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J'^'^rx

Growth and Overgrowth ^nd on the
^ ,^ , Rela,ti6nship between Cell Differen-
-^ : tiation and Proliferative Capacity ;

its Bearing upon the Regeneration

of Tissues and the Development of

Tumours.

flv

Pttftittr of Patkeiogy, McGill UniVtrsHjn Mmtrtai.

■A

^? ••;■•':. -

SHERSAtT &• HOGUES,

BMSitllers ami Pittittt^i,'
2Ji ST. ANN STRtET, MANCIlBmil-

,«,«. r ,3^

I .:^iiMSt-:Mf^yi,^ ^ry-

ON GROWTH AND OVERGROWTH AND ON THE
RELATIONSHIP BETWEEN CELL DIFFEREN-
TIATION AND PROLIFERATIVE CAPACITY;
ITS BEARING UPON THE REGENERATION
OF TISSUES AND THE DEVELOPMENT OF
TUMOURS*

By J. G. ADAM I, M.A., M.D., F.R.SE.,

Professor of Pathology, McGill University, Montreal.

There are in medicine and other sciences not a few beliefs and
ideas which we have taken up we know not how, and which in
general we no more think of discussing than we do, for example,
the subject of good manners. Thus, just as it is difficult if not
impossible for us to state how or where we gained any single article
of our code of personal ethics, so it is with certain of these general
ideas in medicine ; and while we have never discussed these beliefs
we feel individually assured that they are the current ideas of
other workers along the same lines.

One of these tacit beliefs or comprehensions relates to the
subject of the growth of tissues. Asked off-hand we should
assuredly, each one of us, state as his familiar belief that muscle
arises from muscle, epithelium from epithelium, nerve cell from
nerve cell, and so on, and the mental picture which we form of
the process of growth is, I fancy (though here, of course I
speak under correction), that the fully formed epithelial cell
undergoes mitosis and divides into two, and so with the cells of

* By the courtesy of the Editors of the " Festschrift," to be published in honour of
the seventieth birthday of Dr. A. Jacoiu, of New York, we are enabled to publish
this article coincidently, to all purposes, with its appearance in the volume in question.

Cell Differentiatinn and Proliferative Capacity.

other tissues. Yet if we think a little lonjer and recall what we
have actually seen under the microscope, this mental picture is
seen to be incorrect or, at least, imperfect. Thinking recently
over this matter it has been impressed upon me that if .ve obtain
a correct idea of what occurs during the process of growth of
tissues, we not only realize that there is a very broad biological
law underlying this process of growth from the earliest stages of
the embryo upwards, but further, applying this biological law to
the .subject of pathology, we gain a deeper and a fuller compre-
hension of certain matters bearing upon regencation and
degeneration of tissues, and what is more, bearing very directly
upon certain of the phenomena of tumour growth.

While the individual, formed as he is of a marvellous complex
of various tis.sues, is a reproduction of the tissues and organs
present in his paternal and maternal ancestors, he is the outcome
and development, not of the combined fully developed tissues,
nor again of any one highly differentiated cell or cell compound,
but of a single undifferentiated cell — the fertilized ovum — a cell
neither of the component parts of which, ovum or .spermatozoon,
has ever through the whole course of the ages been derived from
other than similar undifferentiated cells ; or, in other vvord.s, these
apparently simple germ cells are capable of giving rise to the whole
series of cells forming the whole mass of tissues from the simplest
connective up to the most highly differentiated nerve tissue.* If
we study the process of the development of the embryo, whether in
plant or animal life, we .see again a somewhat similar phenomenon.

From a very early period in such growth we recognize that
certain cells alone appear to be actively dividing and to be actively
proliferative, whereas other cells, the products of these, while they
take on characteristic appearances, do not thus divide. Very early
indeed in the developing embryo we recognize this existence of
what may be termed " mother-cells,"— cells which themselves

•It is possil)lc that while the cell body of these germ cells is relatively un-
difl'erentiated, the nucleus is peculiarly highly elaborated. We have, indeed, not a
few indications that this is the case. Thus it may be that nuclear and cytoplasmic
differentiation, in germ, and ' mother '-cells and in specific tissue, and ' daughter'-cells
respectively, are ia inverse ratio. We have not as yet reached a point at which any
definite statement can be made in this connection. (Throughout this article I refer to
cytoplasmic and not nuclear differentiation.) ("('juoted by Harlurth zuF Regeneration]
filer Uewebe, Arcli.f. Mikrosc, Aiiat. 37, 1891, p, _4.24^.- ' '

■i,

tnd. /-Q yu/L-j p. g

Cell Differentiation and Proliferative Capacity. 3

remaining embryonic in type give rise by division to other cells
which assume more highly differentiated characters. And this is
true not only of animal organisms, but still more obviously of
plants : we have but, with Sachs, to study the growing points of
plants to realize the existence of these "mother-cells."

Now when we pass to the fully formed individual, we must
still recognize this fact, which we are apt to pass over, namely, that
the specific cells, if I may so term them, of the different tissues —
that is, the highly differentiated and characteristic cells of those
tissues — do not themselves give rise directly, and by division, to
other specific cells, but that in each tissue there are these more
or less undifferentiated mother-cells, which more especially have
the power of proliferating, iJid it is the daughter-cells which
assume the full specific properties in the different tissues, or if, as
would seem to be the case in some instances, the active cells of
certain not very highly differentiated tissues them.selves proliferate,
they only do this after a preliminary reversion to a " mother-
cell," or more embryonic type.

Let me here give a few examples : Immediately I mention
them, everyone will realize that these are facts thoroughly
familiar. One of the simplest cases is that of the skin : in this
it is the lowest layer of the epidermis, the Malpighian layer,
whose cells undergo active proliferation, and this constantly,
throughout the whole period of life, and the cells which are most
active in the process are those of the very lowest layer — cells
which are of a permanently embryonic type.

After injury, it is true, we may come across occasional mitotic
increase, more especially in the lower animals, in the region of
the prickle cells, but, when we do, we see that it is accompanied
by reversion of the cell to a simpler type : the prickles or bridges
disappear, the cell loses its connection with the neighbouring
cells, and passes back to a simpler stage prior to multiplication.

In bone the case is the same. Production of bone tissue is
not brought about by multiplication of the pre-existing and
characteristic bone cells, but by osteoblastic tissue ; or, in other
words, by the mother-cells of bone lying in the immediate
neighbourhood of the vessels of the inner layer of the periosteum,
or again coursing through the Haversian canals and between the

4 Cell Differentiation and Proliferative Capacity.

lamina:. When through injury or otherwise a stiniulation is
afforded, it is these mother-cells which applying themselves to
the pre-existing bone multiply, and there governing the spacer,
around them lead to the deposit of a calcareous or bony matrix
and gradually assume all the characters of typical bone corpuscles.

From the variability of the structure of the glandular organs
it is difficult to lay down any general rule with regard to
regeneration of glandular epithelium, so that it must be confessed
that, partly on account of this variability, partly on account of
the fact that the different observers upon glandular regeneration
have not had this conception of mother-cells before them in their
studies, such glandular epithelium in the present state of our
knowledge affords the least satisfactory demonstration of the
principle. There are, however, so many instances concerning
which we have positive information, as to render it more than
probable that throughout the same principle is in action.

Of the mother-cells of the type seen in the Malpighian layer
of the epidermis, several instances may be called to mind : the
mother-cells of the testicular epithelium and (though differing
somewhat in plan) of the ovarian follicles, of the sebaceous and,
apparently, from Tornier's studies, the mammary glands. In
both of the latter organs there is, during activity, a giving
off of cells, and mitosis occurs especially in the deeper, more
external layers.

In this connection should, I think, be mentioned the columnar
and ciliated epithelia of mucous membranes. It is remarkable
how one histological text book after another figures such columnar
epithelium as formed of a palisade of fully developed columnar
cells in regular series situated upon the basement membrane,
without indicating or even referring to the presence of embryonal
" mother-cells " lying between the bases of the fully differentiated
columnar cells. Certainly under pathological conditions one is
impressed by the fact that these basal cells are present, and that
there is a development of new cells from beneath to take the
place of the degenerating fully formed cells. While in the simpler
acinous glands it is difficult to recognize such permanent mother-
cells (indeed they are probably absent in the adult), here at least
they are present.

Cell DiffevcntiatioH and Proliferative Capacity.

5

In the lymph glands we may have another arranfjcment. In
them the mother-cells arc collected together in the form of small
nodes in the centres of the individual follicles : a somewhat
similar arrangement of foci of embryonal cells is met with in the
thyroid, while in the pancreas, Langerhajjls's bodies or "cell
accumulations " would seem to be of a similar nature, although
this is not as yet absolutely determined.

Closely allied to this condition is ;vhat is seen in the lung
and again in the serous coat of the peritoneum (though neither
of these, it is true, comes strictly under the category of true
gland structure). In the former, certain more embryonic cells
persist, especially at the angles of junction of the alveoli, and
these are generally regarded as centres for the normal prolifera-
tion and regeneration of the alveolar epithelium. On the
peritoneal surface also there are found clumps of smaller cells
capable of active proliferation. With regard to both these cell
layers, the flattened — differentiated — cells are liable, under irrita-
tion, to revert to the fuller, more rounded embryonic condition
and then undergo mitosis and proliferation.

Judging from the fact that mitoses are not observed in the
fundal portions of several acinous glands, while they are frequent
in the neck regions of the same, it would seem at least probable
that mother-cells, or cells capable of reverting to the mother-cell
type, are situated in the latter arei. But generally in acinous
glands of simple type there Is, as Bizzozero has pointed out, little
evidence of continued proliferation under normal conditions,
once they are fully formed. In connection with these, it is that
more exact studier. are requisite ; certainly in .some, ^.^'., in the
kidney tubules, slight continued irritation leads to the differen-
tiated cells, undergoing proliferation, but at the same time these
cells are seen to revert to the simpler more embryonic type.
Thus, while confessing that it is not as yet possible to demonstrate
in every case that neither mother-cells are present or that for
regeneration the differentiated cells revert to a more embryonic
type, the number of examples that can be brought forward, where
either one or other of these processes is seen to occur, is so large
that we may assume that a general principle obtains in connection
with all.

^>t/

6 Cell Differentiation and Proliftrative Capacity.

Passing now to another tissue, namely muscle, the process of
regeneration, as pointwl out by Barfurth, varies largely.

In connection with the muscle, the process of regeneration, as
pointed out by Barfurth, varies largely according to the age of
the individual. Originally the muscle fibres, it is needless to sav,
are recognised as arising from a scries of cells known as sfi^)-
blasts, relatively large cells with abundant protoplasm, the nuclei
of which tend to proliferate, and along one aspect of, or generall>'
around, the periphery there is gradually developed first a
longitudinal fibrillation, and .'.en transverse striation. In young
larval forms of amphibia, for example, after injury such sa(^3blasts
may be seen to be present, to undergo multiplication, and to give
rise to typical muscle fibres ; here, therefore, very clearly there
are mother-cells. The existence of such in the adult is still a
matter of dispute ; for in the older individuals two processes have
more especially been recognized : one, that in which the fully
formed muscle fibres become the seat of an active nuclear
proliferation, and then in certain areas of the fibres the striation,
more especially toward the end, or laterally, becomes indistinct
and little buds containing nuclei are given off, which become the
precursors of the new growth. Or secondly, us pointed out first
by Weismann, there t..ay be recognized, even in perfectly normal
muscle of adult animals, certain occasional spindle-like bodies,
consisting of short striated muscle fibres, characterized by very
abundant nuclei and, according to Kolliker and others, these
bodies represent centres from which by longitudinal division new
fibres are given ofif. Even in this case it will be seen that these
bodies represent a lower imperfect stage of differentiation, and
the richly nucleated mass may strictly be regarded as a " mother-
cell."

Thus from a study of the process of regeneration as seen in
the different tissues in man and vertebrates generally, it is
possible to lay down the following laws :

1. The fully differentiated cells of a tissue proper never arise from
cells thai are themselves fully differentiated.

2. Under the «<?a-/«(7/ conditions of growth and during physiological
regeneration, the fully differentiated cells would seem in nearly every
case to be developed from " mother-cells " — undifferentiated or but

Cell Diffaentiation and Proliferative Capacity, f

partially differentiated cells which tliemselves tiirou^hout the term of
life of the individual never attain to the full dilTerenti;ition [kl iliar to
the tissue to wiiich they belong and wliich indeed they produce. For
these mother-cells by division give origin to the daughter ci'lls, and it is
the daughter-cells which attain full differentiation and form the specific
cells of the tissue. More rarely the functional cells themselves, by
reversion to a more embryonal type, can take on the i)r()pcrties of
mother-cells.

3. Under abnormal conditions, the fully differentiated functioning
cells of certain tissues are capable of proliferation and giving rise to cells
of like nature, but this is only after a preliminary reversion to a simpler,
more embryonic type. 'I'iie fully differentiated cell as such is incapable
of proliferation.

4. Or, otherwise, the energy stored up by the cell may be expended
in one of two directions, but not in both — either in functional activity
or in preparation for proliferation, and, the structure of a cell being the
expression of the activity of that cell, the expenditure of energy in either
direction is attended by corresponding morphological or structural
differences in the cell.

5. The more highly differentiated a cell, the more highly elaborated
its structure, the less the ease witli which it reverts, and the less the
liability to reversion to a simpler reproductive form ; the simpler the cell,
the greater the ease and the greater the liability to such reversion. It is
thus possible, at the one extreme, to conceive cells so simple in function
and in structure that functional or reproductive activity may be called
into play indifferently without recognisable \}x^\\\\\vn'xxy structural altera-
tion, and, at the other, cells so highly difilerentiated that the capacity
for proliferation has become entirely lost.

The law with its corollaries here given does not so far appear
to have obtained general recognition. Certainly I fail to find it
explicitly referred to by writers upon morbid anatomy, and had
it been currently accepted by biologists it would ere this have
become part and parcel of pathological teaching. It is only after
some little search and almost by chance that I find its main
paragraph laid down by Kolliker in 1885, and that only, as it
were, in passing, in an article not dealing directly with regenera-
tion, but dealing with the part played by the nucleus in
inheritance. In that article Kolliker states : " In all cases in
which an organ or a tissue is capable of regenerating itself, it

8

Cell Differentiation and Proliferative Capacity.

must contain elements of an embryonal character, or at least
such elements as can take on that character." And again, in the
same article : " These cells then are dependent upon the same
law, as, in the embryo, is the formation of organs."*

But in the general portion of his great Handbtich dcr
Gezi^edelc/ire des Mensc/ien, pwhWshed in 1889, I cannot find that
he again refers to this principle, hence it would appear that he
did not realize its wide application.

Thus, although the law when once grasped is simple, almost
to the verge of being a truism, it merits being stated for once in
as clear terms as possible that its high importance may be fully
recognized.

Applying now those considerations to certain pathological
conditions, it is in the first place necessary to say but little
concerning pathological regeneration and repair, for I have
already applied some of the facts gained from a study of such
regeneration in the development of my argument. Thus much,
however, may be said, that the more we study the regeneration
of various tissues, the more we see that the phenomena of tlje
process fall into place in consonance with the law above laid
down. The cells of a regenerated tissue are derived from the
pre-existing cells (and mother- cells) of that particular tissue, and
the more highly differentiated the tissue the less is its capacity
for regeneration.

Of all cells, those which are the most highly differentiated,
namely the nerve cells, show the least capacity for proliferative
regeneration ; there is a remarkable lack of evidence of fully
developed nerve cells having been observed in the process of
mitosis, and, corresponding with this lack, when we consider the
histological basis of motor, sensory, and mental acts, it is a
priori hard, if not impossible, to conceive a given cell in any of
the higher nerve centres undergoing proliferation without there
being simultaneous arrest, not to say loss, of function. Every-

•KiJlliker ; " In alien Fallen, in denen ein Orf;an oder ein Gewcbe fahig ist sicli
wieder zu erzeiigen, muss dasselbe Element von embryonalem Charakter enthalten
Oder wenigslens solche, die diesen Charakter anzunehmcn im Stande sind." " Diese
Zellen bedingen dann nach denselben Gesetzen, wie beim Embryo, die Organgestal-
tung." — "Die Bedeutinig der Zellenkerne fiir die Vorgiinge dcr Vererbung,"
Zeitsclirii! f. wiss. ZooL, Vol. xlii., 1885.

'V

i'

Cell Differentiation and Proliferative Capacity. g

thing indicates that of all the cells of the body the neurones are
those endowed with the longest life period.

During fcetal or larval life, prior to the attaining of full
function, such proliferation has been recognized (Barfurth), or
otherwise, the incompletely differentiated nerve cells may take
part in the regenerative process ; though it may be considered an
open question whether the new development of neurones in
experiments upon the spinal cord of the larval newt and other
amphibia is the result of proliferation of developed neurones or
of mother-cells.

That such mother-cells must ex?st even in the human nervous
system has been forcibly brought home to me by a study of
certain sections of the spinal cord to which Dr. Shirres, working
in my laboratory at the Royal Victoria Hospital, recently called
my attention.

These sections are from a case of porencephalus in which
apparently, from all indications, the atrophy and disappearance
I of practically the whole motor area in the left hemisphere dated

; from the last month or two of foetal life. Despite this practically

"S - complete loss of the entire motor area on the left side, the result-

ing evidence, of paralysis and disturbance of function were little
more than a relatively slight want of development of the bones
and muscles of the right side of the body together with paresis of
the musculature of the right hand. In the cord the difference
between the two motor tracts is most marked, there is entire
absence of the crossed pyramidal tract on the left side, of the
direct pyramidal on the right, and, corresponding with this, there
is a most marked atrophy of those groups of cells towards the
periphery of the anterior horn of the grey matter on the right
side which everything indicates as being connected with the
crossed pyramidal tract and being what I may term the spinal
motor centres for the upper extremity. Bit in sections in which
this atrophy is most marked there is a distinct increase in the
number of ganglion cells in the deeper and more central areas of
the grey matter ; here the number of cells is much above the
normal, the cells are large and more numerous than those of the
left side in the same section.

For our present purposes it is clear that these abundant cells

■i

10 Cell Differentiation and Proliferative Capacity.

cannot be regarded as due to proliferation of the atrophied cells —
their relative position forbids such an assumption. Their exist-
ence, however, is strongly in favour of the view that they have
been derived from mother-cells in the grey substance.

The regeneration of nerve fibres is another matter S far as
regards the axones, or axis-cylinder processes themselves, it is
strictly comparable with the new growth of the cell substance of
the amceba when a part of that cell substance has been removed
without direct injury to the nucleus. As regards the investing
sheath of the medullated nerve fibre, regeneration here is in strict
accordance with the third law, there is a preliminary period of
reversion ; the formed substance (myelin), governed or elaborated
by the cell, breaks down, the nucleus becomes more prominent
and surrounded by an increased amount of protoplasm, and then
in place of a single nucleus of a node of Ranviei- one gets
numerous nuclei, and the new cells evidently surround the newly
developed axis cylinder as it grows downwards from the seat of

injury.

I have already referred to the regeneration of muscle, but if
now we pass to the other extreme and consider what happens in
the simplest of all tissues namely, white fibrous connective tissue,
we find that even here for pathological regeneration to occur
there is a preliminary stage of swel'ing of the connective-tissue
cells, the nuclei become larger and more prominent, the
surrounding protoplasm becomes increased in amount, the
surrounding fibrils tend to disappear, and now, only after this
reversion to a simpler, more embryonic condition, do we have
proliferation and the subsequent building up of new connective

tissue.

To enter here into a discussion as to whether connective
tissue can be formed from wandering cells and whether any
special form of wandering cell is capable of taking part in such
new formation, would be imperative if I were dealing more
especially with the law that tissues an^efrom pre-existing specific
tissue cells ; here rather, dealing with the process and the law of
growth, with the law of mother-cells, if I may so term it, the very
limits to which this article is confined by the editors must be an
excuse for not dealing with this subject.

Cell Difff.rentiation and Proliferative Capacity.

II

A few words, however, must be said with regard to metaplasia
in general, for the law of reversion to a more embryonic type is
distinctly in evidence throughout, and indeed helps us to under-
stand how, for example, a columnar-celled epithelium can be
converted into a squamous-celled epithelium and one form of
connective tissue into another ; or, otherwise, metaplasia is never
direct, but is only brought about by preliminary reversion to a
more embryonic type, or, where mother-cells are present, by the
modified development of cells derived from the mother-cells, the
influence of environment altering the character of those daughter-
cells during the period of growth.

If the principle be correct that the more highly differentiated
a cell, the less its capacity for proliferation ; or, in other words,
the more the daughter-cells depart from the type of the mother-
cells, the less their proliferative capacity, then the converse would
seem to hold — that tJie more the daughter-cells in a given tissue
retain the characteristics of the mother-cells, the greater their
prol'^erative capacity. Or — to continue the argument — if through
any cause the daughter-cells in a tissue do not attain full specific
differentiation, then they are peculiarly liable to proliferate and
function, not as specific cells, but as mother-cells. And further,
as Bizzozero has pt)inted out, tis.sues in which the cellular
elements exhibit frequent mitosis are those which more especially
are liable to be the seat of excessive growth and tumour formation.

I am far from saying that this is the one principal concerned
in the development ot the blastomata or tumours proper, but I
would urge that it is one important principle. It is outside the
limits of this article to consider what is the essential stimulus or
what are the stimuli leading to neoplastic growth ; accepting,
however, for the moment, that, whether temporarily or per-
manently, some stimulus or stimuli be in action, at least we gain
a comprehension of why in the first place histioid tumours(in which
one or other tissue is more or less faithfully reproduced) are
essentially benign ; and in the second place why malignancy and
excessive cell proliferation, which is theessenceof malignancy, go
hand-in-hand with tumour formation of a pronounced embryonic
type.

The failure to recognise the normal existence of mother-cells

12

Cell Differentiation and Proliferative Capacity.

in those tissues which are prone to tumour formation is very
obvious in reading over Cohnheim's chapter upon tumours and in
following the course of the argument which led him to conclude
that tumours arise from latent superfluous embryonal tissue lying
either within a tissue of the same nature or heterotopic.

While we must admit the existence of such embryonal rests
in order to explain the development of such tumours as, for
example, myomata of the kidney and primary cancerous growths
developing in bone, the permanent existence of these mother-cells
as the normal constituent of the tissues throughout life is wholly
adequate to explain most benign and malignant tumours. To this
larger conception of what is " embryonal tissue " we must, I think
inevitably come, and with Senn and others we must regard
tumours as product of tissue proliferation of embryonic cells of
either congenital or of post-natal origin, even though we at
present continue unable to state definitely what it is that
immediately induces these cells to undertake excessive growth.
Granting this, that in tumours we have aberrant tissue growth and
that that tissue growth is due to certain cells assuming excessive
proliferative properties wholly outside the needs of the economy,
then such proliferating cells are to be considered as being derived :

1. From embryonic cell "rests" which have for a shorter or
longer period remained latent in one or other tissue and then
have taken upon themselves a rapid proliferation leading to
tumour formation.

2. From the mother-cells of a tissue which, remaining
undifferentiated, but capable of active proliferation throughout
life, now assume excessive proliferative powers, their daughter-
cells retaining to a greater or less extent the characters and the
properties of the mother-cells.

3. From differentiated cells which reverting to a simpler, more
embryonic type, with this reversion gain the capacity for active
and excessive proliferation.

Posoibly, I may add that the tendency to the development of
glandular cancer in later life bears some relationship to the
reversion \nJ degeneration of gland cells at this period. As the
tissues become exhausted, the more highly differentiated cells
tend to become structurally sirnpler, revert, that is to say, to a

»
{

Cell Differentiation and Proliferative Capacity.

13

simpler type, and with this simplification of structure accompany
atrophy there may be, I would suggest, along the lines already
laid down, a greater liability for those cells to assume proliferative

powers.

■t\