Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesi...Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.展开更多
Recently,phage display technology has been announced as the recipient of Nobel Prize in Chemistry 2018.Phage display technique allows high affinity target-binding peptides to be selected from a complex mixture pool of...Recently,phage display technology has been announced as the recipient of Nobel Prize in Chemistry 2018.Phage display technique allows high affinity target-binding peptides to be selected from a complex mixture pool of billions of displayed peptides on phage in a combinatorial library and could be further enriched through the biopanning process;proving to be a powerful technique in the screening of peptide with high affinity and selectivity.In this review,we will first discuss the modifications in phage display techniques used to isolate various cancer-specific ligands by in situ,in vitro,in vivo,and ex vivo screening methods.We will then discuss prominent examples of solid tumor targeting-peptides;namely peptide targeting tumor vasculature,tumor microenvironment(TME)and overexpressed receptors on cancer cells identified through phage display screening.We will also discuss the current challenges and future outlook for targeting peptidebased therapeutics in the clinics.展开更多
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-017National Natural Science Foundation of China,Grant/Award Number:81970107+12 种基金State Key Laboratory of Experimental Hematology Research,Grant/Award Number:Z22-02Tianjin“131”Science Fund for Creative Research Groups,Grant/Award Number:2021Swedish Research Council,Grant/Award Numbers:2016-02215,2019-01502,2020-06121,2021-06122National Key R&D Program of China,Grant/Award Number:2020YFC0846600Hong Kong Centre for Cerebro-cardiovascular Health EngineeringSwedish Cancer Foundation,Grant/Award Number:200734PjFSwedish Children’s Cancer Foundation,Grant/Award Number:PR2018-0107Strategic Research Areas(SFO)-Stem Cell and Regenerative Medicine FoundationKarolinska Institute distinguished professor awardKarolinska Institute FoundationScandinavia-Japan Sasakawa Foundation,Grant/Award Number:81801163Doctor Fund of Shandong Natural Science Foundation,Grant/Award Number:ZR201807060846Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships。
文摘Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.
基金This work was supported by grants from the National Key Research and Development Program of China(2016YFC1302300)the Natural Science Foundation of China(Grant Nos.81720108029,81621004,81490750,81874226 and 81803020)+2 种基金Guangdong Science and Technology Department(2016B030229004)Guangzhou Science Technology and Innovation Commission(201803040015)The research is partly supported by Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foun datio n.
文摘Recently,phage display technology has been announced as the recipient of Nobel Prize in Chemistry 2018.Phage display technique allows high affinity target-binding peptides to be selected from a complex mixture pool of billions of displayed peptides on phage in a combinatorial library and could be further enriched through the biopanning process;proving to be a powerful technique in the screening of peptide with high affinity and selectivity.In this review,we will first discuss the modifications in phage display techniques used to isolate various cancer-specific ligands by in situ,in vitro,in vivo,and ex vivo screening methods.We will then discuss prominent examples of solid tumor targeting-peptides;namely peptide targeting tumor vasculature,tumor microenvironment(TME)and overexpressed receptors on cancer cells identified through phage display screening.We will also discuss the current challenges and future outlook for targeting peptidebased therapeutics in the clinics.