Abstract 1110: Colorectal liver metastases induce a systemic phase shift of the biological clock

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Circadian clock genes drive cyclic expression of 10-15% of the transcriptome. Disruption of the circadian clock may deregulate the cell's normal functions and can lead to carcinogenesis, indicating that clock genes also act as tumor suppressor genes. In previous work, we have shown that circadian rhythmicity is disrupted in C26 colon carcinoma cell-derived hepatic metastases, as compared to the non-cancerous tissue of the liver. It has been suggested that neoplastic tissue can influence the circadian clock of adjacent tissues, causing a tissue specific phase shift. A better understanding of how tumors affect the circadian system may help elucidate the role of the clock in cancer patients suffering from fatigue and sleep disorders. Therefore, we have examined the circadian clock in liver and kidney tissue of mice carrying hepatic C26 colon carcinoma cell metastases. Male BALB/c mice were divided into two groups. In group 1, hepatic metastases were induced by injecting C26 colorectal carcinoma cells into the spleen. Group 2 was sham operated. Three weeks after (sham) surgery, animals were sacrificed over a 24-hour period (6 time points, n=4 per time point) and liver and kidneys were collected to compare circadian rhythmicity in control and tumor bearing animals. RNA was isolated and qRT-PCR was performed to determine the expression levels of 5 clock genes (Rev-Erbα, Per1, Per2, Bmal1, Cry1) and 3 clock controlled genes (Dbp, p21 and Wee1). Liver and kidney tissue of healthy control mice showed normal 24-hour oscillations of all clock genes, consistent with normal circadian rhythmicity. Liver and kidney tissue of tumor-bearing mice, as compared to control mice, showed a marked phase difference in clock rhythms. In the liver we observed a 4-hour phase advance for Bmal1, Rev-Erbα and Dbp. In contrast in the kidney, there was a 4-hour phase delay for Bmal1, Rev-Erbα, Cry1 and DBP, and a 8 hour delay for Per2. These data show that colorectal liver metastases induce a phase advance in the liver, and a phase delay in the kidney . This suggests a systemic effect of the tumor on peripheral clocks. This difference in clock phase between tumor-bearing mice and healthy controls may provide new clues to further understand the role of the clock for fatigue and sleep problems in cancer patients, but may also give opportunities to administer chemotherapeutic treatment in a chronotherapeutical setting . Citation Format: Sander A. Huisman, F. Tamanini, A. Ahmadi, J.N.M. IJzermans, G.T.J. van der Horst, R.W.F. de Bruin. Colorectal liver metastases induce a systemic phase shift of the biological clock. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1110. doi:10.1158/1538-7445.AM2014-1110