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DNA Damage-Mediated Induction of a Chemoresistant Niche
Open accessAbstract
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.
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“These chemoprotective SASP factors include WNT16B, IL-6, and TIMP-1 (tissue inhibitor of metalloproteinases-1).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [134]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Even more ironic is the finding that senescent cells, particularly those that senesce in response to DNA-damaging radiation or chemotherapeutic agents, secrete factors that can protect neighboring tumor cells from being killed by those same chemotherapeutic agents (133, 134).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [134]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Antibody against IL-6, gp130 siRNA, or dominant-negative STAT3 enhanced chemo-induced death in lymphoma (Gilbert and Hemann, 2010), as well as colon cancer (Yun et al., 2012)”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Gilbert and Hemann, 2010
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In the citing paper
“IL-6 and pY-STAT3 induced by chemotherapy promoted premature senescence in lymphoma cells in a paracrine manner, which maintained a minimal residual number of chemoresistant cells that could lead to relapse.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Gilbert and Hemann, 2010
Experimental — accuracy not yet measuredIn the citing paper
“Recent evidence points to tumor microenvironment components as potential participants in the generation of chemoresistance (Denardo et al., 2011; Gilbert and Hemann, 2010; Roodhart et al., 2011; Shaked et al., 2008; Shree et al., 2011).”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Gilbert and Hemann, 2010
In the citing paper
“Recent reports (Denardo et al., 2011; Gilbert and Hemann, 2010) and the present work show that chemotherapy induces a storm of cytokines and chemokines in the tumor microenvironment many of which might be linked to chemoresistance.”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Gilbert and Hemann, 2010
In the citing paper
“The critical role of the microenvironment in tumor progression and response to therapy is being increasingly recognized (Condeelis and Pollard, 2006; Denardo et al., 2011; Gilbert and Hemann, 2010; Shree et al., 2011; Tan et al., 2011).”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Gilbert and Hemann, 2010
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Metadata
- Authors
- Gilbert, L. A., & Hemann, M. T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Corresponding author
- Hemann, Michael T.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 143
- Issue
- 3
- Pages
- 355-366
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2972353
- OpenAlex
- W2124472585
- Cited by
- 428
- References
- 42
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 12 · 2023: 19 · 2022: 32 · 2021: 35 · 2020: 27 · 2019: 37 · 2018: 33 · 2017: 26 · 2016: 29 · 2015: 25 · 2014: 25 · 2013: 40 · 2012: 40
- FWCI
- 22.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1056 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health (5r01ca128803-05)
- Ludwig Center for Molecular Oncology
- National Cancer Institute (R01-CA128803)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- chemoresistance, tumor microenvironment, DNA damage, Burkitt lymphoma, interleukin-6, TIMP-1, thymus, p38 MAPK, genotoxic stress response, senescence, tumor stromal cells, minimal residual disease, tumor recurrence, paracrine signaling
- MeSH terms
- Animals, Burkitt Lymphoma, Cell Survival, DNA Damage, Doxorubicin, Humans, Liver Neoplasms, Thymus Gland, Interleukin-6, Cytokines, Cellular Senescence, Culture Media, Conditioned, Neoplasm, Residual, Cell Culture Techniques, Drug Resistance, Neoplasm, Tissue Inhibitor of Metalloproteinase-1, Paracrine Communication, Endothelial Cells, p38 Mitogen-Activated Protein Kinases, Mice, Janus Kinase 2
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