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A cell cycle hypothesis of cooperative oncogenesis (Review)
Bénédicte Delaval1, Daniel Birnbaum
1Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France.
Abstract:
The development of cancer is a multistep process. To understand oncogenesis and adapt appropriate treatments it is important to have a better definition of a number of factors, including the number and order of oncogenic steps, the identity of the targeted cells and deregulated cellular components, and the genes and pathways altered at each step. We propose here a hypothesis of oncogenesis based on the targeting of the cell cycle in two major steps. Oncogenic hits may occur in two sequences: in one scenario a first oncogenic hit alters the regulation of the G1 phase of the cell cycle leading to a proliferative, premalignant syndrome; oncogenesis is completed when a second oncogenic hit relieves the checkpoints of the late phases of the cell cycle. Alternatively, a genetic alteration may hit the late phases first; this leads to a premalignant disease with signs of senescence. In this scenario, the second hit targets the G1 phase. In the two sequences, oncogenesis is based on the cooperation of two hits targeting different phases of the cell cycle and relieving major checkpoints. Stem cells and progenitor cells of various tissues may be variably sensitive to these hits.
Insights
Cancer development involves two key oncogenic steps targeting cell cycle regulation. Understanding the order of these hits is crucial for defining cancer progression and developing effective treatments.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Cancer development is a complex, multistep process.
- Defining the number, order, and molecular targets of oncogenic steps is critical for understanding cancer.
- Current understanding of oncogenesis requires further refinement of cellular and genetic alterations.
Purpose of the Study:
- To propose a hypothesis for oncogenesis based on a two-step model.
- To investigate the role of cell cycle regulation in cancer development.
- To explore the sequential targeting of different cell cycle phases in oncogenesis.
Main Methods:
- Hypothetical modeling of oncogenic step sequences.
- Analysis of cell cycle regulation and checkpoints.
- Consideration of stem and progenitor cell sensitivity.
Main Results:
- A two-hit hypothesis for oncogenesis is proposed, involving sequential targeting of cell cycle phases.
- The model suggests two possible sequences of oncogenic hits: G1 phase followed by late cell cycle phases, or vice versa.
- Cooperation between hits targeting different cell cycle phases and relieving major checkpoints is fundamental to oncogenesis.
Conclusions:
- Oncogenesis is proposed to result from the cooperative action of two genetic alterations targeting distinct cell cycle phases.
- The order of these hits influences the nature of the premalignant state (proliferative vs. senescent).
- Variations in stem and progenitor cell sensitivity may impact the oncogenic process.
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