Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have ...Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.展开更多
Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role th...Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis.Much of this research has focused on the use of the airway repair model to study response to injury.In this review,we discuss the primary evidence of the role that cancer stem cells play in lung cancer development.The implications of a stem cell origin of lung cancer are reviewed,and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.展开更多
To prevent potential overtreatment of metastatic non-small cell lung cancer, the individual parameters of circulating hematopoietic stem cells (HSCs) (percentage of CD133+ HSCs, CD34+ HSCs, and mitotic activity in the...To prevent potential overtreatment of metastatic non-small cell lung cancer, the individual parameters of circulating hematopoietic stem cells (HSCs) (percentage of CD133+ HSCs, CD34+ HSCs, and mitotic activity in the circulating lymphocyte fraction) were measured before conventional cytotoxic therapy in 35 patients by flow cytometry and then compared retrospectively with their individual survival periods. The plot of dependence of the CD133+ HSC × mitotic activity product versus CD34+ HSC revealed the prognostic properties during the survival period (range 0.3 - 124 months). Discrimination of patients with an expected survival shorter than 12 months was possible based on the positions of individual points on the plot, with a sensitivity and specificity of ∼100 each and a diagnostic odds ratio of 1250. The evaluation of individual lymphoproliferative resources before cytotoxic treatment may be useful for the optimal therapeutic compromise between the desired inhibition of malignant target cells and the life-threatening depression of lymphocytopoiesis.展开更多
Objective To investigate the function and mechanism of embryonic stem cells again Lewis non-small cell lung cancer in vivo. Methods Based on the mouse Lewis non-small cell lung cancer model,we have tested some tumor g...Objective To investigate the function and mechanism of embryonic stem cells again Lewis non-small cell lung cancer in vivo. Methods Based on the mouse Lewis non-small cell lung cancer model,we have tested some tumor growth indexes and investigated the immune response of embryonic stem cells against cancer cells. Results Compared with the mice in control group,mice展开更多
Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that bind...Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.展开更多
AIM:To investigate whether hypoxia induces dedifferentiation of non-small cell lung cancer(NSCLC) cells and whether a hypoxia-inducible factor(HIF) inhibitor is able to suppress the process.METHODS:Human lung adenocar...AIM:To investigate whether hypoxia induces dedifferentiation of non-small cell lung cancer(NSCLC) cells and whether a hypoxia-inducible factor(HIF) inhibitor is able to suppress the process.METHODS:Human lung adenocarcinoma A549 cells and squamous carcinoma QG56 cells were cultured under normoxic(21%O_2) or hypoxic(4%or 1%O_2) conditions.The expression of the following genes were examined by reverse transcription-polymerase chain reaction,Western blotting and/or immunofluorescence:HIF-1α and HIF-2αsubunits;differentiation marker genes,namely surfactant protein C(SP-C)(type Ⅱ alveolar cell marker),CC10(type I alveolar cell marker) and aquaporin 5(AQP5)(Clara cell marker);and stem cell-associated genes,namely CD133,0CT4,and Musashi-1(MSI1).The tumor sphere-forming ability of the cells was evaluated by culturing them in serum-free growth factor-rich medium containing epidermal growth factor(EGF) and fibroblast growth factor(FGF).CD133 expression in hypoxic regions in A549 tumors was examined by double-immunostaining of tissue cryosections with an anti-2-nitroimidazole EF5 antibody and an anti-CD133 antibody.The metastatic ability of A549 cells was examined macroscopically and histologically after injecting them into the tail vein of immunocompromised mice.RESULTS:A549 cells primarily expressed SP-C,and QG56 cells expressed CC10 and AQP5.Exposure of A549 cells to hypoxia resulted in a marked downregulation of SP-C and upregulation of CD133,OCT4,and MSI1 in a time-dependent manner.Moreover,hypoxia mimetics,namely desferrioxamine and cobalt chloride,elicited similar effects.Ectopic expression of the constitutively active HIF-la subunit also caused the downregulation of SP-C and upregulation of CD133 and MSI1 but not OCT4,which is a direct target of HIF-2.Hypoxia enhanced the sphere-forming activity of A549 cells in serum-free medium containing EGF and FGF.Similarly,hypoxia downregulated the expression of CC10 and AQP5 genes and upregulated CD133,OCT4,and MSI1 genes in QG56 cells.TX-402(3-amino-2-quinoxalinecarbonitrile 1,4-dioxide),which is a small molecule inhibitor of the expression of HIF-1α and HIF-2αsubunits under hypoxic conditions,inhibited the upregulation of SP-C'and hypoxia-induced down-regulation of CD133,OCT4,and MSI1.Notably,TX-402 significantly suppressed the hypoxia-enhanced lung-colonizing ability of A549 cells.CONCLUSION:Hypoxia induces the de-differentiation of NSCLC cells into cancer stem cell-like cells,and HIF inhibitors are promising agents to prevent this process.展开更多
Lung cancer has become a leading cause of cancer-related death because of its high morbidity and mortality.Although some progress has been made in the diagnosis,surgery,chemoradiotherapy,and other aspects of lung canc...Lung cancer has become a leading cause of cancer-related death because of its high morbidity and mortality.Although some progress has been made in the diagnosis,surgery,chemoradiotherapy,and other aspects of lung cancer in the last decade,actually there is no substantial breakthrough for the 5-year survival rate of patients has no significant improvement and is still below 15%.Plenty of evidence suggests that malignant tumors including lung cancer have a unique subgroup of cells featured with self-renewal and multidirectional differentiation potential.Cancer stem cells(CSCs)are the root of tumor growth and metastasis,and the characteristic changes of malignant phenotype(such as recurrence,invasion and metastasis,and drug resistance)are closely linked with CSCs.This paper explored the possible correlated mechanism of the complex interaction between lung cancer stem cells(LCSCs)and lung cancer microenvironment,to provide ideas for the R&D of relevant treatment technologies,the promotion of the progress in traditional medical technology,and the breakthrough of the bottleneck of long-term effect of lung cancer.展开更多
Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. H...Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.展开更多
基金supported by the Natural Science Foundation of Hubei Province(no.2021CFB372 to Hua Xiong).
文摘Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.
文摘Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis.Much of this research has focused on the use of the airway repair model to study response to injury.In this review,we discuss the primary evidence of the role that cancer stem cells play in lung cancer development.The implications of a stem cell origin of lung cancer are reviewed,and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.
文摘To prevent potential overtreatment of metastatic non-small cell lung cancer, the individual parameters of circulating hematopoietic stem cells (HSCs) (percentage of CD133+ HSCs, CD34+ HSCs, and mitotic activity in the circulating lymphocyte fraction) were measured before conventional cytotoxic therapy in 35 patients by flow cytometry and then compared retrospectively with their individual survival periods. The plot of dependence of the CD133+ HSC × mitotic activity product versus CD34+ HSC revealed the prognostic properties during the survival period (range 0.3 - 124 months). Discrimination of patients with an expected survival shorter than 12 months was possible based on the positions of individual points on the plot, with a sensitivity and specificity of ∼100 each and a diagnostic odds ratio of 1250. The evaluation of individual lymphoproliferative resources before cytotoxic treatment may be useful for the optimal therapeutic compromise between the desired inhibition of malignant target cells and the life-threatening depression of lymphocytopoiesis.
文摘Objective To investigate the function and mechanism of embryonic stem cells again Lewis non-small cell lung cancer in vivo. Methods Based on the mouse Lewis non-small cell lung cancer model,we have tested some tumor growth indexes and investigated the immune response of embryonic stem cells against cancer cells. Results Compared with the mice in control group,mice
文摘Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.
基金Supported by Grant-in-Aid from the Ministry of Education,Culture,Sports,Science and Technology,(No.18590280)the Foundation for the Promotion of Cancer Research in Japan+1 种基金Grant-in-Aid for Japan Arteriosclerosis Research FoundationShimane University"S-TAKUMI Medical Nanotechnology"Project
文摘AIM:To investigate whether hypoxia induces dedifferentiation of non-small cell lung cancer(NSCLC) cells and whether a hypoxia-inducible factor(HIF) inhibitor is able to suppress the process.METHODS:Human lung adenocarcinoma A549 cells and squamous carcinoma QG56 cells were cultured under normoxic(21%O_2) or hypoxic(4%or 1%O_2) conditions.The expression of the following genes were examined by reverse transcription-polymerase chain reaction,Western blotting and/or immunofluorescence:HIF-1α and HIF-2αsubunits;differentiation marker genes,namely surfactant protein C(SP-C)(type Ⅱ alveolar cell marker),CC10(type I alveolar cell marker) and aquaporin 5(AQP5)(Clara cell marker);and stem cell-associated genes,namely CD133,0CT4,and Musashi-1(MSI1).The tumor sphere-forming ability of the cells was evaluated by culturing them in serum-free growth factor-rich medium containing epidermal growth factor(EGF) and fibroblast growth factor(FGF).CD133 expression in hypoxic regions in A549 tumors was examined by double-immunostaining of tissue cryosections with an anti-2-nitroimidazole EF5 antibody and an anti-CD133 antibody.The metastatic ability of A549 cells was examined macroscopically and histologically after injecting them into the tail vein of immunocompromised mice.RESULTS:A549 cells primarily expressed SP-C,and QG56 cells expressed CC10 and AQP5.Exposure of A549 cells to hypoxia resulted in a marked downregulation of SP-C and upregulation of CD133,OCT4,and MSI1 in a time-dependent manner.Moreover,hypoxia mimetics,namely desferrioxamine and cobalt chloride,elicited similar effects.Ectopic expression of the constitutively active HIF-la subunit also caused the downregulation of SP-C and upregulation of CD133 and MSI1 but not OCT4,which is a direct target of HIF-2.Hypoxia enhanced the sphere-forming activity of A549 cells in serum-free medium containing EGF and FGF.Similarly,hypoxia downregulated the expression of CC10 and AQP5 genes and upregulated CD133,OCT4,and MSI1 genes in QG56 cells.TX-402(3-amino-2-quinoxalinecarbonitrile 1,4-dioxide),which is a small molecule inhibitor of the expression of HIF-1α and HIF-2αsubunits under hypoxic conditions,inhibited the upregulation of SP-C'and hypoxia-induced down-regulation of CD133,OCT4,and MSI1.Notably,TX-402 significantly suppressed the hypoxia-enhanced lung-colonizing ability of A549 cells.CONCLUSION:Hypoxia induces the de-differentiation of NSCLC cells into cancer stem cell-like cells,and HIF inhibitors are promising agents to prevent this process.
文摘Lung cancer has become a leading cause of cancer-related death because of its high morbidity and mortality.Although some progress has been made in the diagnosis,surgery,chemoradiotherapy,and other aspects of lung cancer in the last decade,actually there is no substantial breakthrough for the 5-year survival rate of patients has no significant improvement and is still below 15%.Plenty of evidence suggests that malignant tumors including lung cancer have a unique subgroup of cells featured with self-renewal and multidirectional differentiation potential.Cancer stem cells(CSCs)are the root of tumor growth and metastasis,and the characteristic changes of malignant phenotype(such as recurrence,invasion and metastasis,and drug resistance)are closely linked with CSCs.This paper explored the possible correlated mechanism of the complex interaction between lung cancer stem cells(LCSCs)and lung cancer microenvironment,to provide ideas for the R&D of relevant treatment technologies,the promotion of the progress in traditional medical technology,and the breakthrough of the bottleneck of long-term effect of lung cancer.
基金supported by grants from the Natural Science Foundation of China(Nos.81771966,31371404,31401187 and 31571429)the Fundamental Research Funds for the Central Universities(Lin Mei,China)+4 种基金the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2014A030306036,China)the Natural Science Foundation of Guangdong,China(2015A030311041,2015A030313763)Science and Technology Planning Project of Guangdong Province,China(Nos.2016A020217001 and 2014A020212466)the Shenzhen Science and Technology Innovation Committee(JCYJ20160301152300347,JCYJ20160531195129079,JCYJ20170412095722235,JCYJ2016042-9171931438,and GJHZ20150316160614842,China)Guangdong Province Medical Science and Technology Research Fund(A2016445,China)
文摘Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.
