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Oncodevelopmental Biology and Medicine, 4 (1983) 219-229 ARE THERE FACTORS PREVENTING CANCER DEVELOPMENT DURING

Department of Oncology of the Karolinska Institute and Hospital (Radiumhemmet) and the NationalBacteriological Laboratory, S-104 01 Stockholm, Sweden On the basis of the following literature observations, a hypothesis is advanced that the development of cancer is actively inhibited during embryonic life. Although the processes of cell differentiation andproliferation are - without comparison - most pronounced during embryonic life, cancer is rarely found in thenewborn and is seldom a cause of neonatal death or spontaneous abortion. Attempts to induce cancer inearly-stage animal embryos by irradiation or by transplacental chemical carcinogenesis have beenunsuccessful, even when exposed animals have been observed throughout their lifetime. After the period ofmajor organogenesis, however, the embryos become suceptible to carcinogenesis. In humans, the mostcommon embryonic tumors arise in tissues which have an unusually late ongoing development and are stillpartly immature at or shortly before birth. For many human embryonic tumors the survival rates are higher,and spontaneous regression more frequent, in younger children, i.e. prognosis is age-dependent. Thus,although cancer generally appears in tissues capable of proliferation and differentiation, induction ofmalignancy in the developmentally most active tissues seems to be beset with difficulty. One possibleexplanation for this paradox could be that cancer is controlled by the regulators influencing development,regulators that are most active during embryonic life.
The susceptibility of a tissue to cancer is related to its proliferative capacity [1]. Most human tumors arise in continuously regenerating tissues. In tissues with little or no capacity for renewal,such as adult neural and striated muscle tissue, cancer is rare. Sensitivity to carcinogens also seems tobe heightened during active tissue renewal [1]. The period of life in which the processes of cellulardifferentiation and proliferation are most intense is during the embryonic stage of intra-uterine life.
The embryonic period might, therefore, be expected to be active in the production of malignanttumors.
In this paper, I wish to put forward the view that cancer development is inhibited during this period of life. The hypothesis is based mainly on data culled from the literature.
0167-1618/83/0000- 0000/$03.00 1983 Elsevier Biomedical Press Low incidence of cancer in neonates Only 36.5 per million live-born infants are found to have cancer at birth or within the first 28 days of life [2] (Swedish Cancer Registry data for 1960-74, unpublished data). This should becompared to the 1-4% of live-born who have a diagnosable malformation at birth [3]. The deathrate from cancer within the first 28 days of life has been reported to be 7.6 per million live births[2]. In 3 000 neonatal autopsies, Wells [4] found only four tumors; all were neuroblastomas andthree of them, small nodules in the adrenal glands, were clearly not the cause of death.
A possible explanation for the low incidence of malignant tumors in neonates and infants is spontaneous abortion of the affected fetus. The literature contains few studies in which abortedembryos and fetuses have been examined thoroughly. However, in three reports ofabnormalities in a total of approximately 1,700 spontaneously aborted intact embryos andfetuses [5-7] only one possibly malignant tumor was mentioned, a sacrococcygeal teratoma in arelatively mature fetus. Also, mothers of children developing retinoblastoma (a hereditary orspontaneous embryonic tumor) do not have a higher than normal rate of miscarriage [83].
According to pedigrees shown in the same report, this is true also of mothers with severalretinoblastoma children. The precursor cells of rods and cones, from which retinoblastomasarise, are present from early in gestation [8], and would thus have been available fortransformation.
These circumstances argue against a high rate of malignant tumors arising in utero but disguised by spontaneous abortion of the fetus.
Another possible explanation for a low incidence of neonatal cancer is that cancer may be initiated in the embryo but become manifest only later in life. The results of attempts to inducecancer in animal embryos, however, do not support such an assumption.
In various experiments chemical carcinogens have been administered to pregnant rats and mice, and the offspring have been observed throughout their lifespan. The results appear to beuniform. When carcinogens have been administered before or during the period of majororganogenesis (days 6-12 in mouse and rat), the offspring have developed a high rate ofmalformations but very rarely tumors. However, after the completion of organogenesis,susceptibility to malformations declines and the fetuses rapidly become more at risk oftumor-induction with chemical carcinogens (for reviews, see Refs. 9-12).
Attempts to induce tumors in embryos by ionizing radiation have shown a similar time-response relationship. Mouse embryos were exposed to radiation (l0-80 r) on days 12-18of gestation and were killed 90 weeks later [13]. In mice irradiated on day 16 or day 18 therewas a heightened rate of lung, liver and kidney tumors. This increase was not seen in miceirradiated on day 12 or day 14. In another study [14], mouse embryos were irradiated (200 r) on day 12 or days 16-18 of gestation and the offspring wereobserved throughout their lifespan. Mice irradiated between days 16 and 18 of gestation had asmall but significant increase of lung, pituitary and ovarian tumors. Irradiation on day 12 wasassociated with a significant increase of congenital malformations, but with a decrease in tumorincidence, as compared to non-irradiated controls. This decrease could not be attributed toearlier death in non-neoplastic diseases in the irradiated group.
Rugh et al. [15] X-ray-irradiated (l00 r) mouse embryos at different timepoints of gestation and observed the mice throughout their lifespan. Although the authors report no significantincrease of tumors in prenatally-irradiated mice as compared to nonirradiated mice, their tableshows interesting changes in the susceptibility to oncogenesis during gestation. Mice that hadbeen exposed to irradiation up to day 13 of gestation developed tumors to a lesser extent thannon-irradiated controls (4.8 vs. 6%), whereas mice irradiated thereafter showed a markedincrease in their susceptibility to oncogenesis (10.4%). Brent [81] described different effects ofirradiation on rat and mouse embryos at various stages of gestation. No increase in tumorinduction was observed with irradiation on days 0-8 of gestation (rat). A questionable effect wasseen with irradiation on days 8-13. An effect on tumor induction was demonstrated withirradiation on days 13-22 of gestation.
In another study, X-ray-irradiation (25-200 r) of rat embryos on day 9 of gestation [16] was followed within 3 days by the appearance of tumor-like growths in and around the brains of allembryos irradiated with 100-200 r. Progressive atrophy of the tumors occurred thereafter. Atbirth most of the tumors had disappeared and the few nodules that remained were small, with noevidence of proliferative activity. Neither prenatal nor postnatal death could be attributed to thepresence of tumors.
Tumor transplantation in animal embryos has mostly been done to analyse the concept of tolerance. Donors and recipients, therefore, have usually been of different species. In one studya homologous tumor was transplanted into rat embryos at different stages of gestation [82]. Thetumor, a sarcoma, grew if the embryo had reached the last third of gestation. When the sarcomawas transplanted to younger embryos, the rats were born without tumors. It should be noted,however, that a high percentage of the embryos were aborted.
A study by Dawe et al. [17] indicates that virus-induced tumors in some cases also follow this pattern. They infected submandibular salivary glands from mouse embryos withpolyomavirus at different days of gestation. Subsequently they transplanted the glands to adultmice. Glands infected on day 12 of gestation did not develop tumors. Glands infected on day 13and later developed an increasing number of tumors. However, at all stages 60~ 70% of therecipient adult mice developed tumors in their salivary glands, which shows that the earlynon-tumorous glands also harbored the virus.
Jaenisch and Mintz [18] microinjected SV40 DNA into mouse blastocysts. 40% developed to term and became healthy adults without apparent tumors, although many carried the SV40genome. However, mouse embryos microinjected with Moloney leukemia virus at day 8 or 9 of gestation [19] developed a high rate ofleukemia at 4-6 months of age.
Time response relationships in possible prenatal carcinogenesis in man are difficult to elucidate. Some retrospective studies on the relationship between childhood leukemia andprenatal exposure to irradiation indicate that children with leukemia have a 25-75% higher rateof such exposure than do healthy controls [20-23]. Prospective studies [24, 25] - among those alO-year follow-up study of 1 292 children exposed in utero to irradiation from the atomic bombexplosions in Hiroshima and Nagasaki [26] - have not supported this connection, possiblybecause of the paucity of leukemia cases in these studies. Diamond et al. [25] found a higherincidence of leukemia among children prenatally exposed to irradiation in the white population,but a lower incidence among prenatally exposed in the black population.
Human organogenesis takes place mainly during the first 2 months of gestation. In a retrospective study based on interviews with mothers of leukemic children [27], a higherincidence of X-ray examinations was found particularly during the first trimester of pregnancy.
Another retrospective study [23] failed to confirm this observation, although it confirmed agenerally higher prenatal exposure to irradiation among leukemic children. The hospitals in thelatter study were selected for their accurate X-ray data, and the author, therefore, did not have torely on interviews. It has been argued that the mother of a leukemic child is more likely than themother of a healthy child to recall an X-ray examination during pregnancy [28]. In both of theseretrospective studies, however, the numbers of leukemic children were small. Graham et al. [29]found a similar excess of leukemia in children whose mothers reported diagnostic X-rayexposures as long as 10 years before conception of the child.
In a recent review, MacMahon [30] discussed the different reports concerning childhood cancer and prenatal irradiation and arrived at the conclusion that the question of an association isstill largely unresolved. Herbst et al. [31] noted that a very rare clear cell adenocarcinoma of thevagina was found mostly in adolescent girls whose mothers had been treated with stilbestrolduring pregnancy. Clear cell adenocarcinoma of the cervix was also associated with thisexposure [32]. Although most cancers were found in girls whose mothers had been treated withstilbestrol throughout pregnancy, it is noteworthy that in no case was treatment known to havebeen initiated after the 18th week of gestation [33]. The cancer incidence in the daughters ofstilbestrol-treated mothers was very low, estimated at 0.14-1.4/1 000 [33,34], whereas theincidence of other vaginal epithelial changes, such as adenosis, was as high as 34% [35]. Suchchanges were usually also found in association with the cancers. Furthermore, since nearly allcancer cases were girls in the age group 14-23, with a steep rise in incidence in early puberty,Herbst et al. [33] suggested that stilbestrol in itself is not a complete carcinogen, but that someother factor present during puberty acts to modify the pathological changes initiated by stil-bestrol.
In this context it is interesting to note that although maternal cancer occurs in one out of I 000 pregnancies, there are, in the world literature, only 30-40 reported cases of maternal cancermetastasizing to the product of conception [36-38].
Human embryonic tumors and maturity of affected organs at birth Embryonic tumors form a special group of tumors that in humans arise mainly during the first 4 years of life, but occasionally also later in life. They are comprised of immature tissuesnormally seen only during embryonic development. Although most human organogenesisoccurs during the first 2 months of gestation, some organs are still in a process of additivegenesis at the end of fetal life, and even for some time after birth. Willis [39] noted that thecommonest embryonic tumors in humans - Wilms' tumor, neuroblastoma, medulloblastoma andretinoblastoma - arise in organs with an unusually late ongoing development*.
This suggest that embryonic tumors in humans arise preferably at the end of gestation or after birth. If the embryonic environment is important for counteracting carcinogenesis,processes of additive genesis occurring late in fetal life may be less strictly controlled than thoseoccurring during the period of major organogenesis.
Spontaneous regression and prognosis of embryonic tumors at different ages A hypothetical mechanism preventing tumor development in the embryo may, as indicated, become increasingly less effective in the growing fetus and after birth. At autopsies of childrendead of other causes at ages younger than 3 months, several investigators found a high rate ofwhat they called 'neuroblastoma in situ' [40-42]. Adrenal lesions of this type were reportedfrom autopsies in approximately 1 in 250 children aged less than 3 months [40]. They were notfound in older children, which suggests spontaneous regression. The overall incidence ofneuroblastoma in childhood is only about 1 per 10 000. Similar findings of nephroblastoma insitu have been reported [41]. There * Wilms' tumor is a malignant tumor of the kidney derived from the metanephric blastema. In the normal kidney, new nephrons are formed as late as the last month of gestation, or possibly even after birth [39,80]. Neuroblastoma arises from primitive neuroblasts derived from the neural crest. The tumors are moreor less restricted to sympathetic ganglia and the adrenal medulla. In normal development, neuroblasts fromthe neural crest mature into sympathetic ganglia from the second month of gestation until after birth,possibly as late as the tenth year of life [39]. Remaining nodules of neuroblasts are often found in theadrenals up to 3 months of age (see neuroblastoma in situ) [43]. Medulloblastoma is a poorly differentiatedtumor of the brain. Multiplying medulloblasts of the brain persist up to 2 years after birth [39].
Retinoblastoma is formed from the precursor cells of rods and cones, arising in the nuclear layers of theretina. Rods and cones are the last cells to develop in the retina, around the seventh month of gestation. Inthe macular and fetal fissure areas, retinal development proceeds until the fourth postnatal month [8].
is, however, some controversy as to what extent these lesions can be regarded as true tumors[43]. They may simply represent embryonal rests.
In adults, spontaneous regression of cancer is extremely rare. However, it is relatively common in at least some types of embryonic tumors. Numerous cases of spontaneous regressionhave been reported for neuroblastoma. Of 29 cases of spontaneous regression of neuroblastomamost were infants, and the mean age was 3 months [44]; spontaneous regression ofneuroblastoma after the age of 2 years has seldom, if ever, been observed [45]. Also forretinoblastoma there have been several reports of spontaneous regression [46-49].
The prognosis for at least some types of embryonic tumors is most favorable in very young children. This applies to neuroblastoma [50-53], in which the survival rate in children less thanI year old has been stated as 35%, but of children diagnosed after 2 years of age only 5-6%survive [53]. Similar observations are found for sacrococcygeal teratoma [54, 55]. Donnellanand Swenson [54] found that of teratomas discovered before 2 months of age 10% weremalignant, whereas of those discovered after 2 months of age 92% were malignant. They alsofound that teratomas discovered at birth, but not operated on for more than 4 months, in mostcases remained benign. Some [56-58] but not all [52] investigators have found the same agespecific prognostic differences for Wilms' tumor. Paradoxically, the histologicallydifferentiated forms of nephroblastomas are most often found in the youngest patients [59]. Thereason for the contradictory findings concerning age-specific prognosis may be the controversyas to whether most of the kidney tumors observed in children below I year of age should beregarded as Wilms' tumors at all [59-62]. In general, kidney tumors known to be present atbirth or detected during the first 3 months of life pursue a more benign course than mostlater-appearing tumors [62-64].
Knudson's two-mutational hypothesis Children carrying a germ-line mutation predisposing for retinoblastoma can be born with a normal retina and not necessarily develop retinoblastoma (80-90% penetrance) [65,83],although all retina cells carry the mutation. Knudson and co-workers [65-67] thereforesuggested that an extra, somatic mutation, beside the germ· line mutation, is required for thedevelopment of cancer. Another explanation would be that the development of retinoblastoma isactively inhibited during embryonic, fetal and possibly even during post-natal life and, ifembryonic precursor cells still remain, malignancy develops when this control is ovt'lHidden,rath",r than through an extra mutation*.
* Knudson further argues that the development of the spontaneous, non-germ line-transmitted form of retinoblastoma likewise requires two mutations. Most cases of bilateral hereditary retinoblastoma arediagnosed during the first year of life, whereas spontaneous, non-hereditary cases of retinoblastoma areevenly distributed during the fust 3 years of life. This delay for non-hereditary cases Knudson Development vs. neoplasia - inseparable or incompatible? We thus end up with the curious picture, that, although cancer only arises in tissues capable of developmental processes, it seems that during the most developmentally active period in life,the embryonic period, cancer induction is unlikely. One possible explanation for this paradoxcould be that cancer is a developmental deviation and as such is controlled by those regulatorsinfluencing development, regulators that are most active during embryonic life.
One of the most thoroughly investigated - and one of the most elusive - processes in embryonicdevelopment is the process of induction, the process by which one tissue induces another todifferentiate in a certain direction. Since Spemann and Mangold [68] showed that the blastoporelip of the amphibian gastrula induces formation of the embryonic axis, secondary inductivetussues have been detected throughout fetal development (for reviews, see Refs. 69-71).
Induction usually requires fairly close apposition between the inducing and the reactive tissues,but since, in some cases, induction has been shown to depend on diffusable substances [72-74],inductor signals are probably biochemical. All the same, attempts to isolate and characterizeinductors biochemically have as of yet been largely unsuccessful. The reason may be that manynon-specifically acting compounds can mimic the action of some inductive tissues. Inductors areinteresting in this context, since they are the initiators and probably controllers of developmentand cancer most likely arises as a result of uncontrolled developmental deviations. The modes ofinductor action appear to have some similarities with the few known modes of spontaneousregression of tumors. Cell death, but also cytodifferentiation to benign ganglioneuroma cells,can be seen during regression of neuroblastoma [44]. Necrotic or calcified tumor cells are foundfollowing spontaneous regression of retinoblastoma [47,49]. Tumors in amphibia, likewise, canregress either by cell differentiation or by cell death [75-77]. Death or differentiation of cellsseem, therefore, to be the known modes of spontaneous regression of malignant tumors.
Inductors induce differentiation, but can probably also cause cell death [78, 79]. Although thesimilarities may be coincidental, a closer investigation of the effects of inductive tissues ontumor cells might be rewarding.
attributes to the necessity for two somatic mutations, Le. one more somatic mutation than for hereditarycases. However, these data do not express the same thing in both populations. The age-distribution ofspontaneous cases is a true expression of the risk of developing a tumor at different ages in the generalpopulation. The age-distribution of hereditary germ-line transmitted cases is an expression of the earliestdiagnosis of tumors in a group of people of which the majority will continue developing multiple tumors ifuntreated.
I would like to thank Drs. Eduardo Mitrani and Fanny Doljanski, Jerusalem, and Drs. Britta Wahren and Jerzy Einhorn, Stockholm, for helpful advice.
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