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Abstract Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both “separated” and “contact” scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.
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Can we understand the mechanisms of tumor formation by analyzing dynamics of cancer initiation?
Abstract Cancer is a collection of related genetic diseases exhibiting uncontrolled cell growth that interferes with normal functioning of human organisms. It results from accumulation of unfavorable mutations in tissues. While the biochemical picture of how cancer appears is known, the molecular mechanisms of tumor formation remain not fully understood despite tremendous efforts of researchers in multiple fields. New approaches for investigating cancer are constantly sought. In this paper, we discuss a powerful method of clarifying better a more microscopic picture of cancer by analyzing the dynamics of tumor formation. Using physics- and chemistry-inspired discrete-state stochastic description of cancer initiation, it is shown how the mechanisms of tumor formation can be uncovered. This approach is suggested as a powerful new physical-chemical tool for a better understanding of complex processes associated with cancer.
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- PAR ID:
- 10324760
- Date Published:
- Journal Name:
- Europhysics Letters
- Volume:
- 137
- Issue:
- 2
- ISSN:
- 0295-5075
- Page Range / eLocation ID:
- 27001
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1209/0295-5075/ac5ddc
