Therapy-Induced Cellular Senescence Induces Epithelial-to-Mesenchymal Transition and Increases Invasiveness in Rectal Cancer

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Abstract

We evaluated the effects of the senescence-associated secretome (SAS) in vitro and in clinical samples from patients with rectal cancer who had undergone neoadjuvant chemoradiotherapy (CRT). The effects of the SASs on colorectal cancer cells translated into increased invasiveness and induction of epithelial-to-mesenchymal transition (EMT). In the clinical samples, senescence and EMT co-occurred within a fraction of cancer cell clusters. These results could have important implications in guiding treatment after CRT.

Introduction:

DNA damaging agents and ionizing radiation used in the therapy of human cancers can induce senescence of cancer cells. Senescent cells exhibit a secretory phenotype (senescence-associated secretome [SAS]) that can affect cancer cell behavior and, eventually, clinical prognosis. We assessed the effects of the SAS on the induction of epithelial-to-mesenchymal transition (EMT) in vitro and in clinical samples from patients with rectal cancer who had undergone neoadjuvant chemoradiotherapy (CRT).

Materials and Methods:

Colorectal cancer cells (HCT 116) were induced into senescence by exposure to either 5-fluorouracil (5-FU) or doxorubicin. The senescent state was confirmed by staining for senescence-associated β-galactosidase (SA-β-Gal). The paracrine effects of SASs were assessed on proliferating HCT 116 cells. The quantified parameters were cell proliferation, invasive capacity, and induction of EMT. Senescence and EMT in clinical samples were assessed by the expression levels (reverse transcriptase-quantitative polymerase chain reaction) of genes related to senescence and EMT after laser-assisted microdissection of cancer cell clusters that stained either positive or negative for SA-β-Gal.

Results:

We have shown that cultured colon cancer cells induced into senescence by exposure to 5-FU exhibit a SAS capable of paracrine induction of EMT in colon and rectal cancer cell lines and increased cell invasion in vitro. Using laser-assisted microdissection, we found that in rectal cancer samples from patients treated with neoadjuvant CRT, tumor cell niches enriched for senescent cells bookmark regions of increased mRNA expression levels of EMT-related proteins (Slug, Snail, vimentin) compared with the nearby senescent-null tumor cell niches.

Conclusion:

We have provided, first-hand, strongly suggestive evidence that senescent cancer cells emerging in the context of neoadjuvant CRT for rectal cancer influenced the tumor microenvironment by promoting EMT by way of short-range interactions.

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