Biomedical subjects
M F Woodruff
Publications and source records attributed to M F Woodruff.
The role of immunology in the development of clinical transplantation.
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Tumor clonality and its biological significance.
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Oligoclonal tumours.
Tumours are commonly classified as monoclonal or polyclonal. The question of how many clones are present in a polyclonal tumour is seldom asked; it is important, however, because the answer may show whether or not clones arise and develop independently, and whether the number of clones in tumours of a particular kind tends to increase or decrease with time. We have used two procedures to assess the clonality of chemically-induced murine fibrosarcomas, one based on the heterozygosity of the tumour hosts for an X-linked marker, the other on the expression of tumour-associated transplantation antigens (TATA) by the tumours. As we have reported previously, many of these tumours are pleoclonal. Evidence now presented suggests that the clones do not develop independently and that many of the tumours are biclonal.
The cytolytic and regulatory role of natural killer cells in experimental neoplasia.
NK cells are defined here as cells, other than macrophages and polymorphonuclear leucocytes, from non-immunized animals (or humans) which are cytotoxic for neoplastic and non-neoplastic targets in the absence of specific antibody. Though not requiring antibody, they may function as K cells in ADCC. This definition includes cells activated nonspecifically by such agents as IFN and IL-2. Murine NK cells may be subdivided into two types by differences in the kinetics of target-cell lysis. Those we label Type 1 correspond roughly to what others have called NKA, NKL or simply NK cells; those of Type 2 to NKB, NKS and NC cells. Type 1 cells express various antigens, including NK-1, Thy-1 (50%), Ly-1 (25%), Qa-3, Qa-4, Qa-5, Ly-5, Ly-6, Ly-10, Ly-11 and asialo-GM1, not expressed by Type 2 cells, whereas Mac-1 may be expressed by both types. At least some NK cells appear to be pre-thymic cells which, in the presence of a thymus, can differentiate into T cells. The level of NK activity is influenced by the age and genetic background of the mouse, the organ from which the cells are obtained, and a variety of experimental manipulations. Type 1 activity is increased by IFN and IL-2; Type 2 activity by IL-3. IFN appears to be concerned in the development of spontaneous NK activity in young mice. Many experiments have shown that NK cells may inhibit the growth of tumours which are sensitive to NK cells of the same type in vitro. Inhibitory cells which suppress NK activity may play an important regulatory role in vivo. There is still uncertainty about how NK cells recognize their targets. Possibilities discussed are: (1) specific interacting molecules; (2) more diffuse properties of target cell membranes; (3) absence of MHC-coded self-recognition markers. Certainly, the presence of a Class 1 MHC molecule is not necessary. NK killing appears to be mediated by cytotoxins released by NK cells. In vivo, NK cells contribute to limiting the development of transplanted and primary tumours, and metastasis from established tumours. NK cells seem well qualified to act as a first-line defence against neoplasia, and may kill cells not killed by T cells. Transfer of NK cells may be of value in the treatment of cancer.
The effect of passage in vivo and in vitro on the properties of murine fibrosarcomas: III. Cell surface molecules and production of growth factors.
Three factors may be responsible for the sharp difference in tumourigenicity between cloned murine fibrosarcoma lines maintained in vitro, and cells of the same lines after in vivo passage, initially in a T cell deficient mouse and subsequently in normal mice: acquisition during passage of resistance to NC cells; acquisition during passage of a surface molecule, probably a sialic acid, which protects the cell against T cell-mediated lysis; and ability of the passaged cells, but not the non-passaged cells, to produce sufficient amounts of autocrine growth factors necessary for growth in vivo. The tumourigenicity of the passaged cells cannot be attributed to failure to express TATA or MHC class I molecules.
The provenance of cells in sarcomas induced in chimaeric mice.
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What's going on in the cancer patient?
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The effect of passage in vitro and in vivo on the properties of murine fibrosarcomas. II. Sensitivity to cell-mediated cytotoxicity in vitro.
The sensitivity of cultured and mouse-passaged cloned lines of chemically-induced murine fibrosarcomas to killing by NK and NC cells, and to cell-mediated immunity, has been studied in in vitro assays, using target cells labelled with 51Cr or 125IUDR. None of the lines tested proved sensitive to NK cells. Three cultured lines were, at most, only slightly sensitive to NC cells; a fourth cultured line was moderately sensitive and became less so, but not completely insensitive, after passage in susceptible hosts. The primary object of these experiments was to test the hypothesis that cultured cell lines which ordinarily fail to grow in normal mice are able to grow after being passaged in a susceptible immunodeficient host because, during this passage, they become resistant to NK or NC cells. This has been shown to occur with one clone, but will not serve as a general explanation because, with other clones, both cultured and mouse-passaged lines were NC-insensitive. The cell-mediated immunity assays confirm our previous conclusion that cultured and mouse-passaged lines of the same clone differ little, if it all, in immunogenicity.
The effect of passage in vitro and in vivo on the properties of murine fibrosarcomas I. Tumorigenicity and immunogenicity.
Cloned cell lines of chemically-induced murine fibrosarcomas maintained in tissue culture usually fail to grow when transplanted to normal syngeneic mice. They grow, however, in various categories of T cell deficient mice and after such passage grow readily in normal mice. Both cultured and mouse-passaged lines possess strong TATA. Three alternative explanations are suggested which might account for these findings. Emergence during the initial passage of a population of tumour cells resistant to NC cells. Acquisition during the initial passage of a protective surface molecule that interferes with the efferent side of the immune response when the tumour cells are subsequently transplanted to a normal host. Loss during the initial passage of a Class I MHC molecule which prevents dual recognition of the tumour cells by T cells when they are transplanted to a normal host. New experiments are proposed to distinguish between these possibilities.
Specificity of tumour associated transplantation antigens (TATA) of different clones from the same tumour.
The TATA of two clones from the same murine methylcholanthrene-induced fibrosarcoma have been investigated by immunizing syngeneic mice with irradiated cells of one or both clones and challenging them 14 days later with viable cells. The tumour had been induced in a female backcross CBA mouse heterozygous for the A and B alloenzymes of phosphoglycerate kinase-1 (PGK-1). One clone expressed A and the other B, and both A and B hosts were used in the experiments. Each clone was found to possess strong TATA but there was no demonstrable cross reactivity. The clonal composition of tumours produced by inoculating mice with a mixture of the two clones was profoundly altered by prior immunization with one of them. A second experiment was performed with 3 clones from another tumour; these expressed PGK-1 A, B and AB respectively. Again, there was no evidence of immunological cross reactivity between the A and B clones, but there was some cross reactivity between the A clone and AB clone. These results, coupled with previous observations of changes in the clonal composition of pleoclonal murine fibrosarcomas in culture and on transplantation, suggest that the antigenic specificity of these tumours is less stable than is commonly supposed.
Possible implications of the effect of blood transfusion on allograft survival.
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Cellular heterogeneity in tumours.
Malignant tumours contain normal cells, descendants of transformed cells, and conceivably also initiated cells which have taken some but not all of the steps toward malignancy, and hybrid cells. Tumours are propagated by multiplication of clonogenic cells, which are a subclass of the descendants of transformed cells. The clonogenic cells of a tumour may differ in respect of morphology, karyotype, metastatic capacity, sensitivity to cytotoxic drugs, expression of cell surface antigens and hormone receptors, immunogenicity, sensitivity to the immune reaction of the host, and other properties. Evidence (disputed by some) suggests that selection of particular subpopulations plays a role in tumour metastasis and recurrence. Heterogeneity may be due to pleoclonal origin, generation of phenotypic diversity within a clone, or spontaneous hybridization and chromosome loss. The possibility of interaction between different subpopulations must be taken into account in discussing tumour cell population kinetics. Heterogeneity also has important therapeutic implications and may help to explain the failure of some therapeutic regimes and the success of others.
Clonal interaction in tumours.
The development of cancer is contingent on the emergence of at least one clone of transformed cells. One method used to investigate whether human tumours are monoclonal depends on the mosaicism in the normal tissues of women heterozygous for the two forms of the enzyme glucose-6-phosphate dehydrogenase (G-6-PD). This mosaicism results from the inactivation of one X chromosome in all somatic cells and should not exist in a monoclonal population. Following the discovery in feral mice of an electrophoretic variant (A) of the X-coded enzyme phosphoglycerate kinase (PGK-1) which differs from the form (B) found in common laboratory mouse strains it was reported that fibrosarcomas induced chemically in hybrids of feral and laboratory-bred mice expressed both enzyme phenotypes, but the conclusion that both were expressed by neoplastic cells was based solely on morphological evidence. The development of histocompatible substrains of mice homozygous for one or other alloenzyme has made it possible to study the clonal composition of tumours under experimental conditions in which the neoplastic status of subpopulations of cells can be verified by transplantation. The experiments we now report, while confirming that murine fibrosarcomas are often pleoclonal, show that the clonal composition may change markedly during tissue culture and on transplantation to congenic hosts. These changes presumably reflect changes in the growth kinetics of differentiating subpopulations of the tumour. Cloned sublines are less readily transplantable than uncloned tumour cell populations, and some sublines are less readily transplantable than others; this suggests that sublines resistant to a host's attack are selected on transplantation or that some sublines require the cooperation of others to survive. We postulate that changes in clonal composition occur also during tumour development, metastasis and recurrence.
Some topics of common interest to developmental biologists and oncologists.
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Effect of C. parvum on the number and activity of macrophages in primary and transplanted murine fibrosarcomas.
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Current state of clinical immunotherapy.
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