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The placenta as a substitute for cancerous models
Medical Hypotheses 17: 299-304, 19E.5
THE PLACENTA AS A SUBSTITUTE
FOR CANCEROUS MODELS
A. Hoekstra and J.D.M. Herscheid Radionuclide Centre, Free University, De Boelelaan 1083A, 1007 MC Amsterdam, The Netherlands
ABSTRACT The tissue distribution of various radiopharmaceuticals was investigated in Rhabdomyosarcoma-bearingrats and in pregnant rats during the period of rapid foetal and placental growth (days 17-19 of pregnancy). The results indicate that with the radiopharmaceuticals tested the uptake in placental tissue followed closely the data obtained with tumour tissue in Rhabdomyosarcoma-bearingrats (1). We describe here the parallels between cell replication in the placenta and in malignant tumours and propose that the placenta merits more attention in the field of biomedical research. INTRODUCTION An animal model has an inherited, naturally acquired, or experimentally induced pathological process or condition that closely resembles an abnormality in man (2). Such models provide an important and often a key facet to meaningful investigations of the mechanism of disease. Understanding of certain diseases has been hampered significantly by the unavailability of appropriate spontaneous or induced disease models. Examples of such deficiencies include models of cystic fibrosis, spontaneous arterial thrombosis, cervical cancer, and certain age-associated diseases such as senile osteoporosis. The search for spontaneous models of these and many other diseases and the improvement of existing models are important goals of laboratory animal science, and consequently of biomedical research.
299
The aim of this paper is to draw attention to the developing placenta as a potential model for studying malignancy. Malignant neoplasms are characterized by a greater degree of anaplasia than benign tumours and have the properties of invasion and metastasis, which seems clear enough. But the placenta outstrips most malignant tumours in its normal rate of growth, and the normal trophoblast not only invades maternal tissue but also metastasises, to a limited extent, into lung and brain tissue (3). The parallels between cell replication in utero (placenta) and in malignant tumours are closer in these respects than is commonly recognised. In summary, placental growth has shown that the behaviour of the placenta has more similarities to cancer than differences, especially in the early stages of its development (3). Taking the similarities first, - No stimulus is required for cell division in the placenta, which replicates autonomously beyond the needs of tissue replacement; - The placenta invades at the site of implantation and infiltrates locally; - The placenta produces lytic substances (proteases) during implantation and invasion (3,4); - The placenta is tolerated by the maternal host, and there is no sustained inflammatory response to implantation of the blastocyst or to trophoblastic invasion (3,5); - The placenta induces an adaptive circulatory response in the maternal host tissues (6,7); - Qualitative biochemical similarities can be demonstrated, for example plasminogen activator activity during invasion (4,8), histaminase activity (q,lO), which could limit the inflammatory response to histamine released during the invasive phase of placental growth, and the production of alkaline phosphatase isoenzymes and many peptide hormones (3); - The metabolism of protein in the placenta is largely governed by the demands of rapid growth (11). As for the differences, - Placental growth is limited in extent and duration even outside the uterus; - The placenta does not metastasise in the true sense of the term; - The placenta is shed after a defined period in balance with the maternal host. These differences, however, in no way detract us from the use of the placenta as a model for studying abnormal cell replication or cancer, but enables us to ask what the differences depend on.
300
40
36
r
-o-
placenta/muscle
-o-
tumow/muscle
32 -
26 -
24-
t, I P!: (o
20-
16 -
12 _jj 6
4-
t
Fig. 1. Placenta/muscle and tumour/muscle ratios (mean 2 S.D.) of 67 Ga-citrate (CT),67Ga-ferrichrome (FC), 1251-bleomycin-A2 (blm-A2), 57Co-bleomycin-demethyl-A~(blm-d-A~),57Co-bleomycin14
B2 (blm-B2), 5-fluoro-(6- Cl-uracil (FU), 3',5',7-(3H)-methotrexate (MTX) and (G3H)-vinblastine (VBL), respectively.
301
Because of the placenta’s capacity for rapid cell replication, its its invasiveness and its mosaic of metabolic acticontinuous growth, which does not differ appreciably from a cancerous tumour, we vities, suggest that the placenta is potentially an important tool for evaluating chemical compounds on tumour-localizing properties. For this purpose, tissue distribution values for a variety of radiopharmaceuticals were determined in Rhabdomyosarcoma-bearing rats and in pregnant rats during the period of rapid placental growth. Tumour-bearing rats (Wag/Rij) as well as rats at day 17-19 of pregnani.v. into the dorsal tail vein with a standard volucy, were injected me of 0.5 ml of the vehicle (saline 0.9%) containing 5 uCi of the radiopharmaceutical. All animals were sacrificed under ether anesthesia by cervical dislocation 4 h after injection of the radiopharmaceutical, various tissues removed, weighed, and measured for radioactivity (I). As shown in Fig.1, the placenta-to-muscle ratios, calculated for each radiopharmaceutical, followed closely the tumour-to-muscle ratios (linear correlation regression of r = 0.97), which parameter might be of relevance considering the tumour tissue type used in this study. CONCLUSIONS In conclusion, the preliminary results obtained with various radiopharmaceuticals, using placental and tumour tissue from pregnant and Rhabdomyosarcoma-bearing rats, respectively, suggest that comparisons of prescreening of new and potentially useful tumour-localizing radiopharmaceuticals can be made. Comparative parallels between cancer and foetal cells considering common features from the morphological as well as the biochemical and antigenic point of view were supposed earlier (12,13). However, we have seen little or no accumulation of radiopharmaceuticals in foetal tissue, suggesting that such an approach is not suitable for prescreening of potentially tumour-localizing radiopharmaceuticals. From our data and the literature cited above, we propose that the placenta merits more attention in the field of biomedical research. Moreover, the placenta can also be utilized for investigating the regulation of genetic expression and the operation of gene repressors might lead to the breaking of the DNA code of (31, which application cancer.
302
REFERENCES
Hoekstra A, Vos C M, Herscheid J D M. The developing placenta in selecting potential radiopharmaceuticals on tumour-localizing properties : A simple in vivo pre-screening model. Nuklearmedizin 23, 19, 1984. 2. Wessler S. Animals Models of Thrombosis and Hemorrhagic Diseases. DHEW Pub. No. NIH 76-982, U.S. Dept. of Health, Education and Welfare, Washington, p.203, 1976. 3. Beaconsfield P, Villee C. Placenta a neglected experimental Pergamon Press, New York, 1979.
animal.
,sr,crmanM I, Strickland S, Reich E. Differentiation of early mouse enoryonic and teratocarcinoma cells in vitro: plasminogen activator rjroduction. Cancer Res. 36, 4208, 1976. 5.
Fauve R M, Hevin R, Jacob H, Gaillard J A, Jacob B F. Anti-inflammatory effects of murine malignant cells. Proc. Nat. Acad. Sci. 71, 4052, 1974.
6. Pijnenborg R, Robertson W B, Brosens I. The arterial migration of trophoblast in the uterus of the golden hamster. J. Reprod. Fert. 40, 269, 1974. 7. Brosens I, Robertson W B, Dixon H G. The physiological the vessels of the placental bed to normal pregnancy. J. Path. Bact. 93, 569, 1967.
respons of
8. Ossowski L, Quigley J P, Kellerman G M, Reich E. Fibrinolysis associated with oncogenic transformation; requirement of plasminogen for correlated changes in cellular morphology, colony formation in agar and cell migration. J. Exp. Med. 138, 1056, 1973. 9.
Southern A L, Kobayashi Y, Bremner P, Weingold A B. Diamine oxidase activity in human material and fetal plasma and tissues and parturition. J. Appl. Physiol. 20, 1048, 1965.
0.
Buffoni F. Histaminases and related amino oxidases. Pharmacol. Rev. 118, 1163, 1966. Winick M, Noble A. Quantitative changes in ribonuclear acids and protein during normal growth of rat placenta. Nature 212, 34, 1966.
303
12. Uriel J. Retrodifferentiation and the fetal patterns of gene expression in cancer. Adv. Cancer Res. 29, 127, 1979. 13.
Moro R, Hueguerot C, Vercelli-Retta J, Fielitz W, L6pez J J, Rota R. The use of radioiodinated alpha-fetoprotein for the scintigraphic detection of mouse mammary carcinomas. Nucl. Med. Commun. 5, 5, 1984.
304
THE PLACENTA AS A SUBSTITUTE
FOR CANCEROUS MODELS
A. Hoekstra and J.D.M. Herscheid Radionuclide Centre, Free University, De Boelelaan 1083A, 1007 MC Amsterdam, The Netherlands
ABSTRACT The tissue distribution of various radiopharmaceuticals was investigated in Rhabdomyosarcoma-bearingrats and in pregnant rats during the period of rapid foetal and placental growth (days 17-19 of pregnancy). The results indicate that with the radiopharmaceuticals tested the uptake in placental tissue followed closely the data obtained with tumour tissue in Rhabdomyosarcoma-bearingrats (1). We describe here the parallels between cell replication in the placenta and in malignant tumours and propose that the placenta merits more attention in the field of biomedical research. INTRODUCTION An animal model has an inherited, naturally acquired, or experimentally induced pathological process or condition that closely resembles an abnormality in man (2). Such models provide an important and often a key facet to meaningful investigations of the mechanism of disease. Understanding of certain diseases has been hampered significantly by the unavailability of appropriate spontaneous or induced disease models. Examples of such deficiencies include models of cystic fibrosis, spontaneous arterial thrombosis, cervical cancer, and certain age-associated diseases such as senile osteoporosis. The search for spontaneous models of these and many other diseases and the improvement of existing models are important goals of laboratory animal science, and consequently of biomedical research.
299
The aim of this paper is to draw attention to the developing placenta as a potential model for studying malignancy. Malignant neoplasms are characterized by a greater degree of anaplasia than benign tumours and have the properties of invasion and metastasis, which seems clear enough. But the placenta outstrips most malignant tumours in its normal rate of growth, and the normal trophoblast not only invades maternal tissue but also metastasises, to a limited extent, into lung and brain tissue (3). The parallels between cell replication in utero (placenta) and in malignant tumours are closer in these respects than is commonly recognised. In summary, placental growth has shown that the behaviour of the placenta has more similarities to cancer than differences, especially in the early stages of its development (3). Taking the similarities first, - No stimulus is required for cell division in the placenta, which replicates autonomously beyond the needs of tissue replacement; - The placenta invades at the site of implantation and infiltrates locally; - The placenta produces lytic substances (proteases) during implantation and invasion (3,4); - The placenta is tolerated by the maternal host, and there is no sustained inflammatory response to implantation of the blastocyst or to trophoblastic invasion (3,5); - The placenta induces an adaptive circulatory response in the maternal host tissues (6,7); - Qualitative biochemical similarities can be demonstrated, for example plasminogen activator activity during invasion (4,8), histaminase activity (q,lO), which could limit the inflammatory response to histamine released during the invasive phase of placental growth, and the production of alkaline phosphatase isoenzymes and many peptide hormones (3); - The metabolism of protein in the placenta is largely governed by the demands of rapid growth (11). As for the differences, - Placental growth is limited in extent and duration even outside the uterus; - The placenta does not metastasise in the true sense of the term; - The placenta is shed after a defined period in balance with the maternal host. These differences, however, in no way detract us from the use of the placenta as a model for studying abnormal cell replication or cancer, but enables us to ask what the differences depend on.
300
40
36
r
-o-
placenta/muscle
-o-
tumow/muscle
32 -
26 -
24-
t, I P!: (o
20-
16 -
12 _jj 6
4-
t
Fig. 1. Placenta/muscle and tumour/muscle ratios (mean 2 S.D.) of 67 Ga-citrate (CT),67Ga-ferrichrome (FC), 1251-bleomycin-A2 (blm-A2), 57Co-bleomycin-demethyl-A~(blm-d-A~),57Co-bleomycin14
B2 (blm-B2), 5-fluoro-(6- Cl-uracil (FU), 3',5',7-(3H)-methotrexate (MTX) and (G3H)-vinblastine (VBL), respectively.
301
Because of the placenta’s capacity for rapid cell replication, its its invasiveness and its mosaic of metabolic acticontinuous growth, which does not differ appreciably from a cancerous tumour, we vities, suggest that the placenta is potentially an important tool for evaluating chemical compounds on tumour-localizing properties. For this purpose, tissue distribution values for a variety of radiopharmaceuticals were determined in Rhabdomyosarcoma-bearing rats and in pregnant rats during the period of rapid placental growth. Tumour-bearing rats (Wag/Rij) as well as rats at day 17-19 of pregnani.v. into the dorsal tail vein with a standard volucy, were injected me of 0.5 ml of the vehicle (saline 0.9%) containing 5 uCi of the radiopharmaceutical. All animals were sacrificed under ether anesthesia by cervical dislocation 4 h after injection of the radiopharmaceutical, various tissues removed, weighed, and measured for radioactivity (I). As shown in Fig.1, the placenta-to-muscle ratios, calculated for each radiopharmaceutical, followed closely the tumour-to-muscle ratios (linear correlation regression of r = 0.97), which parameter might be of relevance considering the tumour tissue type used in this study. CONCLUSIONS In conclusion, the preliminary results obtained with various radiopharmaceuticals, using placental and tumour tissue from pregnant and Rhabdomyosarcoma-bearing rats, respectively, suggest that comparisons of prescreening of new and potentially useful tumour-localizing radiopharmaceuticals can be made. Comparative parallels between cancer and foetal cells considering common features from the morphological as well as the biochemical and antigenic point of view were supposed earlier (12,13). However, we have seen little or no accumulation of radiopharmaceuticals in foetal tissue, suggesting that such an approach is not suitable for prescreening of potentially tumour-localizing radiopharmaceuticals. From our data and the literature cited above, we propose that the placenta merits more attention in the field of biomedical research. Moreover, the placenta can also be utilized for investigating the regulation of genetic expression and the operation of gene repressors might lead to the breaking of the DNA code of (31, which application cancer.
302
REFERENCES
Hoekstra A, Vos C M, Herscheid J D M. The developing placenta in selecting potential radiopharmaceuticals on tumour-localizing properties : A simple in vivo pre-screening model. Nuklearmedizin 23, 19, 1984. 2. Wessler S. Animals Models of Thrombosis and Hemorrhagic Diseases. DHEW Pub. No. NIH 76-982, U.S. Dept. of Health, Education and Welfare, Washington, p.203, 1976. 3. Beaconsfield P, Villee C. Placenta a neglected experimental Pergamon Press, New York, 1979.
animal.
,sr,crmanM I, Strickland S, Reich E. Differentiation of early mouse enoryonic and teratocarcinoma cells in vitro: plasminogen activator rjroduction. Cancer Res. 36, 4208, 1976. 5.
Fauve R M, Hevin R, Jacob H, Gaillard J A, Jacob B F. Anti-inflammatory effects of murine malignant cells. Proc. Nat. Acad. Sci. 71, 4052, 1974.
6. Pijnenborg R, Robertson W B, Brosens I. The arterial migration of trophoblast in the uterus of the golden hamster. J. Reprod. Fert. 40, 269, 1974. 7. Brosens I, Robertson W B, Dixon H G. The physiological the vessels of the placental bed to normal pregnancy. J. Path. Bact. 93, 569, 1967.
respons of
8. Ossowski L, Quigley J P, Kellerman G M, Reich E. Fibrinolysis associated with oncogenic transformation; requirement of plasminogen for correlated changes in cellular morphology, colony formation in agar and cell migration. J. Exp. Med. 138, 1056, 1973. 9.
Southern A L, Kobayashi Y, Bremner P, Weingold A B. Diamine oxidase activity in human material and fetal plasma and tissues and parturition. J. Appl. Physiol. 20, 1048, 1965.
0.
Buffoni F. Histaminases and related amino oxidases. Pharmacol. Rev. 118, 1163, 1966. Winick M, Noble A. Quantitative changes in ribonuclear acids and protein during normal growth of rat placenta. Nature 212, 34, 1966.
303
12. Uriel J. Retrodifferentiation and the fetal patterns of gene expression in cancer. Adv. Cancer Res. 29, 127, 1979. 13.
Moro R, Hueguerot C, Vercelli-Retta J, Fielitz W, L6pez J J, Rota R. The use of radioiodinated alpha-fetoprotein for the scintigraphic detection of mouse mammary carcinomas. Nucl. Med. Commun. 5, 5, 1984.
304