THE BIOLOGY OF TERATOMAS
9
derived by differentiation of pluripotent embryonal stem cells. Kleinsmith and Pierce (1964) provided further direct indisputable evidence.
They designed an elegant in vivo cloning technique in order to test the
hypothesis that embryonal carcinoma cells are pluripotent stem cells of
a transplanted teratoma of strain 129 mice. They dissociated cells of
small embryoid bodies and transplanted single cells directly into mice.
They performed over 1700 single cell grafts and obtained 43 tumors
composed of as many as 14 well-differentiated tissues in addition to
embryonal carcinoma. These results demonstrate conclusively that embryonal stem cells of teratomas are pluripotent. Single embryonal carcinoma cells are multipotential and capable of producing all the somatic
tissues of a well-differentiated teratocarcinoma. Embryonal carcinoma
cells have the capacity to differentiate into somatic, adult-appearing
tissues, and since these tissues have been shown to be benign, it is
obvious that the neoplastic stem cells can differentiate into benign,
normal-appearing cells. If cancer cells are not irreversibly changed and
can differentiate, it would seem appropriate that cancer therapy, rather
than attempting to kill or extirpate all the cells of a tumor, might attempt to direct the spontaneously occurring differentiation toward the
production of benign tissues. Peyron (1939) observed that undifferentiated cells of a human teratoma invaded the walls of the spermatic veins
and then formed free-floating embryoid bodies in the blood. He concluded
that the neoplastic stem cells retained the embryonic potential of the egg.
VI. Progression
It has been shown that the stem cells of teratomas are pluripotent.
However, the histological composition of teratomas is a direct reflection
of the embryonic potency of the stem cell, which can change. According
to Foulds (1954), "Progression occurs frequently in transplanted tumors
probably because transplantation prolongs indefinitely the time and
opportunities available for it and also, by selective action, favors the
predominance of the changed cells which, at first, may constitute a small
fraction of the whole tumor." Using morphological criteria, some of the
evolutionary fates exhibited by transplanted strain 129 teratomas have
been classified into seven histogenetic categories ranging in complexity
from a single-cell type to highly pleomorphic growths (Stevens, 1958).
Transplanted teratomas can progress in such a manner that a singlecell type prevails at the expense of all other tissues. Pierce and Dixon
(1959a,b) and Pierce and Verney (1961) studied the conversion of a
transplanted teratoma of strain 129 origin to the ascites form and found
a simplification of the tumor to a yolk sac carcinoma. Originally it was
a pleomorphic tumor, but with increased numbers of intraperitoneal
transplant generations, a single cell type eventually outgrew all other
9
derived by differentiation of pluripotent embryonal stem cells. Kleinsmith and Pierce (1964) provided further direct indisputable evidence.
They designed an elegant in vivo cloning technique in order to test the
hypothesis that embryonal carcinoma cells are pluripotent stem cells of
a transplanted teratoma of strain 129 mice. They dissociated cells of
small embryoid bodies and transplanted single cells directly into mice.
They performed over 1700 single cell grafts and obtained 43 tumors
composed of as many as 14 well-differentiated tissues in addition to
embryonal carcinoma. These results demonstrate conclusively that embryonal stem cells of teratomas are pluripotent. Single embryonal carcinoma cells are multipotential and capable of producing all the somatic
tissues of a well-differentiated teratocarcinoma. Embryonal carcinoma
cells have the capacity to differentiate into somatic, adult-appearing
tissues, and since these tissues have been shown to be benign, it is
obvious that the neoplastic stem cells can differentiate into benign,
normal-appearing cells. If cancer cells are not irreversibly changed and
can differentiate, it would seem appropriate that cancer therapy, rather
than attempting to kill or extirpate all the cells of a tumor, might attempt to direct the spontaneously occurring differentiation toward the
production of benign tissues. Peyron (1939) observed that undifferentiated cells of a human teratoma invaded the walls of the spermatic veins
and then formed free-floating embryoid bodies in the blood. He concluded
that the neoplastic stem cells retained the embryonic potential of the egg.
VI. Progression
It has been shown that the stem cells of teratomas are pluripotent.
However, the histological composition of teratomas is a direct reflection
of the embryonic potency of the stem cell, which can change. According
to Foulds (1954), "Progression occurs frequently in transplanted tumors
probably because transplantation prolongs indefinitely the time and
opportunities available for it and also, by selective action, favors the
predominance of the changed cells which, at first, may constitute a small
fraction of the whole tumor." Using morphological criteria, some of the
evolutionary fates exhibited by transplanted strain 129 teratomas have
been classified into seven histogenetic categories ranging in complexity
from a single-cell type to highly pleomorphic growths (Stevens, 1958).
Transplanted teratomas can progress in such a manner that a singlecell type prevails at the expense of all other tissues. Pierce and Dixon
(1959a,b) and Pierce and Verney (1961) studied the conversion of a
transplanted teratoma of strain 129 origin to the ascites form and found
a simplification of the tumor to a yolk sac carcinoma. Originally it was
a pleomorphic tumor, but with increased numbers of intraperitoneal
transplant generations, a single cell type eventually outgrew all other