Tousled-like kinase 1 promotes gastric cancer progression by regulating the tumor growth factor-beta signaling pathway

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.

Effects of Lvy noise and immune delay on the extinction behavior in a tumor growth model

The combined effects of Ltvy 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.

Stochastic properties of tumor growth with coupling between non-Gaussian and Gaussian noise terms

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.

Numerical simulation of avascular tumor growth based on p27 gene regulation

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 the oxygen distribution over time, and the expression. of the solid tumor, the number of the TCs, inhibiting effect＇ of the up-regulating p27 gene

LCRG1 SUPPRESSES TUMOR GROWTH IN VIVO BY LIPOSOME-MEDIATED GENE TRANSFER

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.

Knockdown of DEAD-box 51 inhibits tumor growth of esophageal squamous cell carcinoma via the PI3K/AKT pathway

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.

ADENOVIRUS-MEDIATED EXPRESSION OF PEX, A NONCATALYTIC FRAGMENT OF MATRIX METALLOPROTEINASE-2, AND IT’S INHIBITION ON ANGIOGENESIS AND TUMOR GROWTH

Objective： To develop an adenovirus system to deliver biologically active peptides or proteins such as angiogenesis inhibitors in vivo for the treatment of cancer. Methods： DNA recombination techniques were employed to construct adenovirus shuttle vector, in which angiogenesis inhibitor was put downstream of rat growth hormone signal peptide, and the C-terminal was the myc-epitope 10-amino-acid peptide for the following up of the protein. Adenovirus was made using the bacteria recombination method. We tested this system using an angiogenesis inhibitor chick MMP-2 C-terminal hemopexin-like fragment （PEX） in Sarcoma 180 （S-180） bearing Kunming mice. The anti-angiogenie effect was performed by chick chorioallantoic membrane assay. Results： PEX was readily secreted outside human stomach carcinoma BGC823 cells as demonstrated by immunofluorcscent staining and western blot infected by adenovirus with rat growth hormone signal peptide （E-T-rGH-PEX）. However, without signal pcptide （E-T-PEX）, PEX was expressed and localized in the cytoplasm of the infected cells, and formed large aggregates, which suggested that PEX was insoluble. The adenovirus E-T-rGH-PEX could inhibit angiogenesis, while E-T-rGH-PEX not. The adenoviruses of E-T-rGH-PEX inhibited the growth of S-180 tumor significantly compared with the empty virus control group E-T （P=0.026） and without signal peptide group E-T-PEX （P=0.006） respectively, while E-T-PEX had little effect. Conelusion： These results suggest that this adenoviral system is likely to be used in the gene therapy of cancer to deliver angiogenesis inhibitors.

Hybrid discrete-continuum model of tumor growth considering capillary points

A hybrid discrete-continuum model of tumor growth in the avascular phase considering capillary points is established. The influence of the position of capillary points on tumor growth is also studied by simulation. The results of the dynamic tumor growth and the distribution of oxygen, matrix-degrading enzymes, and extracellular matrixconcentration in the microenvironment with respect to time are shown by graphs. The relationships between different oxygenated environments and the numbers of surviving, dead, proliferative, and quiescent tumor cells are also investigated.

Existence and Uniqueness of Almost Periodic Solution for a Mathematical Model of Tumor Growth

This article is concerned with a mathematical model of tumor growth governed by 2nd 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) = C0(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.

Implication of serum levels of interleukin-18 and nitric oxide in tumor growth and metastasis of non-small cell lung cancer

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.

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

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.

Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth

瞄准：学习巨噬细胞的角色在在一只老鼠的肿瘤生长的导致切除术的加速肝的转移建模的肝的煽动性的蛋白质(MIP )-2。方法：在 50% 肝切除术以后， 1x10 (5 ) CT26.WT 房间被植入进 syngeneic balb/c 老鼠(PHx ) 的左肝脑叶。另外的动物与抵销 MIP-2 (PHx+mAB ) 的单音的同种细胞的抗体(MAB452 ) 被对待。将切除得非并且 non-mAB-treated 老鼠(反对) 用作控制。在 7 d 以后，象房间增长，肿瘤生长，和 CXCR-2 表示一样的肿瘤血管生成和微循环用生活期内萤光显微镜检查，组织学，免疫组织化学，和流动被分析血细胞计数。结果：增加的部分肝切除术(P【0.05 ) 肿瘤房间上的 MIP-2 受体 CXCR-2 的表示什么时候与将切除得非的控制相比，并且显著地加速了(P【0.05 ) 血管生成和转移瘤生长。(P【0.05 ) 由 MAB452 处理的 MIP-2 的中立化显著地压抑 CXCR-2 表示。进一步， MIP-2 的封锁减少了 angiogenic 反应(P【0.05 ) 并且禁止了肿瘤生长(P【0.05 ) 。兴趣，肝导致切除术的 hepatocyte 增长没被 anti-MIP-2 处理完成。结论：MIP-2 显著地贡献肝颜色的导致切除术的加速表面的 CT26.WT 肝的转移生长。

Dicranostigma leptopodum (maxim) fedde induced apoptosis in SMMC-7721 human hepatoma cells and inhibited tumor growth in mice

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.

A case report of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct

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.

Portal vein ligation accelerates tumor growth in ligated,but not contralateral lobes

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.

Translating new data to the daily practice in second line treatment of renal cell carcinoma:The role of tumor growth rate

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.

Simple Linear Model of Tumor Growth in a Changing Environment

In an environment that is neither static nor in equilibrium, but is dynamic and changing, the kinetics of the reactions that cause the growth of a tumor, which depend on the state of the evolving environment, cannot be parametrized in terms of constant rates. We propose a simple model for describing the growth on an untreated tumor in such environments, which is characterized by a minimal number of parameters and is generalizable to include the effects of various types of therapies. In the simplest version that we consider here, it consists of a linear equation with a time-dependent growth rate, which we interpret as the coupling of the system with a dynamic environment. A complete solution is given in terms of the integral of the growth rate. The essential features of the general solution are illustrated with a few examples, and comparison is made with the models that have been proposed to describe recent data.

GubenyiliuⅡ inhibits breast tumor growth and metastasis associated with decreased heparanase expression and Akt phosphorylation

OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the beneficial effects of GYⅡon murine breast cancer models.METHODS Inhibition of tumor growth and metastasis was evaluated by assessment of tumor weight and analysis of bioluminescent signal after a homograft inoculation.Viability of cultured breast cancer cells was determined using MTT assay andreal-time cell analysis(RTCA).Cell migratory ability was evaluated by Transwell?assay and wound healing assay.Subsequently,the potential anti-tumor and anti-metastatic mechanism was investigated by Western blotting and Immunohistochemistry.RESULTS GYⅡshowed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model.And GYⅡsuppressed theproliferation of 4T1 and MCF-7 cells in a dose-dependent manner.A better inhibitory effect on 4T1 cells proliferation and migration was found in sub-fractions(SF)of GYⅡ.Moreover,heparanase expression and degree of angiogenesis were reduced in tumor tissues.Western blotting analysis showed decreased expression of heparanase and growth factors in the cells treated with GYⅡand its sub-fractions(SF2 and SF3),there by a reduction in phosphorylation of ERK and AKT.CONCLUSION GYⅡexerts anti-tumor growth and anti-metastatic effects on murine breast cancer model.Sub-fractions 2 and 3 exhibits higher potency of the anti-tumor activity that is,at least partly,associated with decreased heparanase and growth factor sexpression,which subsequently sup-pressed activation of ERK and AKT pathways.

The Influence of Glucose on Numerical Simulation of a Vascular Solid Tumor Growth

Glucose is the mainly nutrient substances in tumor growth,which played an important role in tumor cells' growth,proliferation and immigration.Numerical simulation will help a good understanding for the influence of glucose which affected on a vascular solid tumor growth.We present a hybrid on-Lattice Model to simulate the influence of glucose on a-vascular tumor growth.The hybrid model we developed focuses on five key variables implicated in the invasion process:tumor cells,extracellular matrix,matrix-degradative enzymes,oxygen and glucose.And about the discrete model,we consider cell evolution dynamics on cell level.Results indicate that the number of proliferation and quiescent cells is decreasing by decreasing the initial glucose concentration,consequently increase necrotic area relatively.Thus there is inhabitation effect on tumor growth by decreasing initial glucose concentration.

The effects of CO_2 pneumoperitoneum on tumor growth in vivo

Objective:The aim of this study is to evaluate the effect of CO_2 pneumoperitoneum on growth and spread of intraperitoneal tumor in an animal model.Methods:We established an animal model of epithelial ovarian cancer in immunocompetent rat Fischer 344.Twenty rats were randomized to two groups(10rats /group):CO_2 insufflation and sham laparotomy.Tumors were excised from the rats in each group 28 days after operation.Ascites,tumor mass,local regional invasion incidence,lymph node involvement,and liver and lung metastases were evaluated.Sections of tumors were made and then the cell cycle fraction were measured by quantitating DNA in individual cells using flow cytometry analysis.The expressions of Ki-67,VEGF,and CD44v6 protein were determined using immunocytochemistry by flow cytometry.Results:Tumor mass,local regional invasion incidence and the amount of ascites were higher in CO_2 insufflation than those in laparotomy,but there were no significant differences between two groups.The expression of CD44v6 protein was higher in CO_2 insufflation than that in laparotomy(P=0.002).There was no significant difference between two groups in the cells cycle fraction and the expressiones of Ki-67 and VEGF protein.Conclusions:CO_2 pneumoperitoneum has effects on intraperitoneal tumor growth and metastasis in the animal model.