Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death

Abstract

Even though cell death modalities elicited by anticancer chemotherapy and radiotherapy have been extensively studied, the ability of anticancer treatments to induce non-cell-autonomous death has never been investigated. By means of multispectral imaging flow-cytometry-based technology, we analyzed the lethal fate of cancer cells that were treated with conventional anticancer agents and co-cultured with untreated cells, observing that anticancer agents can simultaneously trigger cell-autonomous and non-cell-autonomous death in treated and untreated cells. After ionizing radiation, oxaliplatin, or cisplatin treatment, fractions of treated cancer cell populations were eliminated through cell-autonomous death mechanisms, while other fractions of the treated cancer cells engulfed and killed neighboring cells through non-cell-autonomous processes, including cellular cannibalism. Under conditions of treatment with paclitaxel, non-cell-autonomous and cell-autonomous death were both detected in the treated cell population, while untreated neighboring cells exhibited features of apoptotic demise. The transcriptional activity of p53 tumor-suppressor protein contributed to the execution of cell-autonomous death, yet failed to affect the non-cell-autonomous death by cannibalism for the majority of tested anticancer agents, indicating that the induction of non-cell-autonomous death can occur under conditions in which cell-autonomous death was impaired. Altogether, these results reveal that chemotherapy and radiotherapy can induce both non-cell-autonomous and cell-autonomous death of cancer cells, highlighting the heterogeneity of cell death responses to anticancer treatments and the unsuspected potential contribution of non-cell-autonomous death to the global effects of anticancer treatment.

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

“…Entosis was described as cannibalism by cancer cells in culture after loss of substrate adherence, sometimes resulting in death of the engulfing cell and sometimes lysosomal degradation of the engulfed cell (Overholtzer et al, 2007; Krishna and Overholtzer, 2016). Rates of entosis can be increased by glucose starvation (Hamann et al, 2017) or 12–48 h after radiation/chemotherapy treatment (Martins et al, 2018). Breast cancer cells in 3D culture were shown to engulf bone marrow–derived mesenchymal stem/stromal cells.…”

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

“…9559L, Cell Signaling) (6,15,25), cleaved caspase-3 (1:1,000, catalog no. 9661L, Cell Signaling) (24,53,55), and ␤-actin (as a loading control, 1:1,000, catalog no. 4967L, Cell Signaling) (12,32,54) for 3 h at room temperature or overnight at 4°C.…”

Trial watch: IDO inhibitors in cancer therapy

“…72 Consistent with the immunosuppressive activity of IDO in this setting, ex vivo stimulation of peripheral blood cells with 1-MT increased T cell responses to vaccination. 72 Recently, Hu et al also demonstrated that a methyltryptophan-paclitaxel (MP) albumin-bound drug conjugate (that links indoximod to the microtubular poison paclitaxel [74][75][76][77] through an ester bond) not only significantly elevates the tumor levels of indoximod and local CD8 + T populations, but reduces granulocyte-like myeloid derived suppressor cells (G-MDSCs) and T REG cells. 78…”