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

Abstract

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.

The stroma as a crucial target in rat mammary gland carcinogenesis

“…Moreover, normal epithelial outgrowths were observed at all NMU doses (Guzman et al, 1987;Miyamoto et al, 1988). Using yet another protocol, Kamiya et al showed that NMU-or radiation-exposed mammary epithelial cells yielded mammary carcinomas when grafted into rat fat pads that were 'cleared' by injecting 70% ethanol (Kamiya et al, 1995). They interpreted these data as evidence that tumor formation was due to undefined epigenetic factors rather than to mutations.…”

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

“…15,[17][18][19][20] These epigenetic events are controlled by intra-, inter-and extracellular communication mechanisms. 21 Considering that the number of initiated cells far exceeds the number of tumors that develop in vivo, [22][23][24] it is reasonable to assume that the clonal expansion of an initiated cell or …”

Neoplastic development: paradoxical relation between impaired cell growth at low population density and excessive growth at high density.

“…The evidence for epigenetic change is not restricted to cells adapted for culture. Treatment with x-rays or chemical carcinogens of mammary epithelium or thyroid cells immediately after their removal from mice followed by reinoculation into mice results in 1 cancer per 10-300 clonogens (31,32). Such frequencies of cancer development are orders of magnitude higher than expected from local mutations, and they are likely to be underestimates of the proportion of cells that undergo early, incipient stages of neoplastic development (2,20).…”