Changes in the Differentiation Level of
Transplanted Tumours
by GEORGE KLEIN 1
From the Wallenberg Laboratory for Experimental Cytology, Institute for Cell Research,
Karolinska Institutet
I T has been well established that the serial transplantation of an originally highly
differentiated mammalian neoplasm leads regularly to a gradual loss of most or
all visible expressions of histological differentiation within the tumour tissue. In
a tumour that has undergone many years of serial transplantation there can
usually be detected no resemblance to the tissue of origin, but rather a similarity
to early embryonic tissue. Simultaneously with these morphological changes a
gradual increase in growth rate takes place. The completely anaplastic tumour
with a long transplantation history grows usually at a very rapid rate as compared to the original spontaneous tumour. The growth rate of such tumours is,
however, still inferior to, or, at its maximum, equal to the growth rate of embryos
of the same species (Schrek, 1936; Klein & Revesz, 1953), but has never been
found to exceed it. These changes in growth rate and level of differentiation
are usually coincident with a gradual decrease in the number of histocompatibility factors the presence of which in the implanted host is necessary for the progressive growth of the tumour. This decrease has been interpreted as somatic
mutation (Strong, 1926), antigenic simplification (Gorer, 1948), or, more recently,
as immunological selection from among the antigenic variants in a population of
malignant cells, where the antigenic variants arise mainly as a consequence of
disturbances in chromosome number (Hauschka, 1952).
The often correlated changes in growth rate, differentiation level, and antigenic strain specificity can be well studied in a series of tumours that arose in the
same tissue of a certain inbred mouse strain at different times and have undergone
different numbers of transfer generations. Considering, for instance, the readily
available spontaneous mammary carcinomas of certain inbred mouse strains, it
can be pointed out that the changes occurring during the prolonged transplantation of these tumours show many tendencies similar to those that have been
observed during the period while the normal mammary gland of these highcancer strain mice passes through the series of changes considered as precancerous and develops finally into the spontaneous tumour. These similarities may be
only superficial, but it is intriguing to speculate that the gradual changes that can
1
Author's address: Institute for Cell Research, Karolinska Institutet, Stockholm 60, Sweden.
[J. Embryol. exp. Morph. Vol. 1, Part 3, pp. 313-314, September 1953]
314
G. K L E I N — D I F F E R E N T I A T I O N L E V E L OF T U M O U R S
be observed while the spontaneous tumour is serially transplanted, and thus gets
its life prolonged indefinitely, are merely a continuation of the gradual processes
that have led from the normal tissue to the spontaneous tumour.
We have attempted to study several biochemical and growth characteristics
within a series of tumours that have undergone varying numbers of transfer
generations. One interesting quality that seems to be entirely absent on the higher
levels of differentiation (and therewith correlated lower growth rate) is the capacity of the tumour cells to grow as free cells in the peritoneal fluid, forming there
a concentrated suspension. This so-called ascites tumour form of growth has been
found to be limited to tumours of the highest growth rate and anaplasticity, with
a long transplantation history (Klein, 1951). A very great number of cell generations are necessary before cells appear and can be selected that are able to multiply in body fluids as dissociated free cells. Some results were obtained indicating
that such cells may originate by mutations, using mutation in the broader sense,
not necessarily meaning gene mutation (Klein, 1953). Such 'mutants' may have
some significance with respect to the mechanism of metastasis.
Transplanted tumours that have originated at different times within the same
tissue of the same inbred mouse strain are favourable objects for study of the
changes in growth rate, differentiation level, and histocompatibility factor requirement that invariably follow serial propagation and the morphological or
biochemical correlates of these changes. Such correlates may give information
with regard to the apparently related changes that occurred earlier, during the
cancerization of the normal cell.
REFERENCES
GORER, P. A. (1948). Brit. J. Cancer, 2,103.
HAUSCHKA, T. S. (1952). Cancer Res. 12, 615.
KLEIN, G. (1951). Exp. Cell Res. 2, 518.
(1953). Nature, Lond. 171, 398.
& REVESZ, L. (1953). /. nat. Cancer Inst. (in the press).
SCHREK, R. (1936). Amer. J. Path. 12, 525.
STRONG, L. C. (1926). Genetics, 11,294.