Reversible Upregulation of the Senescence-Associated Beta-Galactosidase Marker Induced by Cell Detachment in Cancer Cells

TL;DR

Cancer cells become temporarily non-dividing when detached, which may explain their resistance to drugs and help prevent metastasis.

Contribution

Cell detachment alone induces a reversible senescence-like state in cancer cells, distinct from drug-induced senescence.

Findings

Detached cancer cells show increased β-galactosidase activity, a marker of quiescence/senescence.

Reattachment reverses β-galactosidase activity and restores cell proliferation.

Detached cells without drug treatment recover faster than drug-induced senescent cells.

Abstract

During metastasis, cancer cells detach from the primary tumor, and the floating cells enter the circulation and reattach in distant organs. Floating cells are highly chemoresistant to anticancer drugs, but the underlying mechanisms are poorly understood. We hypothesized that floating cells transition into a quiescent/senescent (Q/S) state. Using human lung carcinoma H460 and H23, human prostate adenocarcinoma PC3, and human breast adenocarcinoma MDA-MB-231 cells, we found (1) a progressive increase in activity of β-galactosidase (β-Gal), a marker associated with Q/S cells, (2) a transition to a non-proliferative state while growing under anchorage-independent conditions, and (3) upon reattachment, the β-Gal activity returned to the basal level and cells resumed proliferation. Similar experiments were performed in parallel with cells treated with etoposide (Eto), a well-known inductor of senescence. Eto-untreated floating cells resumed proliferation faster and showed a quicker decrease in β-Gal activity compared to Eto-induced senescent cells. We conclude that cell detachment per se triggers a reversible (plastic) increase in β-Gal. Our findings provide a partial explanation for chemoresistance under anchorage-independent conditions and a new target to eliminate highly resistant floating cells. Ultimately, eliminating Q/S floating cells may prevent or reduce metastasis.

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