Specific chemotherapeutic agents induce metastatic behaviour through stromal‐ and tumour‐derived cytokine and angiogenic factor signalling

Liu, Guanghua; Chen, Yang; Qi, Feifei; Jia, Lin; Lu, Xiangjun; He, Ting; Fu, Yan; Li, Lin; Luo, Yongzhang

doi:10.1002/path.4564

Cited by 34 publications

(35 citation statements)

References 45 publications

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“…As selective pressure occurring upon drug-based therapies can lead to changes in expression levels of genes favoring metastasis and relapse, 31 , 32 we asked whether expression of CD271 and its responsive genes may be involved in mediating a migratory/metastatic phenotype. We took advantage of a life cell imaging system based wound-healing assay, which allowed us to monitor migration of A375 NGFR/CD271 and MeWo Par-NGFR/CD271 and control cells (A375 GFP , MeWo Par-GFP ) within 2 days.…”

Section: Resultsmentioning

confidence: 99%

The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells

et al. 2017

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Several lines of evidence have suggested that stemness and acquired resistance to targeted inhibitors or chemotherapeutics are mechanistically linked. Here we observed high cell surface and total levels of nerve growth factor receptor/CD271, a marker of melanoma-initiating cells, in sub-populations of chemoresistant cell lines. CD271 expression was increased in drug-sensitive cells but not resistant cells in response to DNA-damaging chemotherapeutics etoposide, fotemustine and cisplatin. Comparative analysis of melanoma cells engineered to stably express CD271 or a targeting short hairpin RNA by expression profiling provided numerous genes regulated in a CD271-dependent manner. In-depth analysis of CD271-responsive genes uncovered the association of CD271 with regulation of DNA repair components. In addition, gene set enrichment analysis revealed enrichment of CD271-responsive genes in drug-resistant cells, among them DNA repair components. Moreover, our comparative screen identified the fibroblast growth factor 13 (FGF13) as a target of CD271, highly expressed in chemoresistant cells. Further we show that levels of CD271 determine drug response. Knock-down of CD271 in fotemustine-resistant cells decreased expression of FGF13 and at least partly restored sensitivity to fotemustine. Together, we demonstrate that expression of CD271 is responsible for genes associated with DNA repair and drug response. Further, we identified 110 CD271-responsive genes predominantly expressed in melanoma metastases, among them were NEK2, TOP2A and RAD51AP1 as potential drivers of melanoma metastasis. In addition, we provide mechanistic insight in the regulation of CD271 in response to drugs. We found that CD271 is potentially regulated by p53 and in turn is needed for a proper p53-dependent response to DNA-damaging drugs. In summary, we provide for the first time insight in a CD271-associated signaling network connecting CD271 with DNA repair, drug response and metastasis.

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Section: Resultsmentioning

confidence: 99%

The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells

et al. 2017

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“…Thus, cytotoxic cancer therapy is a double-edged sword; the very treatment meant to control cancer is also helping it survive and grow by inducing a protumorigenic microenvironment. Notably, a single dose of paclitaxel or carboplatin, the chemotherapeutic agents most commonly used in ovarian cancer, stimulates metastasis in mice (11). However, the mechanisms of chemotherapyinduced tumor growth remain poorly understood, providing a challenge for the development of effective treatments (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Gartung

Yang

Sukhatme

et al. 2019

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

113

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While chemotherapy remains a mainstay in cancer treatment, growing evidence indicates that it may stimulate tumor growth. Other cancer therapies including radiation, immunotherapy, and stem cell transplantation may also trigger the release of pro‐inflammatory and pro‐tumorigenic cytokines in the tumor stroma. We recently demonstrated that although cancer therapy reduces tumor burden by killing tumor cells, the resulting dead cells, or ‘debris', can promote tumor growth by stimulating the release of cytokines. Chemotherapy fails to generate remission in over 70% of patients with ovarian cancer, is rarely curative, and simultaneously creates tumor cell debris. Thus, cancer therapy is inherently a double‐edged sword and targeting a single cytokine or pathway may not prevent therapy‐induced cancer. Soluble epoxide hydrolase (sEH) inhibitors have been shown to stimulate the resolution of inflammation by promoting the synthesis of pro‐resolving mediators and counter‐regulating pro‐inflammatory cytokines. In this study, tumor cell debris was prepared in vitro by treating either murine or human ovarian tumor cells with first‐line platinum or taxane‐based cytotoxic chemotherapies used for treating ovarian cancer (e.g. cisplatin, carboplatin, or paclitaxel). Chemotherapy‐generated tumor cell debris stimulated ovarian tumor growth in both immunocompetent and immunocompromised hosts. Debris triggered macrophage production of a series of pro‐inflammatory and pro‐angiogenic cytokines. Further, LC‐MS‐MS–based oxylipin profiling of tumor cell debris generated by chemotherapy revealed a pathological release of tumor‐promoting bioactive lipids (‘eicosanoid storm’) including cyclooxygenase (COX)‐derived prostaglandins, lipoxygenase‐derived HETEs, CYP450‐derived DiHOMEs and EpOMEs. We hypothesize that dual COX‐2/sEH inhibition may be a novel modality in suppressing ovarian tumor growth by stimulating the natural debris‐clearing process. A dual COX‐2/sEH inhibitor, PTUPB, suppressed debris‐induced cytokines (e.g. TNFα, CCL2, CCL4, CXCL2, G‐CSF, ICAM‐1, MMP‐9, and PAI‐1) and eicosanoids (e.g. PGF2a, PGD2, and PGJ2). PTUPB also delayed the onset of debris‐stimulated tumor growth in an ovarian cancer (ID8) model, achieving sustained survival over 80 days post‐injection. It is imperative to overcome the predicament between killing tumor cells and the inherent tumor‐promoting activity of the debris. Thus, dual inhibition of COX‐2/sEH may be a novel approach in cancer therapy to suppress the therapy‐induced cytokine/eicosanoid storm and debris‐stimulated tumor growth. Support or Funding Information National Cancer Institute grant RO1 01CA170549‐02; ROCA148633‐01A4; NIEHS Superfund Research Program RO1 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…A single dose of PXL to breast cancer (BC) patients doubles the blood level of inflammatory cytokines [225]. An independent study of BC patients before and after PXL therapy confirmed these data and further demonstrated in mice that PXL significantly increases tumor recruitment of BM-derived progenitors [226]. An additional study in BC patients found that PXL increased mobilization of myeloid-derived progenitors by >300% [227].…”

Section: Indirect Provascular Effects Of Tlr4 Through Differentiationmentioning

confidence: 82%

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Ran¹,

Bhattarai²,

Patel³

et al. 2020

Translational Studies on Inflammation

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Toll-like receptor-4 (TLR4) is a powerful pathway best known for inducing inflammation in response to bacteria-produced lipopolysaccharide. TLR4 is also activated by endogenous ligands produced by host-damaged cells and a chemo-drug paclitaxel. Under normal conditions, TLR4 is expressed mainly in macrophages and, at a lower level, in epithelial, endothelial, and stromal cells. Activated TLR4 significantly increases inflammatory cytokines and enhances cell proliferation, migration, invasion, and survival. While these functions in normal cells are essential for host defense and tissue repair, TLR4 overexpression in malignant cells promotes tumor growth and metastasis. This is because pro-oncogenic effects of activated TLR4 in tumor cells are amplified by similar event in TLR4-positive tumor-associated cells including endothelial cells and their mobilized progenitors. The collective activation of multiple cell types within the tumor promotes chemoresistance and metastasis. Here, we summarize the current knowledge of the TLR4 pathway and its functional outcomes in normal and tumor cells. We also discuss its underappreciated role in supporting tumor progression through vascular activation and recruitment of endothelial progenitors. The review considers several open questions regarding the impact of TLR4-mediated pro-and antitumor effects, structural requirements for recognition of the TLR4 complex, and a potential contribution of chemotherapy to tumor spread.

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Specific chemotherapeutic agents induce metastatic behaviour through stromal‐ and tumour‐derived cytokine and angiogenic factor signalling

Cited by 34 publications

References 45 publications

The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells

The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

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