A Role for Fibroblasts in Mediating the Effects of Tobacco-Induced Epithelial Cell Growth and Invasion

Coppé, Jean‐Philippe; Boysen, Megan; Sun, Chung Ho; Wong, Brian J. F.; Kang, Mo K.; Park, No-Hee; Desprez, Pierre-Yves; Campisi, Judith; Krtolica, Ana

doi:10.1158/1541-7786.mcr-08-0062

Cited by 66 publications

(53 citation statements)

References 53 publications

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“…Chemotactic signaling is commonly observed in response to DNA damage (11)(12)(13). We previously reported a loss of villus goblet cells and an increase in acute inflammatory cells in the SI of irinotecan-treated mice (14).…”

Section: Significancementioning

confidence: 97%

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Tinkum

Stemler

White

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to highdose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.stem cells | DNA damage | chemotherapy | fasting C ancer patients undergoing chemotherapy experience high rates of morbidity, despite regimens that attempt to balance timing and dose intensity to mitigate off-target effects and doselimiting toxicities (1-3). Interestingly, fasting has been shown to provide host-protective effects against high-dose chemotherapyinduced toxicity in preclinical and clinical studies. For example, etoposide, which forms a ternary complex with DNA and topoisomerase II causing DNA double-strand breaks (DSBs), is far less toxic if mice are fasted before treatment (4). Fasting has also been shown to protect normal, but not cancer cells, from the toxicity of chemotherapy, thereby extending the lifespan of tumorbearing mice (4-8).Because of the rapid rate of epithelial cell proliferation in the small intestine (SI), gastrointestinal (GI) toxicity is one of the most common complications for a variety of chemotherapeutic treatments (9). Therefore, we investigated if fasting was capable of mitigating the GI toxicity normally associated with high-dose chemotherapy. Herein, we demonstrate that mice allowed to feed ad libitum before receiving high-dose chemotherapy showed marked histological changes to SI epithelium before death. These histological changes reflected loss of regenerative capacity as a result of stem cell depletion as well as structural damage from inflammatory cell infiltrates, similar to the SI response to high-dose ionizing radiation (10). In contrast, SI homeostasis was preserved in fasted mice by protection of stem cell viability and prevention of proinflammatory cell infiltrates. These results indicate that fasting mitigates GI side effects associated with chemotherapy by activating pathways that preserve SI stem cell integrity and by maintaining barrier function.

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Section: Significancementioning

confidence: 97%

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Tinkum

Stemler

White

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…1). As discussed below, the EMT is an important phenotypic switch that enables cancer cells to migrate and invade [49].…”

Section: Effects Of the Sasp On Cell Migration And Invasionmentioning

confidence: 99%

Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Laberge

Awad

Campisi

et al. 2011

Cancer Microenvironment

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216

154

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Depending on the cell type and tissue environment, epithelial and mesenchymal cell phenotypes are not static and can be highly dynamic. Epithelial-mesenchymal transitions (EMTs) and reverse EMTs provide flexibility during embryogenesis. While EMTs are a critical normal process during development and wound healing, properties of the EMT have been implicated in human pathology, particularly cancer metastasis. A normal undamaged epithelium does not typically exhibit features of an EMT. However, particularly under the influence of the surrounding microenvironment, cancer cells may reactivate developmental phenotypes out of context in the adult. This reactivation, such as the EMT, can facilitate tumor cell invasion and metastasis, and therefore is a major mechanism of tumor progression. Conversely, cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, thereby constituting a potent tumor suppressive mechanism. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescenceassociated secretory phenotype (SASP) that turns senescent fibroblasts into pro-inflammatory cells having the ability to promote tumor progression, in part by inducing an EMT in nearby epithelial cells. Here, we summarize the potential impacts of SASP factors, particularly interleukins, on tissue microenvironments and their ability to stimulate tumor progression through induction of an EMT.

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“…In another perspective, cancer treatments currently applied as the mainstay of clinical oncology indeed represent a double-edged sword, which is frequently compromised in reality by a therapeutically remodeled TME. The structural change, and more importantly, the functional modification of such a TME, casts a critical step toward development of more advanced malignancies including but not limited to the phenotypic switch via EMT, generation of circulating tumor cells (CTCs), local invasion in primary foci and metastasis to distant organs [76].…”

Section: Patient Centered Medicine 82mentioning

confidence: 99%

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

Sun¹,

Chiao²

2017

Patient Centered Medicine

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Despite successive advances in clinical diagnosis and therapeutic intervention, cancerassociated morbidity and mortality keeps up with escalating cost to human society. Clinicians are confronted with an unprecedented challenge in curing cancers with de novo or acquired resistance. Failure to achieve effective and long-lasting treatment effects arises from the complexity of malignancies, particularly when plasticity of cancer cells is coupled with survival adaptability conferred by the pathologically co-opted stroma in the tumor microenvironment (TME). Targeting immune checkpoints, such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA4), provide significant benefit in multiple tumor types and produce substantial anticancer responses. Tissue resident stromal cells, although damaged together with cancer cells upon cytotoxic treatments, represent an everreplenishing source that contributes to tumor restoration from residual cancer cells in the post-therapy stage. The TME displays a continually changing landscape, generating significant impacts on treatment outcome in clinics. Moving forward, implementing patient-specific analysis in clinical oncology with TME-oriented agents will significantly improve the specificity and efficacy of targeted therapies, thereby accelerating the translation of novel conceptions and groundbreaking discoveries in the TME biology through multiple bench-to-bed pipelines in current settings of precision cancer medicine.

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A Role for Fibroblasts in Mediating the Effects of Tobacco-Induced Epithelial Cell Growth and Invasion

Cited by 66 publications

References 53 publications

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

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