Abstract
Cancer cells should be seen not as exclusively a problem in cell proliferation, but rather as a problem combining the processes of proliferation and differentiation, hence the phrase introduced in 1968: "oncogeny is blocked ontogeny". Cancer tissues resemble foetal tissues in many ways but they differ from foetal tissue in being unable to "recapitulate the total programme leading to an orchestrated collection of organism-serving cells" that are programmed "to make the organ as adaptive as possible to the range of environmental variations in which it evolved". Citing the "Osgood Principle" from the 1950's, recent supporting evidence was described, in which the most mature differentiated cells exert positive and negative feedback upon the proliferation of their progenitor stem cells. Advanced examples in the haemopoietic series were drawn from the work of Sachs, Metcalf, Till and McCulloch, and Kurland and Moore. The blocked ontogeny hypothesis was further elaborated in the concept of "partially-blocked ontogeny", which is intended to describe a situation in which highly differentiated slowly growing tumours contain some cells which have left the proliferating pool to differentiate along the normal pathway, but are blocked somewhere short of the final organism-serving state, in harmony with earlier suggestions by Osgood, by Pierce, and by Sachs.
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Selected References
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- Abramson S., Miller R. G., Phillips R. A. The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J Exp Med. 1977 Jun 1;145(6):1567–1579. doi: 10.1084/jem.145.6.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alexander P. Foetal "antigens" in cancer. Nature. 1972 Jan 21;235(5334):137–140. doi: 10.1038/235137a0. [DOI] [PubMed] [Google Scholar]
- BECKER A. J., McCULLOCH E. A., TILL J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963 Feb 2;197:452–454. doi: 10.1038/197452a0. [DOI] [PubMed] [Google Scholar]
- BROOKE J. H., OSGOOD E. E. Long-term mixed cultures of human hemic cells, with granulocytic, lymphocytic, plasmocytic and erythrocytic series represented. Blood. 1959 Jul;14(7):803–815. [PubMed] [Google Scholar]
- Bradley T. R., Metcalf D. The growth of mouse bone marrow cells in vitro. Aust J Exp Biol Med Sci. 1966 Jun;44(3):287–299. doi: 10.1038/icb.1966.28. [DOI] [PubMed] [Google Scholar]
- Broxmeyer H. E., Baker F. L., Galbraith P. R. In vitro regulation of granulopoiesis in human leukemia: application of an assay for colony-inhibiting cells. Blood. 1976 Mar;47(3):389–402. [PubMed] [Google Scholar]
- Broxmeyer H. E., Moore M. A., Ralph P. Cell-free granulocyte colony inhibiting activity derived from human polymorphonuclear neutrophils. Exp Hematol. 1977 Mar;5(2):87–102. [PubMed] [Google Scholar]
- Butcher F. R., Potter V. R. Control of the adenosine 3',5'-monophosphate-adenyl cyclase system in the livers of developing rats. Cancer Res. 1972 Oct;32(10):2141–2147. [PubMed] [Google Scholar]
- Butcher F. R., Scott D. F., Potter V. R., Morris H. P. Endocrine control of cyclic adenosine 3',5'-monophosphate levels in several Morris hepatomas. Cancer Res. 1972 Oct;32(10):2135–2140. [PubMed] [Google Scholar]
- CRONE M., ITZHAKI S. ON THE RELATIVE FUNCTIONING OF THE PATHWAYS FOR FORMATION OF THYMIDINE NUCLEOTIDES IN THE REGNERATING LIVER AND SPLEEN OF THE RAT. Biochim Biophys Acta. 1965 Jan 11;95:8–13. doi: 10.1016/0005-2787(65)90205-4. [DOI] [PubMed] [Google Scholar]
- Cohen P. The subunit structure of rabbit-skeletal-muscle phosphorylase kinase, and the molecular basis of its activation reactions. Eur J Biochem. 1973 Apr 2;34(1):1–14. doi: 10.1111/j.1432-1033.1973.tb02721.x. [DOI] [PubMed] [Google Scholar]
- Fibach E., Hayashi M., Sachs L. Control of normal differentiation of myeloid leukemic cells to macrophages and granulocytes. Proc Natl Acad Sci U S A. 1973 Feb;70(2):343–346. doi: 10.1073/pnas.70.2.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorman R. R., Bunting S., Miller O. V. Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins. 1977 Mar;13(3):377–388. doi: 10.1016/0090-6980(77)90018-1. [DOI] [PubMed] [Google Scholar]
- Greengard P. Phosphorylated proteins as physiological effectors. Science. 1978 Jan 13;199(4325):146–152. doi: 10.1126/science.22932. [DOI] [PubMed] [Google Scholar]
- Gruber D. F., Zucali J. R., Mirand E. A. Identification of erythropoietin producing cells in fetal mouse liver cultures. Exp Hematol. 1977 Sep;5(5):392–398. [PubMed] [Google Scholar]
- HECHT L. I., POTTER V. R. Nucleic acid metabolism in regenerating rat liver. III. Intermediates in the synthesis of DNA pyrimidine nucleotides. Cancer Res. 1956 Nov;16(10 Pt 1):999–1004. [PubMed] [Google Scholar]
- Holliday R., Pugh J. E. DNA modification mechanisms and gene activity during development. Science. 1975 Jan 24;187(4173):226–232. [PubMed] [Google Scholar]
- Kelley D. S., Potter V. R. Amino acid concentrating ability of slowly growing autochthonous hepatomas and host livers. Biochem Biophys Res Commun. 1977 Mar 21;75(2):219–225. doi: 10.1016/0006-291x(77)91031-2. [DOI] [PubMed] [Google Scholar]
- Korn A. P., Henkelman R. M., Ottensmeyer F. P., Till J. E. Investigations of a stochastic model of haemopoiesis. Exp Hematol. 1973;1(6):362–375. [PubMed] [Google Scholar]
- Kroes R., Sontag J. M., Sell S., Williams G. M., Weisburger J. H. Elevated concentrations of serum alpha-fetoprotein in rats with chemically induced liver tumors. Cancer Res. 1975 May;35(5):1214–1217. [PubMed] [Google Scholar]
- Kurland J. I., Bockman R. S., Broxmeyer H. E., Moore M. A. Limitation of excessive myelopoiesis by the intrinsic modulation of macrophage-derived prostaglandin E. Science. 1978 Feb 3;199(4328):552–555. doi: 10.1126/science.304600. [DOI] [PubMed] [Google Scholar]
- Kurland J., Moore M. A. Modulation of hemopoiesis by prostaglandins. Exp Hematol. 1977 Sep;5(5):357–373. [PubMed] [Google Scholar]
- Laishes B. A., Roberts E., Farber E. In vitro measurement of carcinogen-resistant liver cells during hepatocarcinogenesis. Int J Cancer. 1978 Feb 15;21(2):186–193. doi: 10.1002/ijc.2910210210. [DOI] [PubMed] [Google Scholar]
- Leffert H. L., Koch K. S., Rubalcava B. Present paradoxes in the environmental control of hepatic proliferation. Cancer Res. 1976 Nov;36(11 Pt 2):4250–4255. [PubMed] [Google Scholar]
- Lotem J., Sachs L. Different blocks in the differentiation of myeloid leukemic cells. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3507–3511. doi: 10.1073/pnas.71.9.3507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MALEY F., MALEY G. F. Nucleotide interconversions. II. Elevation of deoxycytidylate deaminase and thymidylate synthetase in regenerating rat liver. J Biol Chem. 1960 Oct;235:2968–2970. [PubMed] [Google Scholar]
- MALEY F., MALEY G. F. Nucleotide interconversions. IV. Activities of deoxycytidylate deaminase and thymidylate synthetase in normal rat liver and hepatomas. Cancer Res. 1961 Nov;21:1421–1426. [PubMed] [Google Scholar]
- Maeda S., Sachs L. Control of normal differentiation of myeloid leukemic cells. XIII. Inducibility for some stages of differentiation by dimethylsulfoxide and its disassociation from inducibility by MGI. J Cell Physiol. 1978 Feb;94(2):181–185. doi: 10.1002/jcp.1040940207. [DOI] [PubMed] [Google Scholar]
- McCulloch E. A., Mak T. W., Price G. B., Till J. E. Organization and communication in populations of normal and leukemic hemopoietic cells. Biochim Biophys Acta. 1974 Dec 31;355(3-4):260–299. doi: 10.1016/0304-419x(74)90013-4. [DOI] [PubMed] [Google Scholar]
- Metcalf D. Regulation of granulocyte and monocyte-macrophage proliferation by colony stimulating factor (CSF): a review. Exp Hematol. 1973;1(4):185–201. [PubMed] [Google Scholar]
- OSGOOD E. E. A unifying concept of the etiology of the leukemias, lymphomas, and cancers. J Natl Cancer Inst. 1957 Feb;18(2):155–166. [PubMed] [Google Scholar]
- OSGOOD E. E., KRIPPAEHNE M. L. The gradient tissue culture method. Exp Cell Res. 1955 Aug;9(1):116–127. doi: 10.1016/0014-4827(55)90165-8. [DOI] [PubMed] [Google Scholar]
- PITOT H. C., POTTER V. R. An enzymic study on the cellular origin of the Dunning and the Novikoff hepatomas in the rat. Biochim Biophys Acta. 1960 Jun 3;40:537–539. doi: 10.1016/0006-3002(60)91398-6. [DOI] [PubMed] [Google Scholar]
- POTTER V. R. Guest editorial: a plea for formal support for study and reflection. Cancer Res. 1956 Sep;16(8):725–727. [PubMed] [Google Scholar]
- POTTER V. R. MODELS AS AIDS TO COMMUNICATION. Natl Cancer Inst Monogr. 1964 Apr;13:111–116. [PubMed] [Google Scholar]
- Pace-Asciak C. R. Oxidative biotransformations of arachidonic acid. Prostaglandins. 1977 May;13(5):811–817. doi: 10.1016/0090-6980(77)90211-8. [DOI] [PubMed] [Google Scholar]
- Pariza M. W., Butcher F. R., Kletzien R. F., Becker J. E., Potter V. R. Induction and decay of glucagon-induced amino acid transport in primary cultures of adult rat liver cells: paradoxical effects of cycloheximide and puromycin. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4511–4515. doi: 10.1073/pnas.73.12.4511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pitot H. C., Barsness L., Goldsworthy T., Kitagawa T. Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature. 1978 Feb 2;271(5644):456–458. doi: 10.1038/271456a0. [DOI] [PubMed] [Google Scholar]
- Pluznik D. H., Sachs L. The cloning of normal "mast" cells in tissue culture. J Cell Physiol. 1965 Dec;66(3):319–324. doi: 10.1002/jcp.1030660309. [DOI] [PubMed] [Google Scholar]
- Pluznik D. H., Sachs L. The induction of clones of normal mast cells by a substance from conditioned medium. Exp Cell Res. 1966 Oct;43(3):553–563. doi: 10.1016/0014-4827(66)90026-7. [DOI] [PubMed] [Google Scholar]
- Potter V. R. Recent trends in cancer biochemistry: the importance of studies on fetal tissue. Proc Can Cancer Conf. 1969;8:9–30. [PubMed] [Google Scholar]
- Reynolds R. D., Scott D. F., Potter V. R., Morris H. P. Induction of tyrosine aminotransferase and amino acid transport in Morris hepatomas and in adult and neonatal rat liver. Cancer Res. 1971 Nov;31(11):1580–1589. [PubMed] [Google Scholar]
- Scott D. F., Butcher F. R., Potter V. R., Morris H. P. Naturally occurring and induced levels of amino acid transport and tyrosine aminotransferase in rats bearing Morris hepatomas. Cancer Res. 1972 Oct;32(10):2127–2134. [PubMed] [Google Scholar]
- Sell S., Morris H. P. Relationship of rat alpha 1-fetoprotein to growth rate and chromosome composition of Morris hepatomas. Cancer Res. 1974 Jun;34(6):1413–1417. [PubMed] [Google Scholar]
- Sell S., Nichols M., Becker F. F., Leffert H. L. Hepatocyte proliferation and alpha 1-fetoprotein in pregnant, neonatal, and partially hepatectomized rats. Cancer Res. 1974 Apr;34(4):865–871. [PubMed] [Google Scholar]
- Senn J. S., McCulloch E. A., Till J. E. Comparison of colony-forming ability of normal and leukaemic human marrow in cell culture. Lancet. 1967 Sep 16;2(7516):597–598. doi: 10.1016/s0140-6736(67)90742-8. [DOI] [PubMed] [Google Scholar]
- Sneider T. W., Potter V. R. Deoxycytidylate deaminase and related enzymes of thymidine triphosphate metabolism in hepatomas and precancerous rat liver. Adv Enzyme Regul. 1969;7:375–394. doi: 10.1016/0065-2571(69)90029-6. [DOI] [PubMed] [Google Scholar]
- Sneider T. W., Potter V. R., Morris H. P. Enzymes of thymidine triphosphate synthesis in selected Morris hepatomas. Cancer Res. 1969 Jan;29(1):40–54. [PubMed] [Google Scholar]
- Stanley E. R., Hansen G., Woodcock J., Metcalf D. Colony stimulating factor and the regulation of granulopoiesis and macrophage production. Fed Proc. 1975 Dec;34(13):2272–2278. [PubMed] [Google Scholar]
- Steel G. G., Adams K., Barrett J. C. Analysis of the cell population kinetics of transplanted tumours of widely-differing growth rate. Br J Cancer. 1966 Dec;20(4):784–800. doi: 10.1038/bjc.1966.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stephenson J. R., Axelrad A. A., McLeod D. L., Shreeve M. M. Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro. Proc Natl Acad Sci U S A. 1971 Jul;68(7):1542–1546. doi: 10.1073/pnas.68.7.1542. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stöcker E., Heine W. D. Regeneration of liver parenchyma under normal and pathological conditions. Beitr Pathol. 1971;144(4):400–408. [PubMed] [Google Scholar]
- TILL J. E., MCCULLOCH E. A., SIMINOVITCH L. A STOCHASTIC MODEL OF STEM CELL PROLIFERATION, BASED ON THE GROWTH OF SPLEEN COLONY-FORMING CELLS. Proc Natl Acad Sci U S A. 1964 Jan;51:29–36. doi: 10.1073/pnas.51.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- TILL J. E., McCULLOCH E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961 Feb;14:213–222. [PubMed] [Google Scholar]
- Walker P. R., Potter V. R. Isozyme studies on adult, regenerating, precancerous and developing liver in relation to findings in hepatomas. Adv Enzyme Regul. 1972;10:339–364. doi: 10.1016/0065-2571(72)90022-2. [DOI] [PubMed] [Google Scholar]
- Watabe H., Hirai H., Sato H. -Fetoprotein in rats transplanted with ascites hepatoma. Gan. 1972 Apr;63(2):189–199. [PubMed] [Google Scholar]
- de Néchaud B., Uriel J. Antigènes cellulaires transitoires du foie de rat. I. Sécrétion et synthèse des protéines sériques foetospécifiques au cours du développement et de la régénération hépatiques. Int J Cancer. 1971 Jul 15;8(1):71–80. doi: 10.1002/ijc.2910080110. [DOI] [PubMed] [Google Scholar]
