The Clonogenic Cells of the Rat Mammary and Thyroid Glands: Their Biology, Frequency of Initiation, and Promotion/Progression to Cancer

Evidence is presented in support of the hypothesis that cancer development depends on an imbalance between highly frequent epigenetic initiation and suppression of promotion ofthe initiated cells. When irradiated clonogenic mammary epithelial cells are transplanted and hormonally stimulated, they give rise to clonal glandular structures within which carcinomas may arise. In the current study, the cancer incidence in grafts of '13 7-Gy-irradiated clonogens per site indicated that at least 1 of -95 clonogens was radiogenically initiated. A similar initiation frequency had been seen in grafts of -5 methylnitrosourea (MNU)-treated clonogens. Such initiation is thus far more frequent than specific locus mutations. In sites grafted with larger cell inocula, cancer incidences per clonogen were suppressed inversely as the numbers of irradiated or MNU-treated clonogens per graft increased. Addition of unirradiated cells to small irradiated graft inocula also suppressed progression. Radiation and MNU thus produce quantitatively, and perhaps qualitatively, similar carcinogenesis-related sequelae in mammary clonogens.

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“…and/or first subgrafts of epithelial cells and often epithelial cell cultures (8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion.

Kamiya¹,

Yasukawa-Barnes²,

Mitchen³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…With this assay, it has been demonstrated that: a) the cell dose-FU formation response follows that to be expected if each FU were clonal in origin, i.e. arose from a single cell; b) the results of morphological studies during their formation also are consistent with the clonal origin of FU; c) the radiation dose-FU formation response and potentially lethal damage repair capacity follow the relationship and kinetics to be expected if FU are clonal structures; and d) radiogenic cancer can develop within FU in TSH-stimulated graft sites (reviewed in Clifton 1990). The term clonogen has thus been applied to the cells which give rise to FU and are the presumptive progenitor cells of cancer in thyroid cell grafts.…”

Section: Introductionmentioning

confidence: 80%

On the Cells of Origin of Radiogenic Thyroid Cancer: New Studies Based on an Old Idea

Clifton¹,

Domann²,

Groch³

1991

JRR

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We have presented evidence that the functional thyroid follicles (follicular units, FU) which are formed in grafts of monodispersed rat thyroid cells, and hence the thyroid tumors which later develop in such grafts, are clonal in origin. Transplantation assays indicate that the clonogens comprise -1% of the cells in monodis persed suspensions of normal thyroid tissue. Carcinogenesis studies show that neoplastic initiation of thyroid clonogens by radiation is a common event. Promotion-progression to cancer from radiation initiated clonogens has, however, been shown to be inversely related to the total grafted thyroid cell number; i.e. more tumors develop per irradiated clonogen in grafts of small cell numbers than of large cell numbers. Recent studies have been designed to investigate: a) whether the cell number-dependent inhibition of promotion-progres sion is mediated by remote hormonal feed-back, local cell-cell interactions, or both; b) the cell population kinetics of the clonogen subpopulation during goitrogenesis and goiter involution; and c) the effect of prolonged exposure to high levels of TSH (thyrotropin) on the capacity of the clonogens to give rise to functional FU. The results indicate that local cell-cell interactions play an important role in the cell number dependent suppression of neoplastic promotion-progression. They also show that if sufficient thyroid cells are grafted, the thyroid-pituitary axis can be reestablished in thyroidectomized rats fed normal diets. In such animals given iodine deficient diets, the FU that develop in the thyroid grafts shift their secretory pattern to increase the ratio of T3 (triiodothyronine) to T4 (thyroxine), and thus conserve the available iodine. Finally, the clonogenic subpopulation is conserved during both goitrogenesis and goiter involution. When they are transplanted to thyroidectomized recipients, clonogens from two types of goiters form FU that are mor phologically indistinguishable from those that develop in grafts of normal thyroid clonogens. Furthermore, the secretion of T3 and T4 by such grafts is dependent on the grafted clonogen number, and hence FU formation, and not on the total number of thyroid cells transplanted. We conclude that the thyroid clono gens, the presumptive cancer progenitor cells, have many of the characteristics of stem cells.

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“…With this assay, it has been demonstrated that: a) the cell dose-FU formation response follows that to be expected if each FU were clonal in origin, i.e. arose from a single cell; b) the results of morphological studies during their formation also are consistent with the clonal origin of FU; c) the radiation dose-FU formation response and potentially lethal damage repair capacity follow the relationship and kinetics to be expected if FU are clonal structures; and d) radiogenic cancer can develop within FU in TsH-stimulated graft sites (reviewed in Clifton 1990). The term c/onogen has thus been applied to the cells which give rise to FU and are the presumptive progenitor cells of cancer in th_'oid cell grafts.…”

Section: Introductionmentioning

confidence: 80%

On the Cells of Origin of Radiogenic Thyroid Cancer: New Studies Based on an Old Idea<xref ref-type="fn" rid="fn1">*</xref><xref ref-type="fn" rid="fn2">+</xref>

1991

Journal of Radiation Research

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We have presented evidence that the functional thyroid follicles (follicular units, FU) which are formed in grafts of monodispersed rat thyroid cells, and hence the thyroid tumors which later develop in such grafts, are clonal in origin. Transplantation assays indicate that the clonogens comprise "1% of the cells in monodispersed suspensions of normal thyroid tissue. Carcinogenesis studies show that neoplastic initiation of thyroid c]onogens by radiation is a common event. Promotion-progression to cancer from radiation initiated clonogens has, however, been shown to be inversely related to the total grafted thyroid cell number, i.e. more tumors develop per irradiated clonogen in grafts of small cell numbers than of large cell numbers. Recent studies have been designed to investigate: a) whether the cell number-dependent inln'bition of promotion-progression is mediated by remote hormonal feed-back, local ceU-ceU interactions, or both; b) the cell population kinetics of the clonoge, l subpopulation during goitrogenesis and goiter involution; and c) the effect of prolonged exposure to high levels of TSH (thyrotropin) on the capacity of the clonogens to give rise to functional FU. The results indicate that local ceU-celi interactions play an important role in the cell number-dependent suppression of neoplastic promotionprogression. They also show that if sufficient thyroid cells are grafted, the thyroid-pituitary axis can be reestablished in thyroidectomized rats fed normal diets. In such animals given iodine deficient diets, the FU that develop in the thyroid grafts shift theft secretory pattern to increase the ratio of T3 (triiodothyronine) to T4 (thyroxine), and thus conserve the t | available iodine.Finally, the clonogenic subpopulation is conserved during both goitrogenesis and goiter involution. When they are transplanted to thyroidectomized recipients, clonogens fxom two types of goiters form FU that are morphologically indistinguishable from those that develop in grafts of normal thyroid clonogens.Furthermore, the secretion of T3 and T4 by such grafts is dependent on the grafted clonogen number, and hence FU formation, and not on the total number of thyroid cells transplanted. We conclude that the thyroid clonogens, the presumptive cancer progenitor cells, have many of the characteristics of stem cells.

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The Clonogenic Cells of the Rat Mammary and Thyroid Glands: Their Biology, Frequency of Initiation, and Promotion/Progression to Cancer

Cited by 10 publications

References 27 publications

Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion.

Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion.

On the Cells of Origin of Radiogenic Thyroid Cancer: New Studies Based on an Old Idea

On the Cells of Origin of Radiogenic Thyroid Cancer: New Studies Based on an Old Idea<xref ref-type="fn" rid="fn1">*</xref><xref ref-type="fn" rid="fn2">+</xref>

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