Coarse powders of acid-insoluble matrix of diaphysis and calvarial parietal bone rapidly and consistently transformed fibroblasts into masses of cartilage and bone containing hemopoietic marrow. The transformant was encapsulated by fibroblasts within 24 hr to form a plaque. Transformation was restricted to the central thicknesses of the plaque. Under the stated conditions the alteration of the phenotype, fibroblast to chondroblast, was an unstable transformation, whereas the phenotype change, fibroblast to osteoblast, was stable. The transformation occurred on a rigid timetable of sequences. Measurements of alkaline phosphatase activity and incorporation of radioactive sulfate, phosphate, and calcium were sensitive and quantitative assays for the appearance of the transformed products, cartilage and bone.The aim of this work was to develop reproducible, rapid, and quantitative methods (a) to induce the fibroblast-chondroblast-osteoblast transformation, and (b) to differentiate the major links in the biological sequence.Long after embryonic differentiation has ceased, fibroblasts still retain the singular potential of transformability (1) into cells of other sorts, an attribute that persists throughout the life of the animal. The visible and biochemical characters are altered so profoundly that we refer to the phenomenon as transformation (2). Approximation of transformant (TF) and competent responding fibroblasts (R) initiates a series of interconnected biological reactions that yield products which we shall designate: Pi, cartilage; P2, bone; P3, hemopoietic bone marrow.Urist discovered that intramuscular transplants of lyophilized segments of demineralized bone (3) or tooth (4) transform fibroblasts to form bone by endochondral ossification in 24-26 days. Chondrogenesis occurs in cell culture (5), as well as in vivo. There are two convenient enzyme assays to study the transformation of the fibroblasts of fascia into cartilage, followed by bone: a. activity of alkaline phosphatase (6); b. determination of the quotient of activity: lactate dehydrogenase/malate dehydrogenase (7).The present experiments consisted of allogeneic transplantation of a weighed amount of sized desiccated powder of acidinsoluble bone matrix to the subcutaneous tissues of young rats. This technique provided a simple, quick, and standardized method to induce the transformation. The biochemical sequences of cartilage and bone in the chain reaction were analyzed by measurement of enzyme activities and incorporation of isotopes in the transformation products.
MATERIALS AND METHODSPreparation of Transformant. Manufacture and final storage of all preparations were at room temperature (about 250).When liquids of any sort were used, the biological materials were immersed in the fluids in a jar with a magnetic stirrer, where they were propelled around the vortex created by vigorous stirring.Large adult rats of both sexes were used as donors throughout. The rats were decapitated. Parietal bones of the calvarium were removed and fragmented. ...
It has been known for some years that certain aromatic hydrocarbons induce mammary tumors in some species of rodents. This paper is concerned with the conditions required for the rapid and invariable induction of mammary cancer in the rat by administering 3-methylcholanthrene v/a the gastro-intestinal tract and with some of the functional characteristics of the tumors which were evoked. During the experiments, a novel observation was made when it was found that the majority of the induced carcinomas of the breast are hormonedependent, since they regress when the supporting internal secretions are removed. Whilst the concept of hormone dependence has been established in human mammary cancer, this property has not been recognized previously in mammary carcinomas of laboratory animals.Tumors develop preferentially in the mammary gland of certain strains of mice and rats following the remote administration of some aromatic compounds; the local application of such carcinogens to the region of the mammary gland is unnecessary for the production of breast tumors. This effect was discovered by Lacassagne (I) who found that the administration of estrone induced mammary cancer in mice of the R I I I strain.But mammary cancer can be evoked by compounds without hormonal activity; amongst these carcinogens are 3-methylcholanthrene (2), 2-acetylaminofluorene (2-AAF) 1 (3, 4), and 7,12-dimethylbenz-a-anthracene (DMBA) ~ (5). This remarkable activity of non-estrogenic carcinogens in inducing cancers of the mammary glands was first observed by Maisin and Coolen (2) who painted the skin of mice with 3-methylcholanthrene and found that, in addition to production of skin cancer, carcinoma of the mammary gland developed in high incidence. Mammary tumors have also been elicited with great frequency after the repeated instillation of 3-methylcholanthrene in the mouth (6), nares (7), or stomach (8) of the mouse or rat. Repeated intravenous injections of DMBA evoked similar tumors (5).
Cancer is not necessarily autonomous and intrinsically self-perpetuating. Its growth can be sustained and propagated by hormonal function in the host which is not unusual in kind or exaggerated in rate but which is operating at normal or even subnormal levels. Hormones, or synthetic substances inducing physiologic effects similar thereto, are of crucial significance for survival of several kinds of hormone-responsive cancers in man and animals. Opposite sorts of change of the hormonal status can induce regression and, in some instances, cure such cancers. These modifications are deprivation of essential hormones and hormone interference by giving large amounts of critical compounds. The control of cancer by endocrine methods can be described in three propositions: (i) Some types of cancer cells differ in a cardinal way from the cells from which they arose in their response to change in their hormonal environment. (ii) Certain cancers are hormone-dependent and these cells die when supporting hormones are eliminated. (iii) Certain cancers succumb when large amounts of hormones are administered.
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