Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

Dong, Kechen; Liu, Jianping; Zhou, Wei; Zhang, Guanglin

doi:10.3389/fgene.2022.930248

Cited by 4 publications

(2 citation statements)

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“…Furthermore, senescent cells may also favor cancer stemness, 86 as observed here and by others in response to 5FU 87 and, to a greater extent, to OXA 51,88–90 . As a final consequence of the enrichment of senescent cells in the tumor microenvironment, the protumor effects exerted by senescence have a dominant effect on the nonproliferative phenotype of these cells since high levels of senescence are associated with a worse prognosis in CRC 91–93 . Thus, CRC patients with a molecular background susceptible to senescence, such as the HCT116 lineage, could benefit from the use of senolytic therapies after chemotherapy, a strategy that has already been tested in other tumor types 94…”

Section: Discussionmentioning

confidence: 54%

“…51,[88][89][90] As a final consequence of the enrichment of senescent cells in the tumor microenvironment, the protumor effects exerted by senescence have a dominant effect on the nonproliferative phenotype of these cells since high levels of senescence are associated with a worse prognosis in CRC. [91][92][93] Thus, CRC patients with a molecular background susceptible to senescence, such as the HCT116 lineage, could benefit from the use of senolytic therapies after chemotherapy, a strategy that has already been tested in other tumor types. 94 Finally, the use of different drug concentrations in the cell lines due to the differential acute sensitivity is also translationally relevant since patients may have varied pharmacokinetics, culminating in varying levels of serum drug concentration even in response to similar doses of chemotherapy administered.…”

Section: Discussionmentioning

confidence: 99%

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The rational modulation of autophagy sensitizes colorectal cancer cells to 5‐fluouracil and oxaliplatin

Baldasso‐Zanon,

Silva,

Franco

et al. 2024

J of Cellular Biochemistry

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Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5‐fluorouracil (5FU) and Oxaliplatin (OXA) are the first‐line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single‐drug treatments, the co‐treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co‐treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time‐specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.

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