Reliability of proliferation controls. The Hayflick limit and its breakdown in cancer

Abstract

This paper presents a new theory of the Hayflick limit and its role in cancer. The Hayflick limit is identified as a fail-safe mechanism that limits to harmless size descendent clones of cells in which normal proliferation controls have broken down. Malignancy arises when the Hayflick limit is inactivated. It is argued that the Hayflick limit is due to differentiation towards a non-proliferating state. Redundant developmental clocks are envisioned as the mechanism. Chemical carcinogens and promoters can interfere with these clocks. Also, viral gene products and integration of viral DNA can stop the developmental clock and lead to malignant transformation in cells that have already suffered mutations in their normal regulatory mechanisms that control proliferation. Viral transformation can be understood as a viral strategy of survival and transmission to a new host. Malignant clones may constitute a niche for many slow viruses. Normal functioning of the Hayflick limit implies senescence of tissues due to differentiation towards a non-proliferating state. Hence, the limit may be the cause of senescence even though it is not due to an accumulation of somatic mutations.