Are cancer stem cells radioresistant?

Abstract

Based on findings that cancer cell clonogens exhibit stem cell features, it has been suggested that cancer stem-like cells are relatively radioresistant owing to different intrinsic and extrinsic factors, including quiescence, activated radiation response mechanisms (e.g., enhanced DNA repair, upregulated cell cycle control mechanisms and increased free-radical scavengers) and a surrounding microenvironment that enhances cell survival mechanisms (e.g., hypoxia and interaction with stromal elements). However, these radiosensitivity features are probably dynamic in nature and come into play at different times during the course of chemo/radiotherapy. Therefore, different molecularly targeted radiosensitization strategies may be needed at different stages of therapy. This article describes potential sensitization approaches based on the dynamics and changing properties of cancer stem-like cells during therapy.

Figure 1. Tumor control dose 50% value plotted versus tumor cell dose 50% value for murine tumors

Best-fit lines are shown for each group and for all tumors. TCD₅₀ values decrease as the TD₅₀ values increase. TCD₅₀: Tumor control dose 50%; TD₅₀: Tumor cell dose 50%. Reproduced with permission from [8].

Figure 2. Doses to achieve local control in 50% of cases (tumor control dose 50%) as a function of overall treatment time for squamous cell tumors of the head and neck

The data points include many published results from the literature, including HBO and the trial of Miso. The dashed line shows the rate of increase in tumor control dose 50% predicted from a 2-month cancer stem-like cell doubling rate. HBO: High-pressure oxygen trial; Miso: Misonidazole. Reproduced with permission from [43].

Figure 3. Effect of cetuximab on radiocurability of A431 tumor after fractionated irradiation

Mice bearing 8-mm tumors in the right hind leg were given cetuximab, local tumor irradiation or both as graded doses of γ-rays delivered twice daily for 7 consecutive days. Cetuximab (1 mg intraperitoneally) was given at 3-day intervals either three times during fractionated radiation or six times, both during and after fractionated radiation. Radiation dose–response curves were generated. Circles, solid line: local tumor control at 130 days after fractionated radiation alone (tumor control dose 50% [TCD₅₀] = 83.1 [95% CI: 73.2–124.8] Gy). Squares, dashed line: cetuximab concurrent with radiation (TCD₅₀ = 46.2 [95% CI: 39.1–57.5] Gy). Triangles, heavily dashed line: cetuximab given during and after radiation (TCD₅₀ = 30.8 [95% CI: 22.2–38.0] Gy). Error bars are 95% CIs on the TCD₅₀. Reproduced with permission from [96].

Figure 4. Effect of cetuximab on the growth of A431 xenografts in tumor-bed irradiation

Tumor-bed irradiation of the right hind leg of mice was performed with 20-Gy single-dose γ-irradiation 1 day before subcutaneous injection of A431 tumor cells (TBE). Mice were treated intraperitoneally with cetuximab (C225) in three 1-mg doses in 3-day intervals when tumors reached 5 mm in diameter. The error bars show mean values ± standard error. Reproduced with permission from [97].