Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T...Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T cells,have attracted much attention for their excellent therapeutic effects.In this study,we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core viruslike particles(HBc VLPs)therapy using a mouse colon cancer model.Methods Humanized B-h OX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-h OX40 antibody.Tumor growth was monitored.Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors.Results The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth,suggesting that a potent antitumor immunity was induced by the combination therapy.Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells(Teffs)and a significant decrease in regulatory T cells(Tregs)in the tumor microenvironment(TME),which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs.Conclusion Combination therapy of anti-h OX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice,which may represent a potential design strategy for cancer immunotherapy.展开更多
BACKGROUND The role of Tousled-like kinase 1(TLK1)in in gastric cancer(GC)remains unclear.AIM To investigate the expression,biological function,and underlying mechanisms of TLK1 in GC.METHODS We measured TLK1 protein ...BACKGROUND The role of Tousled-like kinase 1(TLK1)in in gastric cancer(GC)remains unclear.AIM To investigate the expression,biological function,and underlying mechanisms of TLK1 in GC.METHODS We measured TLK1 protein expression levels and localized TLK1 in GC cells and tissues by western blot and immunofluorescence,respectively.We transfected various GC cells with lentiviruses to create TLK1 overexpression and knockdown lines and established the functional roles of TLK1 through in vitro colony formation,5-ethynyl-2`-deoxyuridine,and Transwell assays as well as flow cytometry.We applied bioinformatics to elucidate the signaling pathways associated with TLK1.We performed in vivo validation of TLK1 functions by inducing subcutaneous xenograft tumors in nude mice.RESULTS TLK1 was significantly upregulated in GC cells and tissues compared to their normal counterparts and was localized mainly to the nucleus.TLK1 knockdown significantly decreased colony formation,proliferation,invasion,and migration but increased apoptosis in GC cells.TLK1 overexpression had the opposite effects.Bioinformatics revealed,and subsequent experiments verified,that the tumor growth factor-beta signaling pathway was implicated in TLK1-mediated GC progression.The in vivo assays confirmed that TLK1 promotes tumorigenesis in GC.CONCLUSION The findings of the present study indicated that TLK1 plays a crucial role in GC progression and is,therefore,promising as a therapeutic target against this disease.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase f...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.展开更多
This article is concerned with a mathematical model of tumor growth governed by 2<sup>nd</sup> order diffusion equation . The source of mitotic inhibitor is almost periodic and time-dependent within the ti...This article is concerned with a mathematical model of tumor growth governed by 2<sup>nd</sup> order diffusion equation . The source of mitotic inhibitor is almost periodic and time-dependent within the tissue. The system is set up with the initial condition C(r, 0) = C<sub>0</sub>(r) and Robin type inhomogeneous boundary condition . Under certain conditions we show that there exists a unique solution for this model which is almost periodic.展开更多
To study the effect of IL-18 and nitric oxide(NO) on the growth and metastasis of non-small cell lung cancer (NSCLC).Methods Serum IL-18 and nitrate and nitrite levels in 82 patients with NSCLC and 20 healthy control ...To study the effect of IL-18 and nitric oxide(NO) on the growth and metastasis of non-small cell lung cancer (NSCLC).Methods Serum IL-18 and nitrate and nitrite levels in 82 patients with NSCLC and 20 healthy control subjects were measured by using ELISA and Griess.Results The levels of serum IL-18 were (334.2±31.0)ng/L in NSCLC patients and (151.3±22.0)ng/L in control subjects,respectively.The levels of nitrate and nitrite were (237.1±21.0)μmol/L in NSCLC patients and (44.2±15.0)μmol/L in control subjects.The levels of serum IL-18 and nitrate and nitrite were not related with age,gender,histological types in patients with NSCLC.The levels of serum IL-18 was closely associated with TNM stage,lymph node metastasis and distal metastasis,but not with its degree and organ types of metastasis.There was a negative correlation between the levels of serum IL-18 and nitrate and nitrite.Conclusion Serum IL-18 and nitrate and nitrite levels may be useful to evaluate the prognosis of the patients with NSCLC.16 refs,2 tabs.展开更多
AIM:To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation,apoptosis,redox status and vascularization.METHODS:Xenografts of PANC-1 cells were developed in nude mice. Th...AIM:To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation,apoptosis,redox status and vascularization.METHODS:Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups:control and aminoguanidine treated. Tumor growth,survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS),catalase,copper-zinc superoxide dismutase (CuZnSOD),manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally,vascularization was determined by Massons trichromic staining,and by VEGF and CD34 expression.RESULTS:Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells,intratumoral vascularization (trichromic stain) and the expression of Ki-67,Bax,eNOS,CD34,VEGF,catalase,CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01),while the expression of Bcl-2 and GPx did not change.CONCLUSION:The antitumoral action of aminoguanidine is associated with decreased cell proliferation,reduced angiogenesis,and reduced expression of antioxidant enzymes.展开更多
The combined effects of Lvy noise and immune delay on the extinction behavior in a tumor growth model are explored. The extinction probability of tumor with certain density is measured by exit probability. The expre...The combined effects of Lvy noise and immune delay on the extinction behavior in a tumor growth model are explored. The extinction probability of tumor with certain density is measured by exit probability. The expression of the exit probability is obtained using the Taylor expansion and the infinitesimal generator theory. Based on numerical calculations, it is found that the immune delay facilitates tumor extinction when the stability index α < 1, but inhibits tumor extinction when the stability index α > 1. Moreover, larger stability index and smaller noise intensity are in favor of the extinction for tumor with low density. While for tumor with high density, the stability index and the noise intensity should be reduced to promote tumor extinction.展开更多
Dynamical behavior of a tumor-growth model with coupling between non-Gaussian and Gaussian noise terms is investigated. The departure from the Gaussian noise can not only reduce the probability of tumor cells in the a...Dynamical behavior of a tumor-growth model with coupling between non-Gaussian and Gaussian noise terms is investigated. The departure from the Gaussian noise can not only reduce the probability of tumor cells in the active state, induce the minimum of the average tumor-cell population to move toward a smaller non-Gaussian noise, but also decrease the mean first-passage time. The increase of white-noise intensity can increase the tumor-cell population and shorten the mean first-passage time, while the coupling strength between noise terms has opposite effects, and the noise correlation time has a very small effect.展开更多
Dicranostigma Leptopodum (Maxim) Fedde (DL- F), which had been previously documented to suppress oxidative hemolysis of erythrocytes and enhance immune functions of murine peri- toneal macrophages, was investigated fo...Dicranostigma Leptopodum (Maxim) Fedde (DL- F), which had been previously documented to suppress oxidative hemolysis of erythrocytes and enhance immune functions of murine peri- toneal macrophages, was investigated for its effect on anti-tumor activity. Of alkaloids extracted from DLF, five have been identified with employment of chromatographic analysis. An antiproliferative role of these alkaloids was determined on SMMC-7721 Human Hepatoma Ce- lls in an apoptosis-inducing manner, through MTT assaying, Trypan blue exclusion assaying and cytometric analysis of cell cycle distribution. To further examine their inhibitory effects on tumor progression, murine H22 cells were inoculated into Kunming mice to determine the role of these alkaloids of DLF in inhibiting tumor growth in the tumor-implanted mice. It was found that these alkaloids of DLF enhanced the tumor shrinkage effectively wherein its tumor inhibitory rate and immunohistochemistry stain- ing of the tumor were determined and profiled, respectively.展开更多
AIM: To investigate the mechanisms of liver growth and atrophy after portal vein ligation (PVL) and its effects on tumor growth. METHODS: Mice were subjected to PVL, partial hepatectomy, or sham surgery. The morpholog...AIM: To investigate the mechanisms of liver growth and atrophy after portal vein ligation (PVL) and its effects on tumor growth. METHODS: Mice were subjected to PVL, partial hepatectomy, or sham surgery. The morphological alterations, activation of transcription factors, and expression of cytokines and growth factors involved in liver regeneration were evaluated. In a separate set of experiments, murine colorectal carcinoma cells were injected via the portal vein and the effect of each operation on liver tumor growth was studied. RESULTS: Liver regeneration after PVL and partial hepatectomy were very similar. In ligated lobes, various cytokines, transcription factors and regulatory factors were signifi cantly upregulated compared to nonligated lobes after PVL. Atrophy in ligated lobes was a result of early necrosis followed by later apoptosis. Tumor growth was signifi cantly accelerated in ligated compared to non-ligated lobes.CONCLUSION: Tumor growth was accelerated in ligated liver lobes and appeared to be a result of increased growth factor expression.展开更多
We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct.A 76-year-old male was referred to our hospital for treatment of a pancreatic tumo...We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct.A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor.Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas,accompanied with severe dilatation of the main pancreatic duct,which was diagnosed as an intraductal papillary-mucinous neoplasm.We performed distal pancreatectomy and splenectomy.The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma(giant cell type)and adenocarcinoma in the pancreas.There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct.The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery.In this case,we could observe a remarkable intraductal tumor growth into the main pancreatic duct.We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.展开更多
Objective: To investigate whether LCRG1 (Laryngeal Carcinoma Related Gene 1) has tumor suppressor function. Methods: The recombinant plasmid pcDNA3.1(+)/LCRG1 was successfully constructed. The biological effects of LC...Objective: To investigate whether LCRG1 (Laryngeal Carcinoma Related Gene 1) has tumor suppressor function. Methods: The recombinant plasmid pcDNA3.1(+)/LCRG1 was successfully constructed. The biological effects of LCRG1 on Hep-2 cell line were studied by cell transfection, cell growth observation colony formation analysis and tumorigenicity experiments. Results: The LCRG1 gene potently inhibited tumorgenesis in vitro and in vivo, as showed by dramatic growth arrest observed in cell growth analysis and suppression of anchorage-independent growth and tumorigenicity in nude mice. Conclusion: Our results suggested that LCRG1 may be a candidate of tumor suppressor gene.展开更多
Background:Reduced expression of tripartite motif-containing 3(TRIM3) has been reported to be involved in the pathogenesis of human glioblastoma.In our previous research,we found that TRIM3 expression was markedly red...Background:Reduced expression of tripartite motif-containing 3(TRIM3) has been reported to be involved in the pathogenesis of human glioblastoma.In our previous research,we found that TRIM3 expression was markedly reduced in human primary hepatocellular carcinoma(HCC) tissues and that low TRIM3 expression was associated with short survival of HCC patients.However,the role of TRIM3 in liver cancer remains unknown.This study aimed to investigate the function of TRIM3 in liver cancer cells.Methods:The protein levels of TRIM3 in five liver cancer cell lines(SK-Hep1,Hep3 B,Huh7,HepG2,Bel-7402) and one normal liver cell line(L02) were detected with Western blotting.HepG2 and Bel-7402 cells with low TRIM3 expression were infected with recombinant lentiviruses overexpressing TRIM3(LV-TRIM3),whereas Huh7 and Hep3 B cells with high TRIM3 expression were transfected with TRIM3-targeted small interfering RNA(siTRIM3).The functions of TRIM3 in the proliferation,colony formation,cell cycle,migration,invasion,and apoptosis of the above cell lines were examined.The effect ofTRIM3 on tumor growth and metastases in nude mice was also investigated.Results:TRIM3 was overexpressed in HepG2 and Bel-7402 cells with LV-TRIM3 infection,which further reduced proliferation,colony formation,migration,and invasion of both cell lines.Cell cycle analysis showed that TRIM3 overexpression induced G_0/G_1 phase arrest in HepG2 and Bel-7402 cells.Moreover,apoptosis was not increased in HepG2 or Bel-7402 cells overexpressing TRIM3.Contrarily,silencing TRIM3 expression in Huh7 and Hep3 B cells by siTRIM3 led to significantly decreased percentages of both cells in the G_0/G_1 phase and promoted cell proliferation,colony formation,migration,and invasion.In vivo experiment results confirmed that TRIM3 overexpression suppressed tumor growth and metastasis.Conclusions:TRIM3 plays a tumor-suppressing role in the regulation of liver cancer development by reducing cell proliferation through cell cycle arrest at the G_0/G_1 phase.展开更多
<正>A multi-scale continuous-discrete model based on the effects of the p27 gene control is built to simulate the avascular tumor growth. At the tissue level, the continuous Eulerian model is adopted to determin...<正>A multi-scale continuous-discrete model based on the effects of the p27 gene control is built to simulate the avascular tumor growth. At the tissue level, the continuous Eulerian model is adopted to determine the distribution of the concentration of oxygen, the extracellular matrix (ECM), and the matrix-degradative enzyme (MDE). At the cellular level, the discrete Lagrangien model is adopted to determine the movement, the proliferation, and the death of single tumor cells (TCs). At the genetic level, whether a cell is committed to mitosis is determined by solving a set of equations modeling the effects of the p27 gene control. The avascular morphological evolution of the solid tumor growth is simulated, including the radius of the solid tumor, the number of the TCs, the oxygen distribution over time, and the inhibiting effect of the up-regulating p27 gene expression.展开更多
Objective:To study the regulating effect of HSP70 inhibitor(PES) combined with cisplatin on cervical cancer proliferation in vitro and transplanted tumor growth.Methods:Cervical cancer Hela cell lines were cultured an...Objective:To study the regulating effect of HSP70 inhibitor(PES) combined with cisplatin on cervical cancer proliferation in vitro and transplanted tumor growth.Methods:Cervical cancer Hela cell lines were cultured and divided into control group,cisplatin group,PES group and cisplatin+PES group that were treated with serum-free DMEM,cisplatin with final concentration of 10 μmol/L,PES 20 μmol/L and cisplatin 10 μmol/L combined with PES with 20 μmol/L,respectively;animal models with cervical cancer xenografts were established and divided into control group,cisplatin group,PES group and cisplatin+PES group who received intra-tumor injection of normal saline,10 μmol/L cisplatin,20 μmol/L PES as well as 10 μmol/L cisplatin+20 μmol/L PES,respectively.Cell proliferation activity,transplanted tumor volume and mitochondria apoptosis molecule expression were detected.Results:Cell viability value and Bcl-2 mRNA expression in cells of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 mRNA expression in cells were significantly higher than those of control group;transplanted tumor volume and the Bcl-2 mRNA expression in transplanted tumor tissue of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 m RNA expression in transplanted tumor tissue were significantly higher than those of control group.Conclusions:HSP70 inhibitor combined with cislatin can inhibit cervical cancer cell proliferation in vitro and transplanted tumor growth through mitochondrial apoptosis pathway.展开更多
To understand the relationship between the expression of vasCular endothelial growth factor (VEGF) and the growth, metastasis of hepatocellular car cinoma (HCC), immunohistochemistry and Northern blot were used to inv...To understand the relationship between the expression of vasCular endothelial growth factor (VEGF) and the growth, metastasis of hepatocellular car cinoma (HCC), immunohistochemistry and Northern blot were used to investigate VEGF protein and mRNA in 21 cases of HCC with and without rnetastasis.VEGF protein was found in 8 of 9 cases with metastasis, whereas only in 4 of 12 cases without rnetastasis. The Positive rate of the former was significantly higher than that in the latter. VEGF mRNA was detectable in both carcinoma and its surrounding liver tissues, but its level in the former was 2 - 3 times higher than that in the latter. In carcinoma with metastasis, the mRNA level was 5-6 times higher than that without metastasis. It is concluded that VEGF Is closely related to the growth of HCC as well as its metastasis and it might be a useful indicator for the metastatic potential of HCC.展开更多
The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased i...The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased in daily practice and now it is not uncommon to see patients surviving kidney cancer for more than four to five years. Once treatment fails with the first line targeted therapy, head to head comparisons have shown that cabozantinib, nivolumab and the combination of lenvatinib plus everolimus are more effective than everolimus alone and that axitinib is more active than sorafenib. Unfortunately, it is very unlikely that we will ever have prospective data comparing the activity of axitinib, cabozantinib, lenvatinib or nivolumab. It is frustrating to observe the lack of biomarkers that we have in this field, thus there is no firm recommendation about the optimal sequence of treatment in the second line. In the absence of reliable biomarkers, there are several clinical endpoints that can help physicians to make decisions for an individual patient, such as the tumor burden, the expected response rate and the time to achieve the response to each agent, the prior response to the agent administered, the toxicity profile of the different compounds and patient preference. Here, we propose the introduction of the tumor-growth rate(TGR) during first-line treatment as a new tool to be used to select the second line strategy in m RCC. The rapidness of TGR before the onset of the treatment reflects the variability between patients in terms of tumor growth kinetics and it could be a surrogate marker of tumor aggressiveness that may guide treatment decisions.展开更多
Directed capillary ingrowth has long been considered synonymous with tumor vascularization.However,the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting;instead,malig...Directed capillary ingrowth has long been considered synonymous with tumor vascularization.However,the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting;instead,malignant tumors can acquire blood vessels via alternative vascularization mechanisms,such as intussusceptive microvascular growth,vessel co-option,and glomeruloid angiogenesis.Importantly,in response to anti-angiogenic therapies,malignant tumors can switch from one vascularization mechanism to another.In this article,we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology.展开更多
Objective:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhi...Objective:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhibit an M2 phenotype.Our previous studies have shown that the interleukin-33/ST2(IL-33/ST2)axis is essential for activation of the M1 phenotype.This study investigates the role of the IL-33/ST2 axis in TAMs,its effects on tumor growth,and whether it participates in the mutual conversion between the M1 and M2 phenotypes.Methods:Bone marrow-derived macrophages were extracted from wildtype,ST2 knockout(ST2-/-),and Il33-overexpressing mice and differentiated with IL-4.The mitochondrial and lysosomal number and location,and the expression of related proteins were used to analyze mitophagy.Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes.Results:The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels.The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation,thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth(P<0.05)(Figure 4).This metabolic shift was not due to mitochondrial damage,because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout;however,it might be associated with the m TOR activity.Conclusions:These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization,and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.展开更多
基金supported by National Major Science and Technology Projects of China 2017ZX10105015-001-002。
文摘Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T cells,have attracted much attention for their excellent therapeutic effects.In this study,we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core viruslike particles(HBc VLPs)therapy using a mouse colon cancer model.Methods Humanized B-h OX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-h OX40 antibody.Tumor growth was monitored.Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors.Results The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth,suggesting that a potent antitumor immunity was induced by the combination therapy.Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells(Teffs)and a significant decrease in regulatory T cells(Tregs)in the tumor microenvironment(TME),which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs.Conclusion Combination therapy of anti-h OX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice,which may represent a potential design strategy for cancer immunotherapy.
基金Supported by the Key Programs of the Educational Commission of Anhui Province,No.2023AH053313the Research Project of Higher Education in Anhui Province in 2022,No.2022AH051192.
文摘BACKGROUND The role of Tousled-like kinase 1(TLK1)in in gastric cancer(GC)remains unclear.AIM To investigate the expression,biological function,and underlying mechanisms of TLK1 in GC.METHODS We measured TLK1 protein expression levels and localized TLK1 in GC cells and tissues by western blot and immunofluorescence,respectively.We transfected various GC cells with lentiviruses to create TLK1 overexpression and knockdown lines and established the functional roles of TLK1 through in vitro colony formation,5-ethynyl-2`-deoxyuridine,and Transwell assays as well as flow cytometry.We applied bioinformatics to elucidate the signaling pathways associated with TLK1.We performed in vivo validation of TLK1 functions by inducing subcutaneous xenograft tumors in nude mice.RESULTS TLK1 was significantly upregulated in GC cells and tissues compared to their normal counterparts and was localized mainly to the nucleus.TLK1 knockdown significantly decreased colony formation,proliferation,invasion,and migration but increased apoptosis in GC cells.TLK1 overexpression had the opposite effects.Bioinformatics revealed,and subsequent experiments verified,that the tumor growth factor-beta signaling pathway was implicated in TLK1-mediated GC progression.The in vivo assays confirmed that TLK1 promotes tumorigenesis in GC.CONCLUSION The findings of the present study indicated that TLK1 plays a crucial role in GC progression and is,therefore,promising as a therapeutic target against this disease.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2020QH194.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.
文摘This article is concerned with a mathematical model of tumor growth governed by 2<sup>nd</sup> order diffusion equation . The source of mitotic inhibitor is almost periodic and time-dependent within the tissue. The system is set up with the initial condition C(r, 0) = C<sub>0</sub>(r) and Robin type inhomogeneous boundary condition . Under certain conditions we show that there exists a unique solution for this model which is almost periodic.
文摘To study the effect of IL-18 and nitric oxide(NO) on the growth and metastasis of non-small cell lung cancer (NSCLC).Methods Serum IL-18 and nitrate and nitrite levels in 82 patients with NSCLC and 20 healthy control subjects were measured by using ELISA and Griess.Results The levels of serum IL-18 were (334.2±31.0)ng/L in NSCLC patients and (151.3±22.0)ng/L in control subjects,respectively.The levels of nitrate and nitrite were (237.1±21.0)μmol/L in NSCLC patients and (44.2±15.0)μmol/L in control subjects.The levels of serum IL-18 and nitrate and nitrite were not related with age,gender,histological types in patients with NSCLC.The levels of serum IL-18 was closely associated with TNM stage,lymph node metastasis and distal metastasis,but not with its degree and organ types of metastasis.There was a negative correlation between the levels of serum IL-18 and nitrate and nitrite.Conclusion Serum IL-18 and nitrate and nitrite levels may be useful to evaluate the prognosis of the patients with NSCLC.16 refs,2 tabs.
基金Supported by Grants from University of Buenos Aires (B098 and B112)
文摘AIM:To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation,apoptosis,redox status and vascularization.METHODS:Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups:control and aminoguanidine treated. Tumor growth,survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS),catalase,copper-zinc superoxide dismutase (CuZnSOD),manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally,vascularization was determined by Massons trichromic staining,and by VEGF and CD34 expression.RESULTS:Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells,intratumoral vascularization (trichromic stain) and the expression of Ki-67,Bax,eNOS,CD34,VEGF,catalase,CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01),while the expression of Bcl-2 and GPx did not change.CONCLUSION:The antitumoral action of aminoguanidine is associated with decreased cell proliferation,reduced angiogenesis,and reduced expression of antioxidant enzymes.
基金supported by the National Natural Science Foundation of China(Grant Nos.11172233,11272258,and 11302170)
文摘The combined effects of Lvy noise and immune delay on the extinction behavior in a tumor growth model are explored. The extinction probability of tumor with certain density is measured by exit probability. The expression of the exit probability is obtained using the Taylor expansion and the infinitesimal generator theory. Based on numerical calculations, it is found that the immune delay facilitates tumor extinction when the stability index α < 1, but inhibits tumor extinction when the stability index α > 1. Moreover, larger stability index and smaller noise intensity are in favor of the extinction for tumor with low density. While for tumor with high density, the stability index and the noise intensity should be reduced to promote tumor extinction.
基金Project supported by the National Natural Science Foundation of China (Grant Nos. 11005077, 11105095, and 11074184)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (Grant No. 10KJD140003)
文摘Dynamical behavior of a tumor-growth model with coupling between non-Gaussian and Gaussian noise terms is investigated. The departure from the Gaussian noise can not only reduce the probability of tumor cells in the active state, induce the minimum of the average tumor-cell population to move toward a smaller non-Gaussian noise, but also decrease the mean first-passage time. The increase of white-noise intensity can increase the tumor-cell population and shorten the mean first-passage time, while the coupling strength between noise terms has opposite effects, and the noise correlation time has a very small effect.
文摘Dicranostigma Leptopodum (Maxim) Fedde (DL- F), which had been previously documented to suppress oxidative hemolysis of erythrocytes and enhance immune functions of murine peri- toneal macrophages, was investigated for its effect on anti-tumor activity. Of alkaloids extracted from DLF, five have been identified with employment of chromatographic analysis. An antiproliferative role of these alkaloids was determined on SMMC-7721 Human Hepatoma Ce- lls in an apoptosis-inducing manner, through MTT assaying, Trypan blue exclusion assaying and cytometric analysis of cell cycle distribution. To further examine their inhibitory effects on tumor progression, murine H22 cells were inoculated into Kunming mice to determine the role of these alkaloids of DLF in inhibiting tumor growth in the tumor-implanted mice. It was found that these alkaloids of DLF enhanced the tumor shrinkage effectively wherein its tumor inhibitory rate and immunohistochemistry stain- ing of the tumor were determined and profiled, respectively.
文摘AIM: To investigate the mechanisms of liver growth and atrophy after portal vein ligation (PVL) and its effects on tumor growth. METHODS: Mice were subjected to PVL, partial hepatectomy, or sham surgery. The morphological alterations, activation of transcription factors, and expression of cytokines and growth factors involved in liver regeneration were evaluated. In a separate set of experiments, murine colorectal carcinoma cells were injected via the portal vein and the effect of each operation on liver tumor growth was studied. RESULTS: Liver regeneration after PVL and partial hepatectomy were very similar. In ligated lobes, various cytokines, transcription factors and regulatory factors were signifi cantly upregulated compared to nonligated lobes after PVL. Atrophy in ligated lobes was a result of early necrosis followed by later apoptosis. Tumor growth was signifi cantly accelerated in ligated compared to non-ligated lobes.CONCLUSION: Tumor growth was accelerated in ligated liver lobes and appeared to be a result of increased growth factor expression.
文摘We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct.A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor.Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas,accompanied with severe dilatation of the main pancreatic duct,which was diagnosed as an intraductal papillary-mucinous neoplasm.We performed distal pancreatectomy and splenectomy.The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma(giant cell type)and adenocarcinoma in the pancreas.There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct.The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery.In this case,we could observe a remarkable intraductal tumor growth into the main pancreatic duct.We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.
基金This work was supported by the National Natural Science Foundation of China(No. 39900052) and a grant from the Ministry of Health of PR China (No. 98-1-118).
文摘Objective: To investigate whether LCRG1 (Laryngeal Carcinoma Related Gene 1) has tumor suppressor function. Methods: The recombinant plasmid pcDNA3.1(+)/LCRG1 was successfully constructed. The biological effects of LCRG1 on Hep-2 cell line were studied by cell transfection, cell growth observation colony formation analysis and tumorigenicity experiments. Results: The LCRG1 gene potently inhibited tumorgenesis in vitro and in vivo, as showed by dramatic growth arrest observed in cell growth analysis and suppression of anchorage-independent growth and tumorigenicity in nude mice. Conclusion: Our results suggested that LCRG1 may be a candidate of tumor suppressor gene.
基金primarily supported by grants from the National Natural Science Foundation of China(Nos.81472387 and 81402560)Guangdong Province Science and Technology Plan Project(No.2012A030400059)
文摘Background:Reduced expression of tripartite motif-containing 3(TRIM3) has been reported to be involved in the pathogenesis of human glioblastoma.In our previous research,we found that TRIM3 expression was markedly reduced in human primary hepatocellular carcinoma(HCC) tissues and that low TRIM3 expression was associated with short survival of HCC patients.However,the role of TRIM3 in liver cancer remains unknown.This study aimed to investigate the function of TRIM3 in liver cancer cells.Methods:The protein levels of TRIM3 in five liver cancer cell lines(SK-Hep1,Hep3 B,Huh7,HepG2,Bel-7402) and one normal liver cell line(L02) were detected with Western blotting.HepG2 and Bel-7402 cells with low TRIM3 expression were infected with recombinant lentiviruses overexpressing TRIM3(LV-TRIM3),whereas Huh7 and Hep3 B cells with high TRIM3 expression were transfected with TRIM3-targeted small interfering RNA(siTRIM3).The functions of TRIM3 in the proliferation,colony formation,cell cycle,migration,invasion,and apoptosis of the above cell lines were examined.The effect ofTRIM3 on tumor growth and metastases in nude mice was also investigated.Results:TRIM3 was overexpressed in HepG2 and Bel-7402 cells with LV-TRIM3 infection,which further reduced proliferation,colony formation,migration,and invasion of both cell lines.Cell cycle analysis showed that TRIM3 overexpression induced G_0/G_1 phase arrest in HepG2 and Bel-7402 cells.Moreover,apoptosis was not increased in HepG2 or Bel-7402 cells overexpressing TRIM3.Contrarily,silencing TRIM3 expression in Huh7 and Hep3 B cells by siTRIM3 led to significantly decreased percentages of both cells in the G_0/G_1 phase and promoted cell proliferation,colony formation,migration,and invasion.In vivo experiment results confirmed that TRIM3 overexpression suppressed tumor growth and metastasis.Conclusions:TRIM3 plays a tumor-suppressing role in the regulation of liver cancer development by reducing cell proliferation through cell cycle arrest at the G_0/G_1 phase.
基金Project supported by the National Natural Science Foundation of China （Nos. 10372026 and 10772751）
文摘<正>A multi-scale continuous-discrete model based on the effects of the p27 gene control is built to simulate the avascular tumor growth. At the tissue level, the continuous Eulerian model is adopted to determine the distribution of the concentration of oxygen, the extracellular matrix (ECM), and the matrix-degradative enzyme (MDE). At the cellular level, the discrete Lagrangien model is adopted to determine the movement, the proliferation, and the death of single tumor cells (TCs). At the genetic level, whether a cell is committed to mitosis is determined by solving a set of equations modeling the effects of the p27 gene control. The avascular morphological evolution of the solid tumor growth is simulated, including the radius of the solid tumor, the number of the TCs, the oxygen distribution over time, and the inhibiting effect of the up-regulating p27 gene expression.
基金supported by Provincial Natural Science Research Projects of Colleges and Universities in Anhui Province(No KJ2015B096by)
文摘Objective:To study the regulating effect of HSP70 inhibitor(PES) combined with cisplatin on cervical cancer proliferation in vitro and transplanted tumor growth.Methods:Cervical cancer Hela cell lines were cultured and divided into control group,cisplatin group,PES group and cisplatin+PES group that were treated with serum-free DMEM,cisplatin with final concentration of 10 μmol/L,PES 20 μmol/L and cisplatin 10 μmol/L combined with PES with 20 μmol/L,respectively;animal models with cervical cancer xenografts were established and divided into control group,cisplatin group,PES group and cisplatin+PES group who received intra-tumor injection of normal saline,10 μmol/L cisplatin,20 μmol/L PES as well as 10 μmol/L cisplatin+20 μmol/L PES,respectively.Cell proliferation activity,transplanted tumor volume and mitochondria apoptosis molecule expression were detected.Results:Cell viability value and Bcl-2 mRNA expression in cells of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 mRNA expression in cells were significantly higher than those of control group;transplanted tumor volume and the Bcl-2 mRNA expression in transplanted tumor tissue of cisplatin group,PES group and cisplatin+PES group were significantly lower than those of control group while Bax,Caspase-3 and Caspase-9 m RNA expression in transplanted tumor tissue were significantly higher than those of control group.Conclusions:HSP70 inhibitor combined with cislatin can inhibit cervical cancer cell proliferation in vitro and transplanted tumor growth through mitochondrial apoptosis pathway.
文摘To understand the relationship between the expression of vasCular endothelial growth factor (VEGF) and the growth, metastasis of hepatocellular car cinoma (HCC), immunohistochemistry and Northern blot were used to investigate VEGF protein and mRNA in 21 cases of HCC with and without rnetastasis.VEGF protein was found in 8 of 9 cases with metastasis, whereas only in 4 of 12 cases without rnetastasis. The Positive rate of the former was significantly higher than that in the latter. VEGF mRNA was detectable in both carcinoma and its surrounding liver tissues, but its level in the former was 2 - 3 times higher than that in the latter. In carcinoma with metastasis, the mRNA level was 5-6 times higher than that without metastasis. It is concluded that VEGF Is closely related to the growth of HCC as well as its metastasis and it might be a useful indicator for the metastatic potential of HCC.
文摘The therapeutic options for patients with metastatic renal cell carcinoma(mRCC) have completely changed during the last ten years. With the sequential use of targeted therapies, median overall survival has increased in daily practice and now it is not uncommon to see patients surviving kidney cancer for more than four to five years. Once treatment fails with the first line targeted therapy, head to head comparisons have shown that cabozantinib, nivolumab and the combination of lenvatinib plus everolimus are more effective than everolimus alone and that axitinib is more active than sorafenib. Unfortunately, it is very unlikely that we will ever have prospective data comparing the activity of axitinib, cabozantinib, lenvatinib or nivolumab. It is frustrating to observe the lack of biomarkers that we have in this field, thus there is no firm recommendation about the optimal sequence of treatment in the second line. In the absence of reliable biomarkers, there are several clinical endpoints that can help physicians to make decisions for an individual patient, such as the tumor burden, the expected response rate and the time to achieve the response to each agent, the prior response to the agent administered, the toxicity profile of the different compounds and patient preference. Here, we propose the introduction of the tumor-growth rate(TGR) during first-line treatment as a new tool to be used to select the second line strategy in m RCC. The rapidness of TGR before the onset of the treatment reflects the variability between patients in terms of tumor growth kinetics and it could be a surrogate marker of tumor aggressiveness that may guide treatment decisions.
基金supported by the Grants from KTIA AIK 12-1-2013-0041Semmelweis University Start-Up Grant 40148-11658+3 种基金OTKA K109626,OTKA SNN1 14490,OTKA K100931,OTKA PD109201,EUREKA_HU_12-1-2012-0057TAMOP 4.2.4.A/1-11-1-2012-0001ONB Jubilaumsfondsprojekt Nr.14043 and Nr.14574the Vienna Fund for Innovative Interdisciplinary Cancer Research
文摘Directed capillary ingrowth has long been considered synonymous with tumor vascularization.However,the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting;instead,malignant tumors can acquire blood vessels via alternative vascularization mechanisms,such as intussusceptive microvascular growth,vessel co-option,and glomeruloid angiogenesis.Importantly,in response to anti-angiogenic therapies,malignant tumors can switch from one vascularization mechanism to another.In this article,we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81672948 and 81772794)Jilin Provincial Research Foundation for Health Technology Innovation(Grant No.2019J009)+1 种基金Jilin Provincial Research Foundation for the Development of Science and Technology Projects(Grant Nos.20191004004TC and 20190103095JH)Jilin Provincial Industrial Innovation Project(Grant No.2018C052-7)。
文摘Objective:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhibit an M2 phenotype.Our previous studies have shown that the interleukin-33/ST2(IL-33/ST2)axis is essential for activation of the M1 phenotype.This study investigates the role of the IL-33/ST2 axis in TAMs,its effects on tumor growth,and whether it participates in the mutual conversion between the M1 and M2 phenotypes.Methods:Bone marrow-derived macrophages were extracted from wildtype,ST2 knockout(ST2-/-),and Il33-overexpressing mice and differentiated with IL-4.The mitochondrial and lysosomal number and location,and the expression of related proteins were used to analyze mitophagy.Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes.Results:The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels.The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation,thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth(P<0.05)(Figure 4).This metabolic shift was not due to mitochondrial damage,because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout;however,it might be associated with the m TOR activity.Conclusions:These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization,and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.
