Great efforts have been made in revealing the mechanisms governing cancer resistance and recurrence. The in-situ effects of cell death, caused by hypoxia and metabolic stress, were largely studied in association with inflammation. However, in this work, we focused on the direct effects of necrosis on cancer promotion and on the tumor microenvironment. The conditions leading to cell necrosis, upon nutrient and oxygen deprivation, were recapitulated in-vitro and were used to generate samples for computational proteomic analysis. Under these conditions, we identified clusters of enriched pathways that may be involved in tumor resistance, leading to cancer recurrence. We show that the content of necrotic cells enhances angiogenesis and proliferation of endothelial cells, induces vasculature, as well as increases migration, invasion, and cell-cell interactions. In-vivo studies, where MDA-MB-231 xenografts were exposed to necrotic lysates, resulted in an increase in both proliferation and angiogenesis. Histological analysis of tumor tissues revealed high expression levels of key mediators that were identified by proteomic analysis. Moreover, when cells were injected systemically, coupled with necrotic lysates, a higher number of large lesions was detected in the lung. Finally, using xenografts, we demonstrated that combining an antagonist of a necrotic signal with an anticancer treatment potentiates the prolonged therapeutic effect. This approach suggests a paradigm shift in which targeting late necrotic-secreted factors may increase survival and enhance the efficacy of anticancer therapy.
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This study was kindly supported by grants from the Marie Curie Career Integration Grants (CIG) (No. 0305116), Israel Cancer Association (ICA) (No. 0394691), Israel Foundation of Science (ISF) (No. 0394883), David R. Blum Center for Pharmacy at The Hebrew University, The Shukor Gladi fund, The Frances Brody fund, and Eliyahu Pen Fund. We thank Dr. Gil Hornung and The De Botton Protein Profiling Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, for their support of the proteomic data generating process.
BO: conceived the concept, provided valuable discussions regarding interpreting the experimental data, and was involved in drafting the manuscript. KBA: prepared the manuscript, analyzed all the data (except for the proteomics experiment), performed the S.C. and I.V. in-vivo experiments, and the majority of the in-vitro experiments. FA: performed the computational analysis of the proteomic assay. EA: performed the transfection and siRNA analysis ST: performed the spheroid assembly and spheroid invasion assays. SH: performed the cell migration assays. SO: assisted in the in-vivo experiments. BM: provided valuable scientific interpretation. All authors read and approved the final manuscript.
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The authors declare that they have no conflict of interest.
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Karsch-Bluman, A., Feiglin, A., Arbib, E. et al. Tissue necrosis and its role in cancer progression. Oncogene 38, 1920–1935 (2019) doi:10.1038/s41388-018-0555-y
International Journal of Molecular Sciences (2019)
Pathology - Research and Practice (2019)