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W Den Otter

Publications and source records attributed to W Den Otter.

172 records · Page 10Linked to original sources
PubMedDate not supplied

Oncogenesis by mutations in anti-oncogenes: a view.

Oncogenesis is the result of accumulation of specific gene mutations. Two classes of specific cancer mutations are distinguished: namely those affecting anti-oncogenes and those in which oncogenes are involved. Anti-oncogenes are thought to regulate normal growth by encoding proteins that inhibit the expression of the oncogenes. This is in line with the observation that tumor cells are often homozygous for a defect in an anti-oncogene, as this will allow the expression of an oncogene. In this paper we attempt to calculate the number of anti-oncogenes involved in the genesis of a malignant tumour cell. These calculations were initially performed using a simplified model for oncogenesis and later applied to more complicated situations. These calculations indicate that usually four mutations in anti-oncogenes are required for oncogenesis in adults. This is in contradiction to the well-known 2-hit model of oncogenesis of Knudson which predicts about 10(9) times more de novo arising tumour cells than are observed in reality. Oncogenesis is only observed in proliferating cells. Cell proliferation and growth kinetics in various organs differ greatly. Therefore the time of oncogenesis and tumour manifestation also varies in the different organs. In organs that develop in early life (e.g. retina and neurons of the brain) mitotic activity ceases soon after birth. Consequently neural and retinal tumours emerge only early in life. In contrast, the main development of the female breast occurs after puberty, and the earliest breast tumours will become apparent in young adults. The four recessive mutations in anti-oncogenes required for oncogenesis imply that probably recessive mutations are involved in two loci. It is clear that an inherited mutation in an anti-oncogene at a particular locus causes different tumour types depending on the various organs in which the tumours arise. Comparison of (a) results of calculations about the number of malignant neuroendocrine tumour cells that arise in a pancreatic islet of a patient with inherited MEN1-syndrome with (b) the pathological anatomy of such a patient, suggests that a cell with two or three oncogenic mutations has a growth advantage over normal cells. This leads to cell proliferation in a premalignant lesion until the set of four oncogenic mutations is complete. The clinically premalignant lesions have a maximal mean diameter of about 0.4 cm when the first true malignant tumour cell develops, and the pathologist will probably note malignancy when the lesion has the size of 1-2 cm.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
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Hereditary cancer and its clinical implications: a view.

In hereditary cancers the responsible inherited cancer genes are defective (mutated) anti-oncogenes (tumour suppressor genes). This inherited mutation is present in all cells of the organism, and only leads to cancer if in a somatic cell a complete set of specific cancer mutations is accumulated. Since one defective anti-oncogene has been inherited, only three additional somatic cancer mutations are required, according to our previously published view (Anticancer Res 10:1990). The number of de novo arising tumour cells in such a person is thus multiplied by a factor equal to the reverse of the mutant frequency, that is about 10(4)-10(5). This can be observed e.g. in retinoblastoma. Mutations occur in proliferating cells only. Consequently cancer mutations also depend on cell proliferation. If an inherited cancer mutation predisposes to cancer formation in certain organs, then the cancer risk in these organs is enhanced by 10(4)-10(5) times. Tumours in these organs will appear simultaneously if the number of cells and the growth kinetics are similar. This is of course observed in paired organs, like the retina and the female breast. In cancer family syndromes different organs may be affected at the same time. Examples are type I and type II cancer family syndrome and multiple endocrine neoplasia type 1 2a, and 2b. The secondly diagnosed tumours are not caused by metastatic spread. Tumours in two organs will arise at difference times if the number of end cells per organ and the growth kinetics differ. In this case the second tumour is called a second primary malignancy and is not caused by metastatic spread. A good example are the second primary malignancies in hereditary retinoblastoma. The inherited defective anti-oncogene is a recessive gene. This defective inherited gene causes a 10(4)-10(5) fold increase of the normal tumour incidence. This means that nearly always one or more tumours will arise. Evidently, this pattern of inheritance has led to the erroneous conclusion that the genetic abnormality is dominant at the level of the chromosome. The 10(4)-10(5) times enhanced tumour incidence in hereditary cancer is helpful for the clinical recognition of hereditary cancer. That is, hereditary cancer can be recognized not only by family history, but also by early occurrence, the multifocal and bilateral localisation, its occurrence as cancer family syndrome or by second primary malignancies. It is thus recommended to screen patients and families with hereditary cancer for first and second primary tumours. Treatment of patients with hereditary tumours requires extra care to avoid additional cancer mutations.(ABSTRACT TRUNCATED AT 400 WORDS)

Genes, Dominant↗
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Stochastic theory of oncogenesis.

It is generally agreed that most malignancies, particularly those that arise "spontaneously", are caused by randomly occurring mutations at specific sites of the genome. Hence oncogenesis of these spontaneous tumors can be described by stochastic mathematical models. In this paper we offer a mathematical approach to oncogenesis. A stochastic model was developed to calculate the number of mutations required for malignant transformation. This model demonstrates that the two hit model, as originally proposed by Knudson for retinoblastoma in children, is not tenable for tumors in adults. Our results show that malignant transformation is more likely to be due to a specific set of four mutations. This stochastic model is compatible with most current views on oncogenesis and most phenomena in oncology.

Cell Transformation, Neoplastic↗
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Pathogenesis of Burkitt's lymphoma in children.

The reason that the classical African type of Burkitt's lymphoma often occurs in children is still not well understood. Several data published during the last months have, however shed some light on this phenomenon.

Burkitt Lymphoma↗
PubMedDate not supplied

A new model for oncogenesis. From tumour immunology to a mathematical approach of oncogenesis.

Around 1970 it was assumed that tumour cells are due to a single specific oncogenic mutation. This implied that daily many thousands of tumour cells would arise de novo and that most of these tumour cells were killed by immune surveillance or natural resistance mechanisms. Recent findings on immune surveillance and natural resistance implicate that tumour cells do not arise frequently, however. Given the fact that mutations occur at a frequency of about 2 X 20(-5) mutants per gene per generation, we calculated that transformation to a tumour cell probably requires 4 oncogenic mutations if a single tumour cell would arise de novo during lifetime. This four-mutation model of oncogenesis can explain many oncological data like the observed peak incidence of cancer in children, the hereditary aspects of some pediatric tumours and the usually non-hereditary cancer in adults, the occurrence of second tumours in children, and the data on the monoclonal and polyclonal origin of tumours.

Age Factors↗
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The difference between benign and malignant tumours explained with the 4-mutation paradigm for carcinogenesis.

In recent years a 4-mutation paradigm for carcinogenesis was developed for mutations in tumour suppressor genes. The major tenet of this paradigm is that transformation of a normal cell into a malignant cell is the result of an accumulation of a set of 4 specific cancer mutations. In this paper we show that this paradigm can explain the characteristic differences between benign and malignant tumours. We surmise that benign tumour cells are due to 2 or 3 specific cancer mutations, whereas malignant tumour cells contain 4 specific cancer mutations and 1-3 tumour progression mutations. The following characteristics, essential for differentiating benign and malignant tumours, are explained by our paradigm: (a) differentiation--anaplasia, (b) rate of growth, (c) encapsulation--invasion, (d) metastasis, and (e) the differences in size of benign epithelial and mesenchymal tumours and the relation between tumour size and malignancy.

Animals↗
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The glycosylation profile of interleukin-2 activated human lymphocytes correlates to their anti-tumor activity.

BACKGROUND: Natural killer cells display spontaneous, non-MHC-restricted cytotoxicity against tumour cells, which is strongly enhanced after incubation with IL-2. The molecular background of the increased anti-tumour activity of these lymphokine-activated killer cells is still only partly understood. MATERIALS AND METHODS: In this paper, investigation has been made of the correlation between cell surface glycosylation and anti-tumour activity of LAK cells by stimulating peripheral blood lymphocytes with interleukin-2, in the presence of inhibitors of N- and O-glycosylation. RESULTS: Inhibition of N- or O-glycosylation of proteins during IL-2 activation leads to a 70-80% decrease in the cytolytic activity of LAK cells against K562 and Daudi tumour cells, coinciding with drastic alterations in their cell surface carbohydrate profile. CONCLUSION: The conclusion is drawn that there is a clear correlation between the glycosylation of LAK cell glycoproteins and their anti-tumour activity which points to the involvement of cell surface glycoconjugates in the development of LAK activity.

1-Deoxynojirimycin↗
PubMedDate not supplied

Breast cancer induction due to mammographic screening in hereditarily affected women.

Breast cancer induction due to mammographic screening has aroused considerable controversy in the discussion of the safety of this procedure. We have attempted to shed some light on this problem by approaching it from both a theoretical and a mathematical point of view. We found that about 99% of mammographically induced breast cancers occur in the group of women who are carriers of a breast cancer gene. Our calculations suggest that in women with an inherited gene for breast cancer an extra tumour in one out of 10 women will be induced by 20 mammographical examinations. On the other hand, mammography is safe for non-gene carriers.

Breast Neoplasms↗