Targeting the Biological Clock Could Slow the Progression of Cancer

    Does the biological clock in cancer cells influence tumor growth?  The answer is Yes. Most of us work more quickly when we’re “on the clock,” but the same cannot be said of cancer cells, which never proliferate more hastily than after they “punch out,” that is, after they lose any sense of circadian rhythm.

    Most of the cells in the human body have an internal clock that sets a rhythm for the activities of our organs according to the time of the day. Cancer cells, however, often have a non-functioning or malfunctioning clock. Cancer cells spin out of control not only if their internal biological clocks stop entirely, but also if they simply malfunction.

    Although circadian disruption has long been associated an increased pace of carcinogenesis, scientists had never demonstrated that directly targeting the biological clock of cancer cells could slow tumor development. A team of scientists at McGill University, however, recently investigated circadian clock function in a mouse model of cancer and found that putting cancer back on the clock could reduce tumor growth.

    “There were indications suggesting that the malfunctioning clock contributed to rapid tumor growth, but this had never been demonstrated,” noted Nicolas Cermakian, Ph.D., a professor in McGill University’s department of psychiatry. “Thanks to the use of a chemical or a thermic treatment, we succeeded in ‘repairing’ these cells’ clock and restoring it to its normal functioning. In these conditions, tumor growth drops nearly in half.”

    These findings appeared February 14 in the journal BMC Biology, in an article entitled, “Enhancing Circadian Clock Function in Cancer Cells Inhibits Tumor Growth.” Although this article describes a preclinical demonstration that was carried out in mice, it provides a glimpse of potential new ways to treat cancer in humans.

    “We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase,” the article’s authors wrote. “Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down.”

    In the current study, the McGill scientists also examined how improved timekeeping might affect cultured human cancer cells. For example, Silke Kiessling, a postdoctoral fellow on Cermakian’s team, successfully adjusted the gears of the internal clocks in two types of cancer cells—skin and colon—to make them function properly. This repair, which was tested in both mice and tissue cultures, slowed cancerous tumor growth. After about a week, the tumor treated in this manner was two-thirds smaller than the control tumor.

    “Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor,” the article’s authors emphasized. “Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events.”

    Essentially, the McGill scientists showed that dexamethasone effects on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. In their conclusions, they suggested that enhancing circadian clock function might represent a novel strategy to control cancer progression.

    “Activating the biological clock in tumors could become an innovative approach in slowing their growth or that of metastases. This would give people more time to use more conventional treatment modalities, such as surgery or chemotherapy,” said Cermakian. “It now remains to be shown that we can target the clocks in human tumors the same way.”