Engulfment and cannibalism drive persistence of chemotherapy-treated tumor cells: can they be targeted?

Abstract

The breast tumors that are most difficult to eradicate with chemotherapy have wild-type TP53 and preferentially enter senescence after treatment. One factor contributing to the persistence of senescent cells in residual disease: acquisition of a novel phenotype that allows cannibalism of entire cells and engulfment of other substrates.

An Indocyanine Green‐Based Nanoprobe for In Vivo Detection of Cellular Senescence

“…This aligns with previous studies that have shown an up‐regulation of endo‐lysosomal machinery as well as the activation of macropinocytosis (as a survival mechanism through nutrient scavenging) and phagocytosis (employed as a form of cell cannibalism) in senescent cells [62–66] . Indeed, due to their capacity to engulf other cells and synthesized materials, [62,63,67] senescent cells have often been compared to macrophages [67] …”

“…[68] Together, these findings suggest that NanoJaggs are internalized through an active mechanism, likely involving both clathrin-mediated endocytosis and macropinocytosis. While this phenomenon has been previously noted within the context of cell engulfment, [62] its application in development of detection strategies or for improved drug delivery remains largely unexplored. Given that ICG has been observed to bind to the cancer cell membrane and subsequently undergo endocytosis, [47] it is tempting to hypothesize that NanoJaggs could potentially recognize specific molecules on the senescent surfaceome thus enabling selective targeting.…”

“…This aligns with previous studies that have shown an upregulation of endo-lysosomal machinery as well as the activation of macropinocytosis (as a survival mechanism through nutrient scavenging) and phagocytosis (employed as a form of cell cannibalism) in senescent cells. [62][63][64][65][66] Indeed, due to their capacity to engulf other cells and synthesized materials, [62,63,67] senescent cells have often been compared to macrophages. [67] Contrary to pre-uptake endocytosis inhibitors, postuptake inhibitors PCZ and Chloroquine, resulted in increased NanoJagg fluorescence in both senescent and nonsenescent cell lines (Figure 3b and c, Figure S25 to S29).…”

Optical Diffraction Tomography and Raman Confocal Microscopy for the Investigation of Vacuoles Associated with Cancer Senescent Engulfing Cells

“…It is reasonable to hypothesize that the biomolecules found in vacuoles derived from broken-down cells previously engulfed, and, assumingly, this biological material was transferred out of the vacuoles to the engulfing cells overtime, concurrently with vacuole shrinking, providing the engulfing cells with nutrients and building blocks necessary for their persistence. This is in line with the results obtained with standard techniques in other laboratories [8,10,46]. Of note, Raman bands between 800 and 900 cm −1 , and particularly a peak at 855 cm −1 (Figure 4E), together with a peak at 965, were found in vacuoles at relatively high concentrations, with peak intensities as high as or higher than in cells.…”

“…However, the low density of vacuoles was consistent with the lower intensity of Raman peaks in the vacuoles than in cells and, taken together and with their Raman profiles, these findings suggest that vacuoles contained macromolecules attributable to biological (cell-derived) material in extremely small concentration. obtained with standard techniques in other laboratories [8,10,46]. Of note, Raman bands between 800 and 900 cm −1 , and particularly a peak at 855 cm −1 (Figure 4E), together with a peak at 965, were found in vacuoles at relatively high concentrations, with peak intensities as high as or higher than in cells.…”