Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

Apr 19, 2008Cold Spring Harbor symposia on quantitative biology

Interactions between the body’s internal clock and cell division influence cancer behavior and treatment

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Abstract

Cancer patients with disrupted circadian rhythms may experience poorer quality of life and survival outcomes.

The circadian clock regulates cellular functions, including cell division, over a 24-hour cycle.
Disruption or reinforcement of the circadian timing system may accelerate or slow cancer growth.
Cancer cells often show mutations in cell cycle genes and significant defects in circadian gene expression.
Research indicates gender can significantly influence survival outcomes in cancer patients receiving chronotherapeutic treatments.
Mathematical models suggest that optimizing drug delivery profiles based on circadian rhythms could enhance the effectiveness of chemotherapy.

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The circadian clock orchestrates cellular functions over 24 hours, including cell divisions, a process that results from the cell cycle. The circadian clock and cell cycle interact at the level of genes, proteins, and biochemical signals. The disruption or the reinforcement of the host circadian timing system, respectively, accelerates or slows down cancer growth through modifications of host and tumor circadian clocks. Thus, cancer cells not only display mutations of cell cycle genes but also exhibit severe defects in clock gene expression levels or 24-hour patterns, which can in turn favor abnormal proliferation. Most of the experimental research actively ongoing in this field has been driven by the original demonstration that cancer patients with poor circadian rhythms had poor quality of life and poor survival outcome independently of known prognostic factors. Further basic research on the gender dependencies in circadian properties is now warranted, because a large clinical trial has revealed that gender can largely affect the survival outcome of cancer patients on chronotherapeutic delivery. Mathematical models further show that the therapeutic index of chemotherapeutic drugs can be optimized through distinct delivery profiles, depending on the initial host/tumor status and variability in circadian entrainment and/or cell cycle length. Clinical trials and systems-biology approaches in cancer chronotherapeutics raise novel issues to be addressed experimentally in the field of biological clocks. The challenge ahead is to therapeutically harness the circadian timing system to concurrently improve quality of life and down-regulate malignant growth.

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Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

Abstract

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