Our previous studies have showed that C-C motif chemokine ligand 20(CCL20)advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell(BCSC)self-renewal....Our previous studies have showed that C-C motif chemokine ligand 20(CCL20)advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell(BCSC)self-renewal.However,it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment(TME).Here,we observed that polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors.Mechanistically,CCL20 activated the differentiation of granulocyte-monocyte progenitors(GMPs)via its receptor C-C motif chemokine receptor 6(CCR6)leading to the PMN-MDSC expansion.PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors(CCL20-modulated PMN-MDSCs)secreted amounts of C-X-C motif chemokine ligand 2(CXCL2)and increased ALDH+BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway.Furthermore,C-X-C motif chemokine receptor 2(CXCR2)antagonist SB225002 enhanced the docetaxel(DTX)effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors.These findings elucidated how CCL20 modulated the TME to promote cancer development,indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer,especially in CCL20high-expressing breast cancer.展开更多
More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin(DOX). Here we obtained outer-membrane vesicles(O...More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin(DOX). Here we obtained outer-membrane vesicles(OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated Klebsiella pneumonia and prepared doxorubicin-loaded O0MVs(DOX-OMV). Confocal microscopy and in vivo distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis in vitro as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs’ appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX in vivo. Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.展开更多
Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we ...Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis(ETBF)was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy.ETBF,albeit at low biomass,secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance.Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein.NOD1 was highly expressed on ALDH+breast cancer stem cells(BCSCs)and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation,thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs.NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.展开更多
基金The National Key Research and Development Program of China(2020YFA0112300)National Natural Science Foundation of China(82230103,81930075,82203399,82073267)+4 种基金“Ten Thousand Plan”-National High-Level Talents Special Support Plan(WR-YK5202101)Program for Outstanding Leading Talents in ShanghaiProgram for Outstanding Medical Academic Leader in Shanghai(2019LJ04)Program of Shanghai Academic/Technology Research Leader(20XD1400700)The innovative research team of high-level local university in Shanghai.
文摘Our previous studies have showed that C-C motif chemokine ligand 20(CCL20)advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell(BCSC)self-renewal.However,it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment(TME).Here,we observed that polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors.Mechanistically,CCL20 activated the differentiation of granulocyte-monocyte progenitors(GMPs)via its receptor C-C motif chemokine receptor 6(CCR6)leading to the PMN-MDSC expansion.PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors(CCL20-modulated PMN-MDSCs)secreted amounts of C-X-C motif chemokine ligand 2(CXCL2)and increased ALDH+BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway.Furthermore,C-X-C motif chemokine receptor 2(CXCR2)antagonist SB225002 enhanced the docetaxel(DTX)effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors.These findings elucidated how CCL20 modulated the TME to promote cancer development,indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer,especially in CCL20high-expressing breast cancer.
基金sponsored by Scientific and Innovative Action Plan of Shanghai(No.18431902800,China)National Natural Science Foundation of China(No.81572979)+1 种基金Project of Shanghai Health and Family Planning Commission(201940102,China)National Key Basic Research Program of China(2015CB931800)
文摘More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin(DOX). Here we obtained outer-membrane vesicles(OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated Klebsiella pneumonia and prepared doxorubicin-loaded O0MVs(DOX-OMV). Confocal microscopy and in vivo distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis in vitro as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs’ appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX in vivo. Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.
基金supported by National Key Research and Development Program of China(2023YFC2506400,2020YFA0112300)National Natural Science Foundation of China(Grant Nos.82230103,81930075,82073267,82203399,82072903)+7 种基金“Ten Thousand Plan”—National High-Level Talents Special Support Plan WR-YK5202101Program of Shanghai Academic/Technology Research Leader 20XD1400700Program for Outstanding Medical Academic Leader in Shanghai(2019LJ04)The innovative research team of high-level local university in ShanghaiThe Fudan University Research Foundation(IDH 1340042)The Research Foundation of the Fudan University Shanghai Cancer Center(YJRC1603)Shanghai Anticancer Association EYAS PROJECT(SACA-CY23B07)The Natural Science Foundation of Hunan Province(2020JJ4916).
文摘Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis(ETBF)was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy.ETBF,albeit at low biomass,secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance.Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein.NOD1 was highly expressed on ALDH+breast cancer stem cells(BCSCs)and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation,thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs.NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.