfunction in the membrane accompanied by
small-scale volume changes within the affected microvilli. It
is possible, as well, that they represent an accommodation
to some physiological requirement peculiar to the tumor
cell. However, until such time as we have a better under
standing of factors affecting the form of microvilli, specula
tion on their pathology seems pointless. One may hope that
the visibility provided by scanning microscopy will stimulate
a more intensive investigation of them, especially as they
occur on these HeLa cells.
The form and number of microvilli on HeLa cells support
the impression that the surfaces of these cells are extraor
dinarily active, i.e., in the sense of movement and exchange
of metabolites. Additionally, there is the thought that their
distribution over the whole surface of the cell as well as their
abnormalities would probably contribute to the cell's invasiveness, its low adhesivity, and its failure to show any
contact inhibition (I). This exaggerated development of
surface extensions is expressed in other tumor cells and
seems indeed to be a fairly general feature of these cells,
in contrast to their normal equivalents (15). This is true
even where the cell of origin is beyond question and is
engaged, like the tumor derivative, in continuous growth.
What one should infer from these surface features is
difficult to decide except that they seem to be logically
equated to most of the well-known behavioral properties of
these cells.
Meaningful comments on the transformation represented
by any tumor cell depend on an accurate identification of
the cell of origin. This in turn depends on the experience and
interest of the pathologist who makes the identification. In
the case of the HeLa cell, the original routine diagnosis
termed it an epidermoid carcinoma (9). However, after
HeLa cells acquired some fame, the original slides were
reexamined and found to show "telltale acinous formation"
characteristic of an adenocarcinoma (12). This relates its
origin to the columnar cells of the endocervical canal rather
than to the squamous epithelium of the external os (11). As
noted here and in other scanning electron microscope
studies of several cervices, including human (10, 13, 21),
these columnar cells are covered on their free surfaces by
microvilli. Since the surfaces of HeLa cells are also
characterized by microvilli, the scanning electron micro
scope findings appear to confirm the latest conclusions from
histopathology.
These conclusions accepted as established, it is appropri
ate to note the differences that are representative of the
transformation. For example, the microvilli on the normal
1388
columnar cell are closely packed, are relatively short (0.2
urn) and uniform in length, and are straight and without
variation in diameter. Those on HeLa cells are much more
widely dispersed and possess the several abnormalities
already noted. Thus a much larger portion of the HeLa cell
surface is involved in the support of microvilli than is true
for the normal cell. Whether one should interpret this as
descriptive of an abnormal production of special surface in
the case of this tumor cell is doubtful. The impression has
grown of late that the free surfaces of tissue cells, especially
where involved in special functions, are assembled in the
Golgi complex out of units fed to it from the rough
endoplasmic reticulum. One may reasonably infer that early
in surface synthesis there is abnormal translation, with
abnormal structural elements being generated. It is curious
that the transformed cells show so little surface that one can
equate with the lateral and basal surfaces of the differenti
ated cell. Is this simply a product of the conditions of
culture or is it another expression of the transformation?
Possibly, the normally lateral surfaces have here intermin
gled with that supporting the microvilli.
Other abnormalities of the surface besides those reflected
by this microvillar activity include the failure of these cells
to assemble into tissues. Apparently, their surfaces are
without special junctional sites, maculae adherens, or
zonulae occludentes (4). It is conceivable that a more
through search of these surfaces would have yielded images
of such sites, but certainly none is obvious.
ACKNOWLEDGMENTS
We are grateful to Dr. Frank Major (Denver General Hospital.
Colo.) for providing the normal cervical tissue.
Denver.
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Fig. I. Living HeLa Ss cells photographed with Zeiss-Nomarski differential interference equipment. The microscope was focused on the extensions on
the lateral surface of the cells. Microvilli of varying lengths can be seen, as well as longer filopodia interconnecting the cells, x 1.900.
Fig. 2. Zeiss-Nomarski optics photograph ot the top surfaces of HeLa cells. Individual microvilli appear to be resolved, x 1.900.
Fig. 3. Low-power scanning electron micrograph of HeLa S3 cells. At this low density of culturing, the rounded cells represent those that have just
divided (arrows). Within a few hr they may flatten in a sheet-like formation. A few blebs (b) can be seen on the cell surfaces and on the substrate, x 2,000.
Fig. 4. Micrograph showing a piling up of HeLa cells in a high-density culture. These cells remain rounded throughout their life cycle and are
interconnected by many filopodia. x 2,000.
Fig. 5. At higher magnification, the irregular distribution of microvilli can be seen. Zeiotic blebs (b) occur in small numbers on their surfaces, x 4,000.
Fig. 6. Between the microvilli. the surfaces of these cells are fairly smooth with the occasional appearance of small pits (arrows). The great variation in
size and shape among the microvilli is also evident, x 10.000.
Fig. 7, a and b. This is a stereo pair of scanning electron micrographs. The incidence of grossly abnormal microvilli is relatively low here, x 4.800.
Fig. 8. HeLa S3 cell in mitosis. The cell is attached to the substrate by long filopodia. x 2,000.
Fig. 9. Scanning electron micrograph showing HeLa cells from the side to illustrate, in this instance, their close attachment to the substrate. Zeiotic
blebs (b). x 2,000.
Fig. 10. This micrograph shows a relatively rare morphology. The surface of the cell is highly blebbed with an enlargement of the attachment
filopodia. This represents a cell in the early Gìphase of the cell cycle, x 10,000.
Fig. 11. Transmission electron micrograph of a thin section showing the surfaces of 2 cells and several microvilli. The internal structure consists
largely of a network of microfilaments (m) with a few ribosomes visible in the cytoplasm (r). x 120.000.
Fig. 12. Scanning electron micrograph of squamous epithelial cells from the external os of normal human cervix. A network of ridges
characteristically covers the cell surfaces in a fingerprint-like pattern and further delineates the intercellular junctions (arrows), x 5,000.
Fig. 13. The free surfaces of the columnar cells from the internal os of normal human cervix are covered by a large number of closely packed
microvilli. Slight variations in length can be seen but all appear to be of equal diameter, x 3,000.
Fig. 14. Higher magnification of the columnar epithelial surface. This field includes one of the ciliated cells occasionally present in this area of the
cervix. Note the fine strands (arrows) connecting many of the microvilli. x 7,250.
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K. R. Porter et al.
1394
CANCER
RESEARCH
VOL. 34
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1974 American Association for Cancer Research.
A Scanning Microscope Study of the Topography of HeLa Cells
Keith R. Porter, Virginia Fonte and Gary Weiss
Cancer Res 1974;34:1385-1394.
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