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The unfolding story of dying tumor cells during cancer treatment.

ABSTRACT: Generally, the demise of cancer cells in different ways enables the body to clear these harmful cells. However, cancer cells obtain unlimited replication and immortality from successful circumvention of cell death via various mechanisms. Some evidence suggests that treatment-induced dying tumor cells even promote cancer progression. Notably, therapeutic interventions to harness the immune system against tumor cells have shown complicated influences in clinics. Herein, there is an urgent need to clarify the underlying mechanisms that influence the outcome and regulation of the immune system during cancer treatment. In this review, we provide an account on the cell death modes and the relationship between dying tumor cells with tumor immune microenvironment during cancer treatment, focusing on immunotherapy, from mechanistic standpoint to emerging limitations and future directions.

SUBMITTER: He S

PROVIDER: S-EPMC10040581 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The unfolding story of dying tumor cells during cancer treatment.

He Sijia S Huang Qian Q Cheng Jin J

Frontiers in immunology 20230313

Generally, the demise of cancer cells in different ways enables the body to clear these harmful cells. However, cancer cells obtain unlimited replication and immortality from successful circumvention of cell death <i>via</i> various mechanisms. Some evidence suggests that treatment-induced dying tumor cells even promote cancer progression. Notably, therapeutic interventions to harness the immune system against tumor cells have shown complicated influences in clinics. Herein, there is an urgent n ...[more]

PMID: 36993986

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Project description:Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed using a pan PKC inhibitor GF109203x and a specific PKCδ inhibitor, rottlerin. Additionally, we found significantly increased phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK1/2) in the irradiated Panc1 cells. Mechanistically, PKCδ cleavage was attenuated in both DN_C3 and DN_C7 transduced Panc1 cells, and both Akt and p38 MAPK phosphorylation were attenuated in DN_PKCδ transduced Panc1 cells following radiation. Thus, this report suggests a novel finding that cellular signaling caspase 3/7-PKCδ-Akt/p38 MAPK is crucial to the repopulation in Panc1 cells after radiotherapy.

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The unfolding story of dying tumor cells during cancer treatment.

Publications

The unfolding story of dying tumor cells during cancer treatment.

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