Stochastic models for tumoral growth

NASA Astrophysics Data System (ADS)

Escudero, Carlos

2006-02-01

Strong experimental evidence has indicated that tumor growth belongs to the molecular beam epitaxy universality class. This type of growth is characterized by the constraint of cell proliferation to the tumor border and the surface diffusion of cells at the growing edge. Tumor growth is thus conceived as a competition for space between the tumor and the host, and cell diffusion at the tumor border is an optimal strategy adopted for minimizing the pressure and helping tumor development. Two stochastic partial differential equations are reported in this paper in order to correctly model the physical properties of tumoral growth in (1+1) and (2+1) dimensions. The advantage of these models is that they reproduce the correct geometry of the tumor and are defined in terms of polar variables. An analysis of these models allows us to quantitatively estimate the response of the tumor to an unfavorable perturbation during growth.

Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)*

PubMed Central

Yang, Weiwei; Lu, Yan; Xu, Yichen; Xu, Lizhi; Zheng, Wei; Wu, Yuanyuan; Li, Long; Shen, Pingping

2012-01-01

Hepatocarcinoma cancer (HCC), one of the most malignant cancers, occurs significantly more often in men than in women; however, little is known about its underlying molecular mechanisms. Here we identified that 17β-estradiol (E2) could suppress tumor growth via regulating the polarization of macrophages. We showed that E2 re-administration reduced tumor growth in orthotopic and ectopic mice HCC models. E2 functioned as a suppressor for macrophage alternative activation and tumor progression by keeping estrogen receptor β (ERβ) away from interacting with ATP5J (also known as ATPase-coupling factor 6), a part of ATPase, thus inhibiting the JAK1-STAT6 signaling pathway. These studies introduce a novel mechanism for suppressing male-predominant HCC. PMID:22908233

Dietary rice bran component γ-oryzanol inhibits tumor growth in tumor-bearing mice.

PubMed

Kim, Sung Phil; Kang, Mi Young; Nam, Seok Hyun; Friedman, Mendel

2012-06-01

We investigated the effects of rice bran and components on tumor growth in mice. Mice fed standard diets supplemented with rice bran, γ-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the γ-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by γ-oryzanol. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer.

PubMed

Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W; Zaytseva, Yekaterina Y; Mitov, Mihail I; Napier, Dana L; Weiss, Heidi L; Mark Evers, B; Gao, Tianyan

2017-02-02

Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells.

Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer

PubMed Central

Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W; Zaytseva, Yekaterina Y; Mitov, Mihail I; Napier, Dana L; Weiss, Heidi L; Mark Evers, B; Gao, Tianyan

2017-01-01

Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells. PMID:28151470

Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth.

PubMed

Paschoalin, Thaysa; Carmona, Adriana K; Rodrigues, Elaine G; Oliveira, Vitor; Monteiro, Hugo P; Juliano, Maria A; Juliano, Luiz; Travassos, Luiz R

2007-07-09

Angiogenesis is a fundamental process that allows tumor growth by providing nutrients and oxygen to the tumor cells. Beyond the oxygen diffusion limit from a capillary blood vessel, tumor cells become apoptotic. Angiogenesis results from a balance of pro- and anti-angiogenic stimuli. Endogenous inhibitors regulate enzyme activities that promote angiogenesis. Tumor cells may express pro-angiogenic factors and hydrolytic enzymes but also kinin-degrading oligopeptidases which have been investigated. Angiogenesis induced by B16F10-Nex2 melanoma cells was studied in a co-culture with HUVEC on Matrigel. A stimulating effect on angiogenesis was observed in the presence of B16F10-Nex2 lysate and plasma membrane. In contrast, the B16F10-Nex2 culture supernatant inhibited angiogenesis in a dose-dependent manner. This effect was abolished by the endo-oligopeptidase inhibitor, JA-2. Thimet oligopeptidase (TOP) and neurolysin activities were then investigated in B16F10-Nex2 melanoma cells aiming at gene sequencing, enzyme distribution and activity, influence on tumor development, substrate specificity, hydrolytic products and susceptibility to inhibitors. Fluorescence resonance energy transfer (FRET) peptides as well as neurotensin and bradykinin were used as substrates. The hydrolytic activities in B16F10-Nex2 culture supernatant were totally inhibited by o-phenanthrolin, JA-2 and partially by Pro-Ile. Leupeptin, PMSF, E-64, Z-Pro-Prolinal and captopril failed to inhibit these hydrolytic activities. Genes encoding M3A enzymes in melanoma cells were cloned and sequenced being highly similar to mouse genes. A decreased proliferation of B16F10-Nex2 cells was observed in vitro with specific inhibitors of these oligopeptidases. Active rTOP but not the inactive protein inhibited melanoma cell development in vivo increasing significantly the survival of mice challenged with the tumor cells. On Matrigel, rTOP inhibited the bradykinin - induced angiogenesis. A possible regulation of

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

PubMed

McIntyre, Alan; Hulikova, Alzbeta; Ledaki, Ioanna; Snell, Cameron; Singleton, Dean; Steers, Graham; Seden, Peter; Jones, Dylan; Bridges, Esther; Wigfield, Simon; Li, Ji-Liang; Russell, Angela; Swietach, Pawel; Harris, Adrian L

2016-07-01

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR. ©2016 American Association for Cancer Research.

Geometrical approach to tumor growth.

PubMed

Escudero, Carlos

2006-08-01

Tumor growth has a number of features in common with a physical process known as molecular beam epitaxy. Both growth processes are characterized by the constraint of growth development to the body border, and surface diffusion of cells and particles at the growing edge. However, tumor growth implies an approximate spherical symmetry that makes necessary a geometrical treatment of the growth equations. The basic model was introduced in a former paper [C. Escudero, Phys. Rev. E 73, 020902(R) (2006)], and in the present work we extend our analysis and try to shed light on the possible geometrical principles that drive tumor growth. We present two-dimensional models that reproduce the experimental observations, and analyze the unexplored three-dimensional case, for which interesting conclusions on tumor growth are derived.

Bioavailable copper modulates oxidative phosphorylation and growth of tumors

PubMed Central

Ishida, Seiko; Andreux, Pénélope; Poitry-Yamate, Carole; Auwerx, Johan; Hanahan, Douglas

2013-01-01

Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment. PMID:24218578

Regional Control of Tumor Growth

PubMed Central

Zaslavsky, Alexander; Chen, Catherine; Grillo, Jenny; Baek, Kwan-Hyuck; Holmgren, Lars; Yoon, Sam S.; Folkman, Judah; Ryeom, Sandra

2010-01-01

Tumors implanted near the scapulae have been shown to grow four-times faster than the same tumors implanted at the iliac crest. While there were marked differences in the vascularization of tumors from these two different sites, the mechanism controlling regional angiogenesis was not identified. Here we demonstrate site-specific growth of intraperitoneal tumor implants in the mouse abdomen. Our data indicate that the angiogenic response of the host differs significantly between the upper and lower sites in the mouse abdomen and reveals that the expansion of tumor mass is restricted at sites with low angiogenic responses such as the bowel mesentery in the lower abdomen. We show that in this model, this suppression of angiogenesis is due to an expression gradient of thrombospondin-1, a potent endogenous angiogenesis inhibitor. Mice with a targeted deletion of thrombospondin-1 no longer demonstrate regional restriction of tumor growth. The physiological relevance of these findings may be seen in patients with peritoneal carcinomatosis, whereby tumors spread within the peritoneal cavity and show differential growth in the upper and lower abdomen. We hypothesize that the difference in tumor growth in these patients may be due to a gradient of thrombospondin-1 expression in stroma. Finally, our studies suggest that upregulation of thrombospondin-1 in tumor cells is one method to suppress the growth of tumors in the upper abdomen. PMID:20736295

SKI knockdown inhibits human melanoma tumor growth in vivo.

PubMed

Chen, Dahu; Lin, Qiushi; Box, Neil; Roop, Dennis; Ishii, Shunsuke; Matsuzaki, Koichi; Fan, Tao; Hornyak, Thomas J; Reed, Jon A; Stavnezer, Ed; Timchenko, Nikolai A; Medrano, Estela E

2009-12-01

The SKI protein represses the TGF-beta tumor suppressor pathway by associating with the Smad transcription factors. SKI is upregulated in human malignant melanoma tumors in a disease-progression manner and its overexpression promotes proliferation and migration of melanoma cells in vitro. The mechanisms by which SKI antagonizes TGF-beta signaling in vivo have not been fully elucidated. Here we show that human melanoma cells in which endogenous SKI expression was knocked down by RNAi produced minimal orthotopic tumor xenograft nodules that displayed low mitotic rate and prominent apoptosis. These minute tumors exhibited critical signatures of active TGF-beta signaling including high levels of nuclear Smad3 and p21(Waf-1), which are not found in the parental melanomas. To understand how SKI promotes tumor growth we used gain- and loss-of-function approaches and found that simultaneously to blocking the TGF-beta-growth inhibitory pathway, SKI promotes the switch of Smad3 from tumor suppression to oncogenesis by favoring phosphorylations of the Smad3 linker region in melanoma cells but not in normal human melanocytes. In this context, SKI is required for preventing TGF-beta-mediated downregulation of the oncogenic protein c-MYC, and for inducing the plasminogen activator inhibitor-1, a mediator of tumor growth and angiogenesis. Together, the results indicate that SKI exploits multiple regulatory levels of the TGF-beta pathway and its deficiency restores TGF-beta tumor suppressor and apoptotic activities in spite of the likely presence of oncogenic mutations in melanoma tumors.

The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

PubMed

Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

2009-02-01

Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.

Hyaluronan Tumor Cell Interactions in Prostate Cancer Growth and Survival

DTIC Science & Technology

2009-12-01

is a high molecular weight polyanionic polysaccharide that is increased in more advanced prostate cancers. Tumor cell interaction with this... polysaccharide by specific receptors CD44 and RHAMM promote tumor growth, survival and invasion. Work during the last funding period have further defined the... polysaccharide to its cognate receptors. These peptides inhibit tumor growth both in vitro and in vivo and the residues important for the activity

Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth

PubMed Central

Paschoalin, Thaysa; Carmona, Adriana K; Rodrigues, Elaine G; Oliveira, Vitor; Monteiro, Hugo P; Juliano, Maria A; Juliano, Luiz; Travassos, Luiz R

2007-01-01

Background Angiogenesis is a fundamental process that allows tumor growth by providing nutrients and oxygen to the tumor cells. Beyond the oxygen diffusion limit from a capillary blood vessel, tumor cells become apoptotic. Angiogenesis results from a balance of pro- and anti-angiogenic stimuli. Endogenous inhibitors regulate enzyme activities that promote angiogenesis. Tumor cells may express pro-angiogenic factors and hydrolytic enzymes but also kinin-degrading oligopeptidases which have been investigated. Results Angiogenesis induced by B16F10-Nex2 melanoma cells was studied in a co-culture with HUVEC on Matrigel. A stimulating effect on angiogenesis was observed in the presence of B16F10-Nex2 lysate and plasma membrane. In contrast, the B16F10-Nex2 culture supernatant inhibited angiogenesis in a dose-dependent manner. This effect was abolished by the endo-oligopeptidase inhibitor, JA-2. Thimet oligopeptidase (TOP) and neurolysin activities were then investigated in B16F10-Nex2 melanoma cells aiming at gene sequencing, enzyme distribution and activity, influence on tumor development, substrate specificity, hydrolytic products and susceptibility to inhibitors. Fluorescence resonance energy transfer (FRET) peptides as well as neurotensin and bradykinin were used as substrates. The hydrolytic activities in B16F10-Nex2 culture supernatant were totally inhibited by o-phenanthrolin, JA-2 and partially by Pro-Ile. Leupeptin, PMSF, E-64, Z-Pro-Prolinal and captopril failed to inhibit these hydrolytic activities. Genes encoding M3A enzymes in melanoma cells were cloned and sequenced being highly similar to mouse genes. A decreased proliferation of B16F10-Nex2 cells was observed in vitro with specific inhibitors of these oligopeptidases. Active rTOP but not the inactive protein inhibited melanoma cell development in vivo increasing significantly the survival of mice challenged with the tumor cells. On Matrigel, rTOP inhibited the bradykinin – induced angiogenesis. A

Growth regulators in connective tissue. Systemic administration of an aortic extract inhibits tumor growth in mice.

PubMed Central

Eisenstein, R.; Schumacher, B.; Meineke, C.; Matijevitch, B.; Kuettner, K. E.

1978-01-01

A low-molecular-weight fraction prepared from extracts of bovine aorta inhibits the growth of a transplantable mammary tumor and a fibrosarcoma in mice when injected systemically. It also inhibits the growth of the fibrosarcoma in cell culture. The effect on the fibrosarcoma is much more marked than on the mammary tumor. Since the extract is more effective against the fibrosarcoma and is known to inhibit the growth of endothelial cells, it appears that the enhanced effect on this tumor is due to its activity on the endothelial cells of the host and the tumor cells themselves. The material injected is enriched in an antiproteinase we have previously isolated, which has anticollagneolytic activity and is presumed to be the effector molecule. Images Figure 1 Figure 2 PMID:645813

Biochemomechanical poroelastic theory of avascular tumor growth

NASA Astrophysics Data System (ADS)

Xue, Shi-Lei; Li, Bo; Feng, Xi-Qiao; Gao, Huajian

2016-09-01

Tumor growth is a complex process involving genetic mutations, biochemical regulations, and mechanical deformations. In this paper, a thermodynamics-based nonlinear poroelastic theory is established to model the coupling among the mechanical, chemical, and biological mechanisms governing avascular tumor growth. A volumetric growth law accounting for mechano-chemo-biological coupled effects is proposed to describe the development of solid tumors. The regulating roles of stresses and nutrient transport in the tumor growth are revealed under different environmental constraints. We show that the mechano-chemo-biological coupling triggers anisotropic and heterogeneous growth, leading to the formation of layered structures in a growing tumor. There exists a steady state in which tumor growth is balanced by resorption. The influence of external confinements on tumor growth is also examined. A phase diagram is constructed to illustrate how the elastic modulus and thickness of the confinements jointly dictate the steady state of tumor volume. Qualitative and quantitative agreements with experimental observations indicate the developed model is capable of capturing the essential features of avascular tumor growth in various environments.

Berberine Inhibits Proliferation and Down-Regulates Epidermal Growth Factor Receptor through Activation of Cbl in Colon Tumor Cells

PubMed Central

Wang, Lihong; Cao, Hailong; Lu, Ning; Liu, Liping; Wang, Bangmao; Hu, Tianhui; Israel, Dawn A.; Peek, Richard M.; Polk, D. Brent; Yan, Fang

2013-01-01

Berberine, an isoquinoline alkaloid, is an active component of Ranunculaceae and Papaveraceae plant families. Berberine has been found to suppress growth of several tumor cell lines in vitro through the cell-type-dependent mechanism. Expression and activation of epidermal growth factor receptor (EGFR) is increased in colonic precancerous lesions and tumours, thus EGFR is considered a tumour promoter. The aim of this study was to investigate the effects and mechanisms of berberine on regulation of EGFR activity and proliferation in colonic tumor cell lines and in vivo. We reported that berberine significantly inhibited basal level and EGF-stimulated EGFR activation and proliferation in the immorto Min mouse colonic epithelial (IMCE) cells carrying the APC min mutation and human colonic carcinoma cell line, HT-29 cells. Berberine acted to inhibit proliferation through inducing G1/S and G2/M cell cycle arrest, which correlated with regulation of the checkpoint protein expression. In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines in the presence or absence of EGF treatment. Knock-down Cbl expression blocked the effects of berberine on down-regulation of EGFR and inhibition of proliferation. Furthermore, berberine suppressed tumor growth in the HT-29 cell xenograft model. Cell proliferation and EGFR expression level was decreased by berberine treatment in this xenograft model and in colon epithelial cells of APC min/+ mice. Taken together, these data indicate that berberine enhances Cbl activity, resulting in down-regulation of EGFR expression and inhibition of proliferation in colon tumor cells. PMID:23457600

Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture.

PubMed

Xuan, Jian-Ai; Schneider, Doug; Toy, Pam; Lin, Rick; Newton, Alicia; Zhu, Ying; Finster, Silke; Vogel, David; Mintzer, Bob; Dinter, Harald; Light, David; Parry, Renate; Polokoff, Mark; Whitlow, Marc; Wu, Qingyu; Parry, Gordon

2006-04-01

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.

Mitogen-activated protein kinase inhibition reduces mucin 2 production and mucinous tumor growth.

PubMed

Dilly, Ashok K; Song, Xinxin; Zeh, Herbert J; Guo, Zong S; Lee, Yong J; Bartlett, David L; Choudry, Haroon A

2015-10-01

Excessive accumulation of mucin 2 (MUC2) protein (a gel-forming secreted mucin) within the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP), a unique mucinous malignancy of the appendix. Mitogen-activated protein kinase (MAPK) signaling pathway is upregulated in PMP and has been shown to modulate MUC2 promoter activity. We hypothesized that targeted inhibition of the MAPK pathway would be a novel, effective, and safe therapeutic strategy to reduce MUC2 production and mucinous tumor growth. We tested RDEA119, a specific MEK1/2 (MAPK extracellular signal-regulated kinase [ERK] kinase) inhibitor, in MUC2-secreting LS174T cells, human PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. RDEA119 reduced ERK1/2 phosphorylation and inhibited MUC2 messenger RNA and protein expression in vitro. In the xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth in an MAPK pathway-dependent manner and this translated into a significant improvement in survival. RDEA119 downregulated phosphorylated ERK1/2 and nuclear factor κB p65 protein signaling and reduced activating protein 1 (AP1) transcription factor binding to the MUC2 promoter in LS174T cells. This study provides a preclinical rationale for the use of MEK inhibitors to treat patients with PMP. Copyright © 2015 Elsevier Inc. All rights reserved.

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth.

PubMed

Barceló, Carles; Paco, Noelia; Morell, Mireia; Alvarez-Moya, Blanca; Bota-Rabassedas, Neus; Jaumot, Montserrat; Vilardell, Felip; Capella, Gabriel; Agell, Neus

2014-02-15

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors. ©2013 AACR.

Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo.

PubMed

Li, Ben Hui; Xu, Shuang Bing; Li, Feng; Zou, Xiao Guang; Saimaiti, Abudukeyoumu; Simayi, Dilixia; Wang, Ying Hong; Zhang, Yan; Yuan, Jia; Zhang, Wen Jie

2012-03-01

Signal transducer and activator of transcription 6 (Stat6) is critical in Th2 polarization of immune cells and active Stat6 activity has been suggested in anti-tumor immunity in animal models. The present study aims at investigating the impact of natural Stat6 activity on tumor microenvironment in human colorectal cancer cells in vitro and in vivo. Using colorectal cancer cell lines HT-29 and Caco-2 whose IL-4/Stat6 activities were known and nude mice as a model, we examined correlative relationships between Stat6 activities and gene expression profiles together with cellular behaviors in vitro and in vivo. HT-29 cells carrying active Stat6 signaling displayed spontaneous expression profiles favoring Th2 cytokines, cell cycle promotion, anti-apoptosis and pro-metastasis with increased mRNA levels of IL-4, IL-13, GATA-3, CDK4, CD44v6 and S100A4 using RT-PCR. In contrast, Caco-2 cells carrying defective Stat6 signaling exhibited spontaneous expression profiles favoring Th1 and Th17 cytokines, cell cycle inhibition, pro-apoptosis and anti-metastasis with elevated mRNA expression of IFNγ, TNFα, IL-12A, IL-17, IL-23, T-bet, CDKN1A, CDKNIB, CDKN2A and NM23-H1. Xenograft tumors of Stat6-active HT-29 cells showed a growth advantage over those of Stat6-defective Caco-2 cells. Furthermore, mice bearing HT-29 tumors expressed increased levels of Th2 cytokines IL-4 and IL-5 in the blood and pro-growth and/or pro-metastasis proteins CDK4 and CD44v6 in the tumor. To the contrary, mice bearing Caco-2 tumors expressed heightened levels of Th1 cytokines IFNγ and TNF in the blood and pro-apoptosis and anti-metastatic proteins p53 and p27(kip1) in the tumor. Colorectal cancer cells carrying active Stat6 signaling may create a microenvironment favoring Th2 cytokines and promoting expression of genes related to pro-growth, pro-metastasis and anti-apoptosis, which leads to a tumor growth advantage in vivo. These findings may imply why Stat6 pathway is constitutively activated in a

Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization.

PubMed

Tsunoda, Satoshi; Nakamura, Toshiyuki; Sakurai, Hiroaki; Saiki, Ikuo

2007-04-01

Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice

PubMed Central

Müller-Brüsselbach, Sabine; Kömhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jürgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Müller, Rolf

2007-01-01

The peroxisome proliferator-activated receptor-β (PPARβ) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb−/− mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb−/− mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57Kip2 as a PPARβ target gene and a mediator of the PPARβ-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb−/− mice. Our data point to an unexpected essential role for PPARβ in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels. PMID:17641685

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice.

PubMed

Müller-Brüsselbach, Sabine; Kömhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jürgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Müller, Rolf

2007-08-08

The peroxisome proliferator-activated receptor-beta (PPARbeta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARbeta target gene and a mediator of the PPARbeta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α.

PubMed

Lowery, Caitlin D; Blosser, Wayne; Dowless, Michele; Knoche, Shelby; Stephens, Jennifer; Li, Huiling; Surguladze, David; Loizos, Nick; Luffer-Atlas, Debra; Oakley, Gerard J; Guo, Qianxu; Iyer, Seema; Rubin, Brian P; Stancato, Louis

2018-02-15

Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors. Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor. Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin. Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847-57. ©2017 AACR . ©2017 American Association for Cancer Research.

AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells

PubMed Central

Maenhout, Sarah K.; Four, Stephanie Du; Corthals, Jurgen; Neyns, Bart; Thielemans, Kris; Aerts, Joeri L.

2014-01-01

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses. PMID:25149535

Purification and identification of a polysaccharide from medicinal mushroom Amauroderma rude with immunomodulatory activity and inhibitory effect on tumor growth.

PubMed

Pan, Honghui; Han, Yuanyuan; Huang, Jiguo; Yu, Xiongtao; Jiao, Chunwei; Yang, Xiaobing; Dhaliwal, Preet; Xie, Yizhen; Yang, Burton B

2015-07-10

Medicinal mushrooms in recent years have been the subject of many experiments searching for anticancer properties. We previously screened thirteen mushrooms for their potential in inhibiting tumor growth, and found that the water extract of Amauroderma rude exerted the highest activity. Previous studies have shown that the polysaccharides contained in the water extract were responsible for the anticancer properties. This study was designed to explore the potential effects of the polysaccharides on immune regulation and tumor growth. Using the crude Amauroderma rude extract, in vitro experiments showed that the capacities of spleen lymphocytes, macrophages, and natural killer cells were all increased. In vivo experiments showed that the extract increased macrophage metabolism, lymphocyte proliferation, and antibody production. In addition, the partially purified product stimulated the secretion of cytokines in vitro, and in vivo. Overall, the extract decreased tumor growth rates. Lastly, the active compound was purified and identified as polysaccharide F212. Most importantly, the purified polysaccharide had the highest activity in increasing lymphocyte proliferation. In summary, this molecule may serve as a lead compound for drug development.

The paradoxical effects of splenectomy on tumor growth.

PubMed

Prehn, Richmond T

2006-06-26

There is a vast and contradictory literature concerning the effect of the spleen and particularly of splenectomy on tumor growth. Sometimes splenectomy seems to inhibit tumor growth, but in other cases it seems, paradoxically, to facilitate both oncogenesis and the growth of established tumors. In this essay I have selected from this large literature a few papers that seem particularly instructive, in the hope of extracting some understanding of the rules governing this paradoxical behavior. In general, whether splenectomy enhances or inhibits tumor growth seems to depend primarily upon the ratio of spleen to tumor. Small proportions of spleen cells usually stimulate tumor growth, in which case splenectomy is inhibitory. Larger proportions of the same cells, especially if they are from immunized animals, usually inhibit tumor growth, in which case splenectomy results in tumor stimulation.

The paradoxical effects of splenectomy on tumor growth

PubMed Central

Prehn, Richmond T

2006-01-01

Background There is a vast and contradictory literature concerning the effect of the spleen and particularly of splenectomy on tumor growth. Sometimes splenectomy seems to inhibit tumor growth, but in other cases it seems, paradoxically, to facilitate both oncogenesis and the growth of established tumors. Approach In this essay I have selected from this large literature a few papers that seem particularly instructive, in the hope of extracting some understanding of the rules governing this paradoxical behavior. Conclusion In general, whether splenectomy enhances or inhibits tumor growth seems to depend primarily upon the ratio of spleen to tumor. Small proportions of spleen cells usually stimulate tumor growth, in which case splenectomy is inhibitory. Larger proportions of the same cells, especially if they are from immunized animals, usually inhibit tumor growth, in which case splenectomy results in tumor stimulation. PMID:16800890

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens.

PubMed

Jordan, Kimberly R; McMahan, Rachel H; Kemmler, Charles B; Kappler, John W; Slansky, Jill E

2010-03-09

Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.

Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity

PubMed Central

Wang, Liang-Chuan S; Lo, Albert; Scholler, John; Sun, Jing; Majumdar, Rajrupa S; Kapoor, Veena; Antzis, Michael; Cotner, Cody E.; Johnson, Laura A; Durham, Amy C; Solomides, Charalambos C.; June, Carl H; Puré, Ellen; Albelda, Steven M

2013-01-01

The majority of chimeric antigen receptor (CAR) T cell research has focused on attacking cancer cells. Here we show that targeting the tumor-promoting, non-transformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single chain Fv FAP (mAb 73.3) with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective suggesting that further clinical development of anti-human FAP-CAR is warranted. PMID:24778279

Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival.

PubMed

Zheng, Qiao; Dunlap, Sarah M; Zhu, Jinling; Downs-Kelly, Erinn; Rich, Jeremy; Hursting, Stephen D; Berger, Nathan A; Reizes, Ofer

2011-08-01

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

Interleukin-10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth.

PubMed

Bolpetti, Aline; Silva, João S; Villa, Luisa L; Lepique, Ana Paula

2010-06-07

Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like, induce T cell regulatory phenotype and play an important role in tumor growth. M2 macrophages secrete several cytokines, among them IL-10, which has been shown to play a role in T cell suppression by tumor macrophages in other tumor models. In this work, we sought to establish if IL-10 is part of the mechanism by which HPV tumor associated macrophages induce T cell regulatory phenotype, inhibiting anti-tumor activity and facilitating tumor growth. TC-1 tumor cells do not express or respond to IL-10, but recruit leukocytes which, within the tumor environment, produce this cytokine. Using IL-10 deficient mice or blocking IL-10 signaling with neutralizing antibodies, we observed a significant reduction in tumor growth, an increase in tumor infiltration by HPV16 E7 specific CD8 lymphocytes, including a population positive for Granzyme B and Perforin expression, and a decrease in the percentage of HPV specific regulatory T cells in the lymph nodes. Our data shows that in the HPV16 TC-1 tumor mouse model, IL-10 produced by tumor macrophages induce regulatory phenotype on T cells, an immune escape mechanism that facilitates tumor growth. Our results point to a possible mechanism behind the epidemiologic data that correlates higher IL-10 expression with risk of cervical cancer development in HPV infected women.

Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells.

PubMed

Mironova, Nadezhda L; Petrushanko, Irina Y; Patutina, Olga A; Sen'kova, Aexandra V; Simonenko, Olga V; Mitkevich, Vladimir A; Markov, Oleg V; Zenkova, Marina A; Makarov, Alexander A

2013-07-01

Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS 40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1-5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS 40 and inhibits metastasis up to 50% in LLC and RLS 40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS 40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-α in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells.

Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

PubMed Central

Yin, Yuan; Cai, Xing; Chen, Xi; Liang, Hongwei; Zhang, Yujing; Li, Jing; Wang, Zuoyun; Chen, Xiulan; Zhang, Wen; Yokoyama, Seiji; Wang, Cheng; Li, Liang; Li, Limin; Hou, Dongxia; Dong, Lei; Xu, Tao; Hiroi, Takachika; Yang, Fuquan; Ji, Hongbin; Zhang, Junfeng; Zen, Ke; Zhang, Chen-Yu

2014-01-01

An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. PMID:25223704

A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.

PubMed

Zhao, Genshi; Li, Wei-Ying; Chen, Daohong; Henry, James R; Li, Hong-Yu; Chen, Zhaogen; Zia-Ebrahimi, Mohammad; Bloem, Laura; Zhai, Yan; Huss, Karen; Peng, Sheng-Bin; McCann, Denis J

2011-11-01

The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity.

PubMed

Lee, Choong-Gu; Kwon, Ho-Keun; Ryu, Jae Ha; Kang, Sung Jin; Im, Chang-Rok; Ii Kim, Jae; Im, Sin-Hyeog

2010-10-20

Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells.

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity

PubMed Central

2010-01-01

Background Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. Methods In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Results Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Conclusions Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells. PMID:20961430

Electrophysiology of glioma: a Rho GTPase-activating protein reduces tumor growth and spares neuron structure and function.

PubMed

Vannini, Eleonora; Olimpico, Francesco; Middei, Silvia; Ammassari-Teule, Martine; de Graaf, Erik L; McDonnell, Liam; Schmidt, Gudula; Fabbri, Alessia; Fiorentini, Carla; Baroncelli, Laura; Costa, Mario; Caleo, Matteo

2016-12-01

Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronal cells to prevent functional deficits and cognitive deterioration. Here, we exploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function in peritumoral areas. We performed a microarray transcriptomic and in-depth proteomic analysis to characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle- and CNF1-treated glioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas. Administration of CNF1 triggered molecular and morphological hallmarks of senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivo induced glioma cell senescence and potently reduced tumor volumes. In peritumoral areas of glioma-bearing mice, neurons showed a shrunken dendritic arbor and severe functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improved several physiological properties of pyramidal neurons, demonstrating functional preservation of the cortical network. Our findings demonstrate that CNF1 reduces glioma volume while at the same time maintaining the physiological and structural properties of peritumoral neurons. These data indicate a promising strategy for the development of more effective antiglioma therapies. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes

PubMed Central

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-01-01

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1′s roles in tumorigenesis of gastric and breast cancers. PMID:28159933

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes.

PubMed

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-06-27

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1's roles in tumorigenesis of gastric and breast cancers.

The unidirectional hypoxia-activated prodrug OCT1002 inhibits growth and vascular development in castrate-resistant prostate tumors.

PubMed

Nesbitt, Heather; Worthington, Jenny; Errington, Rachel J; Patterson, Laurence H; Smith, Paul J; McKeown, Stephanie R; McKenna, Declan J

2017-11-01

OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC). The effect of OCT1002 on tumor growth and vasculature was measured using murine PC3 xenograft and dorsal skin fold (DSF) window chamber models. The effects of abiraterone, docetaxel, and cabazitaxel, both singly and in combination with OCT1002, were also compared. The hypoxia-targeting ability of OCT1002 effectively controls PC3 tumor growth. The effect was evident for at least 42 days after exposure to a single dose (30 mg/kg) and was comparable to, or better than, drugs currently used in the clinic. In DSF experiments OCT1002 caused vascular collapse in the PC3 tumors and inhibited the revascularization seen in controls. In this model OCT1002 also enhanced the anti-tumor effects of abiraterone, cabazitaxel, and docetaxel; an effect which was accompanied by a more prolonged reduction in tumor vasculature density. These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer. © 2017 Wiley Periodicals, Inc.

TNFR2-deficient memory CD8 T cells provide superior protection against tumor cell growth.

PubMed

Kim, Edward Y; Teh, Soo-Jeet; Yang, Jocelyn; Chow, Michael T; Teh, Hung-Sia

2009-11-15

TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2(-/-) CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Ralpha). We determined whether the resistance of activated TNFR2(-/-) CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2(-/-) mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2(-/-) mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2(-/-) mice. In vitro studies indicate that optimally activated OVA-specific TNFR2(-/-) CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2(-/-) CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2(-/-) mice is likely due to the recruitment and activation of OVA-specific memory TNFR2(-/-) CD8 T cells and their prolonged survival at the tumor site.

Numerical modelling of the influence of stromal cells on tumor growth and angiogenesis

NASA Astrophysics Data System (ADS)

Sakiyama, Nobuyuki; Nagayama, Katsuya

2018-01-01

According to the statistics provided by the Ministry of Health, Labor and Welfare the death of one in 3.5 Japanese people is attributed to tumor highlighting the need for active research on malignant tumors. Early detection can be cited as a countermeasure against malignant tumors, but it is often difficult to observe the growth process, and thorough understanding of the phenomena will aid in more efficient detection of such tumors. A malnourished benign tumor may create new blood vessels from existing ones and proliferate abnormally by absorbing nutrients from these newly created blood vessels to become malignant. Different factors influence the shape of tumors and shape is an important factor in evaluating their malignancy. Because interstitial cells greatly influence tumor growth, investigating the influence of stromal cells on tumor growth will help in developing a better understanding of the phenomenon.

Fractal dimension and universality in avascular tumor growth

NASA Astrophysics Data System (ADS)

Ribeiro, Fabiano L.; dos Santos, Renato Vieira; Mata, Angélica S.

2017-04-01

For years, the comprehension of the tumor growth process has been intriguing scientists. New research has been constantly required to better understand the complexity of this phenomenon. In this paper, we propose a mathematical model that describes the properties, already known empirically, of avascular tumor growth. We present, from an individual-level (microscopic) framework, an explanation of some phenomenological (macroscopic) aspects of tumors, such as their spatial form and the way they develop. Our approach is based on competitive interaction between the cells. This simple rule makes the model able to reproduce evidence observed in real tumors, such as exponential growth in their early stage followed by power-law growth. The model also reproduces (i) the fractal-space distribution of tumor cells and (ii) the universal growth behavior observed in both animals and tumors. Our analyses suggest that the universal similarity between tumor and animal growth comes from the fact that both can be described by the same dynamic equation—the Bertalanffy-Richards model—even if they do not necessarily share the same biological properties.

Controlling cytoplasmic c-Fos controls tumor growth in the peripheral and central nervous system.

PubMed

Gil, Germán A; Silvestre, David C; Tomasini, Nicolás; Bussolino, Daniela F; Caputto, Beatriz L

2012-06-01

Some 20 years ago c-Fos was identified as a member of the AP-1 family of inducible transcription factors (Angel and Karin in Biochim Biophys Acta 1072:129-157, 1991). More recently, an additional activity was described for this protein: it associates to the endoplasmic reticulum and activates the biosynthesis of phospholipids (Bussolino et al. in FASEB J 15:556-558, 2001), (Gil et al. in Mol Biol Cell 15:1881-1894, 2004), the quantitatively most important components of cellular membranes. This latter activity of c-Fos determines the rate of membrane genesis and consequently of growth in differentiating PC12 cells (Gil et al. in Mol Biol Cell 15:1881-1894, 2004). In addition, it has been shown that c-Fos is over-expressed both in PNS and CNS tumors (Silvestre et al. in PLoS One 5(3):e9544, 2010). Herein, it is shown that c-Fos-activated phospholipid synthesis is required to support membrane genesis during the exacerbated growth characteristic of brain tumor cells. Specifically blocking c-Fos-activated phospholipid synthesis significantly reduces proliferation of tumor cells in culture. Blocking c-Fos expression also prevents tumor progression in mice intra-cranially xeno-grafted human brain tumor cells. In NPcis mice, an animal model of the human disease Neurofibromatosis Type I (Cichowski and Jacks in Cell 104:593-604, 2001), animals spontaneously develop tumors of the PNS and the CNS, provided they express c-Fos (Silvestre et al. in PLoS One 5(3):e9544, 2010). Treatment of PNS tumors with an antisense oligonucleotide that specifically blocks c-Fos expression also blocks tumor growth in vivo. These results disclose cytoplasmic c-Fos as a new target for effectively controlling brain tumor growth.

Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3β and NF-κB to suppress tumor cell growth.

PubMed

Dudgeon, C; Peng, R; Wang, P; Sebastiani, A; Yu, J; Zhang, L

2012-11-15

Aberrant Ras/Raf/MEK/ERK signaling is one of the most prevalent oncogenic alterations and confers survival advantage to tumor cells. Inhibition of this pathway can effectively suppress tumor cell growth. For example, sorafenib, a multi-kinase inhibitor targeting c-Raf and other oncogenic kinases, has been used clinically for treating advanced liver and kidney tumors, and also has shown efficacy against other malignancies. However, how inhibition of oncogenic signaling by sorafenib and other drugs suppresses tumor cell growth remains unclear. In this study, we found that sorafenib kills cancer cells by activating PUMA (p53-upregulated modulator of apoptosis), a p53 target and a BH3-only Bcl-2 family protein. Sorafenib treatment induces PUMA in a variety of cancer cells irrespective of their p53 status. Surprisingly, the induction of PUMA by sorafenib is mediated by IκB-independent activation of nuclear factor (NF)-κB, which directly binds to the PUMA promoter to activate its transcription. NF-κB activation by sorafenib requires glycogen synthase kinase 3β activation, subsequent to ERK inhibition. Deficiency in PUMA abrogates sorafenib-induced apoptosis and caspase activation, and renders sorafenib resistance in colony formation and xenograft tumor assays. Furthermore, the chemosensitization effect of sorafenib is dependent on PUMA, and involves concurrent PUMA induction through different pathways. BH3 mimetics potentiate the anti-cancer effects of sorafenib, and restore sorafenib sensitivity in resistant cells. Together, these results demonstrate a key role of PUMA-dependent apoptosis in therapeutic inhibition of Ras/Raf/MEK/ERK signaling. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to the therapies that target oncogenic kinase signaling.

Is Anatomic Complexity Associated with Renal Tumor Growth Kinetics Under Active Surveillance?

PubMed Central

Mehrazin, Reza; Smaldone, Marc C.; Egleston, Brian; Tomaszewski, Jeffrey J.; Concodora, Charles W.; Ito, Timothy K.; Abbosh, Philip H.; Chen, David Y.T.; Kutikov, Alexander; Uzzo, Robert G.

2015-01-01

Introduction Linear growth rate (LGR) is the most commonly employed trigger for definitive intervention in patients with renal masses managed with an initial period of active surveillance (AS). Using our institutional cohort, we explored the association between tumor anatomic complexity at presentation and LGR in patients managed with AS. Methods and Materials Enhancing renal masses managed expectantly for at least 6 months were included for analysis. The association between NS and LGR was assessed using generalized estimating equations, adjusting for age, Charlson score, race, sex, and initial tumor size. Results 346 patients (401 masses) met inclusion criteria (18% ≥cT1b), with a median follow-up of 37 months (range: 6-169). 44% of patients progressed to definitive intervention with a median duration of 27 months (range: 6-130). Comparing patients managed expectantly to those requiring intervention, no difference was seen in median tumor size at presentation (2.2 vs. 2.2 cm), while significant differences in median age (74 vs. 65 years, p<0.001), Charlson co-morbidity score (3 vs. 2, p<0.001), and average LGR (0.23 vs. 0.49 cm/year, p<0.001) were observed between groups. Following adjustment, for each 1-point increase in NS sum, the average tumor LGR increased by 0.037 cm/year (p=0.002). Of the entire cohort, 6 patients (1.7%) progressed to metastatic disease. Conclusions The demonstrated association between anatomic tumor complexity at presentation and LGR of clinical stage 1 renal masses under AS may afford a clinically useful cue to tailor individual patient radiographic surveillance schedules and warrants further evaluation. PMID:25778696

Is anatomic complexity associated with renal tumor growth kinetics under active surveillance?

PubMed

Mehrazin, Reza; Smaldone, Marc C; Egleston, Brian; Tomaszewski, Jeffrey J; Concodora, Charles W; Ito, Timothy K; Abbosh, Philip H; Chen, David Y T; Kutikov, Alexander; Uzzo, Robert G

2015-04-01

Linear growth rate (LGR) is the most commonly employed trigger for definitive intervention in patients with renal masses managed with an initial period of active surveillance (AS). Using our institutional cohort, we explored the association between tumor anatomic complexity at presentation and LGR in patients managed with AS. Enhancing renal masses managed expectantly for at least 6 months were included for analysis. The association between Nephrometry Score and LGR was assessed using generalized estimating equations, adjusting for the age, Charlson score, race, sex, and initial tumor size. Overall, 346 patients (401 masses) met the inclusion criteria (18% ≥ cT1b), with a median follow-up of 37 months (range: 6-169). Of these, 44% patients showed progression to definitive intervention with a median duration of 27 months (range: 6-130). On comparing patients managed expectantly to those requiring intervention, no difference was seen in median tumor size at presentation (2.2 vs. 2.2 cm), whereas significant differences in median age (74 vs. 65 y, P < 0.001), Charlson comorbidity score (3 vs. 2, P<0.001), and average LGR (0.23 vs. 0.49 cm/y, P < 0.001) were observed between groups. Following adjustment, for each 1-point increase in Nephrometry Score sum, the average tumor LGR increased by 0.037 cm/y (P = 0.002). Of the entire cohort, 6 patients (1.7%) showed progression to metastatic disease. The demonstrated association between anatomic tumor complexity at presentation and renal masses of LGR of clinical stage 1 under AS may afford a clinically useful cue to tailor individual patient radiographic surveillance schedules and warrants further evaluation. Copyright © 2015 Elsevier Inc. All rights reserved.

Development of a Fully Human Anti-PDGFRβ Antibody That Suppresses Growth of Human Tumor Xenografts and Enhances Antitumor Activity of an Anti-VEGFR2 Antibody

PubMed Central

Shen, Juqun; Vil, Marie Danielle; Prewett, Marie; Damoci, Chris; Zhang, Haifan; Li, Huiling; Jimenez, Xenia; Deevi, Dhanvanthri S; Iacolina, Michelle; Kayas, Anthony; Bassi, Rajiv; Persaud, Kris; Rohoza-Asandi, Anna; Balderes, Paul; Loizos, Nick; Ludwig, Dale L; Tonra, James; Witte, Larry; Zhu, Zhenping

2009-01-01

Platelet-derived growth factor receptor β (PDGFRβ) is upregulated in most of solid tumors. It is expressed by pericytes/smooth muscle cells, fibroblast, macrophage, and certain tumor cells. Several PDGF receptor-related antagonists are being developed as potential antitumor agents and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here, we produced a fully human neutralizing antibody, IMC-2C5, directed against PDGFRβ from an antibody phage display library. IMC-2C5 binds to both human and mouse PDGFRβ and blocks PDGF-B from binding to the receptor. IMC-2C5 also blocks ligand-stimulated activation of PDGFRβ and downstream signaling molecules in tumor cells. In animal studies, IMC-2C5 significantly delayed the growth of OVCAR-8 and NCI-H460 human tumor xenografts in nude mice but failed to show antitumor activities in OVCAR-5 and Caki-1 xenografts. Our results indicate that the antitumor efficacy of IMC-2C5 is primarily due to its effects on tumor stroma, rather than on tumor cells directly. Combination of IMC-2C5 and DC101, an anti-mouse vascular endothelial growth factor receptor 2 antibody, resulted in significantly enhanced antitumor activity in BxPC-3, NCI-H460, and HCT-116 xenografts, compared with DC101 alone, and the trend of additive effects to DC101 treatment in several other tumor models. ELISA analysis of NCI-H460 tumor homogenates showed that IMC-2C5 attenuated protein level of vascular endothelial growth factor and basic fibroblast growth factor elevated by DC101 treatment. Finally, IMC-2C5 showed a trend of additive effects when combined with DC101/chemotherapy in MIA-PaCa-2 and NCI-H460 models. Taken together, these results lend great support to the use of PDGFRβ antagonists in combination with other antiangiogenic agents in the treatment of a broad range of human cancers. PMID:19484148

Muscle Contraction Arrests Tumor Growth

DTIC Science & Technology

2006-09-01

AD_________________ Award Number: W81XWH-05-1-0464 TITLE: Muscle Contraction Arrests Tumor Growth...DATE 01-09-2006 2. REPORT TYPE Annual 3. DATES COVERED 1 Sep 2005 – 31 Aug 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Muscle ... Contraction Arrests Tumor Growth 5b. GRANT NUMBER W81XWH-05-1-0464 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kim Westerlind, Ph.D. 5d. PROJECT NUMBER

Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly.

PubMed Central

Frohman, L A; Szabo, M; Berelowitz, M; Stachura, M E

1980-01-01

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.

PubMed

van Ginkel, Paul R; Darjatmoko, Soesiawati R; Sareen, Dhruv; Subramanian, Lalita; Bhattacharya, Saswati; Lindstrom, Mary J; Albert, Daniel M; Polans, Arthur S

2008-04-01

To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma. The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases. Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3. These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.

Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

NASA Astrophysics Data System (ADS)

Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

2016-06-01

Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth

PubMed Central

Kleffel, Sonja; Posch, Christian; Barthel, Steven R.; Mueller, Hansgeorg; Schlapbach, Christoph; Guenova, Emmanuella; Elco, Christopher P.; Lee, Nayoung; Juneja, Vikram R.; Zhan, Qian; Lian, Christine G.; Thomi, Rahel; Hoetzenecker, Wolfram; Cozzio, Antonio; Dummer, Reinhard; Mihm, Martin C.; Flaherty, Keith T.; Frank, Markus H.; Murphy, George F.; Sharpe, Arlene H.; Kupper, Thomas S.; Schatton, Tobias

2015-01-01

SUMMARY Therapeutic antibodies targeting programmed cell death-1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNA interference, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy. PMID:26359984

Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Qingwen; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433; Jiang, Songmin

2012-11-02

Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, amore » therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.« less

Statistical inference for tumor growth inhibition T/C ratio.

PubMed

Wu, Jianrong

2010-09-01

The tumor growth inhibition T/C ratio is commonly used to quantify treatment effects in drug screening tumor xenograft experiments. The T/C ratio is converted to an antitumor activity rating using an arbitrary cutoff point and often without any formal statistical inference. Here, we applied a nonparametric bootstrap method and a small sample likelihood ratio statistic to make a statistical inference of the T/C ratio, including both hypothesis testing and a confidence interval estimate. Furthermore, sample size and power are also discussed for statistical design of tumor xenograft experiments. Tumor xenograft data from an actual experiment were analyzed to illustrate the application.

Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis

PubMed Central

Nasser, Nicola J.; Avivi, Aaron; Shafat, Itay; Edovitsky, Evgeny; Zcharia, Eyal; Ilan, Neta; Vlodavsky, Israel; Nevo, Eviatar

2009-01-01

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) at the cell surface and in the extracellular matrix. Heparanase is expressed mainly by cancer cells, and its expression is correlated with increased tumor aggressiveness, metastasis, and angiogenesis. Here, we report the cloning of a unique splice variant (splice 36) of heparanase from the subterranean blind mole rat (Spalax). This splice variant results from skipping part of exon 3, exons 4 and 5, and part of exon 6 and functions as a dominant negative to the wild-type enzyme. It inhibits HS degradation, suppresses glioma tumor growth, and decreases experimental B16–BL6 lung colonization in a mouse model. Intriguingly, Spalax splice variant 7 of heparanase (which results from skipping of exon 7) is devoid of enzymatic activity, but unlike splice 36 it enhances tumor growth. Our results demonstrate that alternative splicing of heparanase regulates its enzymatic activity and might adapt the heparanase function to the fluctuating normoxic–hypoxic subterranean environment that Spalax experiences. Development of anticancer drugs designed to suppress tumor growth, angiogenesis, and metastasis is a major challenge, of which heparanase inhibition is a promising approach. We anticipate that the heparanase splicing model, evolved during 40 million years of Spalacid adaptation to underground life, would pave the way for the development of heparanase-based therapeutic modalities directed against angiogenesis, tumor growth, and metastasis. PMID:19164514

Luteolin and its inhibitory effect on tumor growth in systemic malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kapoor, Shailendra, E-mail: shailendrakapoor@yahoo.com

2013-04-01

Lamy et al have provided interesting data in their recent article in your esteemed journal. Luteolin augments apoptosis in a number of systemic malignancies. Luteolin reduces tumor growth in breast carcinomas. Luteolin mediates this effect by up-regulating the expression of Bax and down-regulating the expression of Bcl-xL. EGFR-induced MAPK activation is also attenuated. As a result there is increased G2/ M phase arrest. These effects have been seen both in vivo as well as in vitro. It also reduces ERα expression and causes inhibition of IGF-1 mediated PI3K–Akt pathway. Luteolin also activates p38 resulting in nuclear translocation of the apoptosis-inducingmore » factor. Simultaneously it also activates ERK. As a result there is increased intra-tumoral apoptosis which is caspase dependent as well as caspase independent. - Highlights: ► Luteolin and tumor growth in breast carcinomas. ► Luteolin and pulmonary cancer. ► Luteolin and colon cancer.« less

The effect of CT26 tumor-derived TGF-β on the balance of tumor growth and immunity.

PubMed

Owyang, Stephanie Y; Zhang, Min; Walkup, Grace A; Chen, Grace E; Grasberger, Helmut; El-Zaatari, Mohamad; Kao, John Y

2017-11-01

TGF-β is an important target for many cancer therapies under development. In addition to suppressing anti-tumor immunity, it has pleiotropic direct pro- and anti- tumor effects. The actions of increased endogenous TGF-β production remain unclear, and may affect the outcomes of anti-TGF-β cancer therapy. We hypothesize that tumor-derived TGF-β (td-TGF-β) plays an important role in maintaining tumor remission by controlling tumor proliferation in vivo, and that decreasing td-TGF-β in the tumor microenvironment will result in tumor progression. The aim of this study was to examine the effect of TGF-β in the tumor microenvironment on the balance between its anti-proliferative and immunosuppressive effects. A murine BALB/c spontaneous colon adenocarcinoma cell line (CT26) was genetically engineered to produce increased active TGF-β (CT26-TGF-β), a dominant-negative soluble TGF-β receptor (CT26-TGF-β-R), or the empty neomycin cassette as control (CT26-neo). In vitro proliferation rates were measured. For in vivo studies, the three cell lines were injected into syngeneic BALB/c mice, and tumor growth was measured over time. Immunodeficient BALB/c nude mice were used to investigate the role of T and B cells. In vitro, CT26-TGF-β-R and CT26-TGF-β cells showed increased and suppressed proliferation, respectively, compared to control (CT26-neo), confirming TGF-β has direct anti-tumor effects. In vivo, we found that CT26-TGF-β-R cells displayed slower growth compared to control, likely secondary to reduced suppression of anti-tumor immunity, as this effect was ablated in immunodeficient BALB/c nude mice. However, CT26-TGF-β cells (excess TGF-β) exhibited rapid early growth compared to control, but later failed to progress. The same pattern was shown in immunodeficient BALB/c nude mice, suggesting the effect on tumor growth is direct, with minimal immune system involvement. There was minimal effect on systemic antitumor immunity as determined by peripheral

Stress conditioning in mice: alterations in immunity and tumor growth.

PubMed

Benaroya-Milshtein, Noa; Hollander, Nurit; Apter, Alan; Yaniv, Isaac; Pick, Chaim G

2011-05-01

The neuroendocrine and autonomic nervous systems are known regulators of brain-immune interaction. However, the functional significance of this interaction under stress is not fully understood. We investigated the effect of a stress paradigm by applying electric foot shock followed by three reminders, on behavior, immune parameters, and lymphoma tumor growth. Male C3H mice were divided into two groups: Group 1-exposed to electric foot shock followed by three reminders, and Group 2-untreated (controls). Sets of mice underwent the elevated plus maze, staircase, and hot plate tests. After foot shock, natural killer (NK) cell activity, and lymphocyte proliferation were measured. In addition, sets of mice were either vaccinated twice with B-cell lymphoma 38C-13 immunoglobulin for determination of anti-idiotype (Id) antibodies in sera, or inoculated with tumor cells and monitored for tumor development and survival time. Mice exposed to electric foot shock followed by the three reminders had higher NK cell activity, levels of anti-Id antibodies, and a higher proliferation rate of splenocytes in response to mitogens, than the control mice. The exposed mice also showed attenuated tumor growth. Thus, the stress paradigm inhibited tumor development and lead to some immune changes that were not accompanied by behavioral changes.

Information dynamics in carcinogenesis and tumor growth.

PubMed

Gatenby, Robert A; Frieden, B Roy

2004-12-21

The storage and transmission of information is vital to the function of normal and transformed cells. We use methods from information theory and Monte Carlo theory to analyze the role of information in carcinogenesis. Our analysis demonstrates that, during somatic evolution of the malignant phenotype, the accumulation of genomic mutations degrades intracellular information. However, the degradation is constrained by the Darwinian somatic ecology in which mutant clones proliferate only when the mutation confers a selective growth advantage. In that environment, genes that normally decrease cellular proliferation, such as tumor suppressor or differentiation genes, suffer maximum information degradation. Conversely, those that increase proliferation, such as oncogenes, are conserved or exhibit only gain of function mutations. These constraints shield most cellular populations from catastrophic mutator-induced loss of the transmembrane entropy gradient and, therefore, cell death. The dynamics of constrained information degradation during carcinogenesis cause the tumor genome to asymptotically approach a minimum information state that is manifested clinically as dedifferentiation and unconstrained proliferation. Extreme physical information (EPI) theory demonstrates that altered information flow from cancer cells to their environment will manifest in-vivo as power law tumor growth with an exponent of size 1.62. This prediction is based only on the assumption that tumor cells are at an absolute information minimum and are capable of "free field" growth that is, they are unconstrained by external biological parameters. The prediction agrees remarkably well with several studies demonstrating power law growth in small human breast cancers with an exponent of 1.72+/-0.24. This successful derivation of an analytic expression for cancer growth from EPI alone supports the conceptual model that carcinogenesis is a process of constrained information degradation and that malignant

Pu-erh Tea Inhibits Tumor Cell Growth by Down-Regulating Mutant p53

PubMed Central

Zhao, Lanjun; Jia, Shuting; Tang, Wenru; Sheng, Jun; Luo, Ying

2011-01-01

Pu-erh tea is a kind of fermented tea with the incorporation of microorganisms’ metabolites. Unlike green tea, the chemical characteristics and bioactivities of Pu-erh tea are still not well understood. Using water extracts of Pu-erh tea, we analyzed the tumor cell growth inhibition activities on several genetically engineered mouse tumor cell lines. We found that at the concentration that did not affect wild type mouse embryo fibroblasts (MEFs) growth, Pu-erh tea extracts could inhibit tumor cell growth by down-regulated S phase and cause G1 or G2 arrest. Further study showed that Pu-erh tea extracts down-regulated the expression of mutant p53 in tumor cells at the protein level as well as mRNA level. The same concentration of Pu-erh tea solution did not cause p53 stabilization or activation of its downstream pathways in wild type cells. We also found that Pu-erh tea treatment could slightly down-regulate both HSP70 and HSP90 protein levels in tumor cells. These data revealed the action of Pu-erh tea on tumor cells and provided the possible mechanism for Pu-erh tea action, which explained its selectivity in inhibiting tumor cells without affecting wild type cells. Our data sheds light on the application of Pu-erh tea as an anti-tumor agent with low side effects. PMID:22174618

Improved brain tumor segmentation by utilizing tumor growth model in longitudinal brain MRI

NASA Astrophysics Data System (ADS)

Pei, Linmin; Reza, Syed M. S.; Li, Wei; Davatzikos, Christos; Iftekharuddin, Khan M.

2017-03-01

In this work, we propose a novel method to improve texture based tumor segmentation by fusing cell density patterns that are generated from tumor growth modeling. To model tumor growth, we solve the reaction-diffusion equation by using Lattice-Boltzmann method (LBM). Computational tumor growth modeling obtains the cell density distribution that potentially indicates the predicted tissue locations in the brain over time. The density patterns is then considered as novel features along with other texture (such as fractal, and multifractal Brownian motion (mBm)), and intensity features in MRI for improved brain tumor segmentation. We evaluate the proposed method with about one hundred longitudinal MRI scans from five patients obtained from public BRATS 2015 data set, validated by the ground truth. The result shows significant improvement of complete tumor segmentation using ANOVA analysis for five patients in longitudinal MR images.

Improved brain tumor segmentation by utilizing tumor growth model in longitudinal brain MRI.

PubMed

Pei, Linmin; Reza, Syed M S; Li, Wei; Davatzikos, Christos; Iftekharuddin, Khan M

2017-02-11

In this work, we propose a novel method to improve texture based tumor segmentation by fusing cell density patterns that are generated from tumor growth modeling. In order to model tumor growth, we solve the reaction-diffusion equation by using Lattice-Boltzmann method (LBM). Computational tumor growth modeling obtains the cell density distribution that potentially indicates the predicted tissue locations in the brain over time. The density patterns is then considered as novel features along with other texture (such as fractal, and multifractal Brownian motion (mBm)), and intensity features in MRI for improved brain tumor segmentation. We evaluate the proposed method with about one hundred longitudinal MRI scans from five patients obtained from public BRATS 2015 data set, validated by the ground truth. The result shows significant improvement of complete tumor segmentation using ANOVA analysis for five patients in longitudinal MR images.

CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

PubMed Central

Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

2014-01-01

Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer. PMID:24722501

MELK expression correlates with tumor mitotic activity but is not required for cancer growth

PubMed Central

Smith, Joan C; Palladino, Ann C

2018-01-01

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies. PMID:29417930

IL-33 activates tumor stroma to promote intestinal polyposis.

PubMed

Maywald, Rebecca L; Doerner, Stephanie K; Pastorelli, Luca; De Salvo, Carlo; Benton, Susan M; Dawson, Emily P; Lanza, Denise G; Berger, Nathan A; Markowitz, Sanford D; Lenz, Heinz-Josef; Nadeau, Joseph H; Pizarro, Theresa T; Heaney, Jason D

2015-05-12

Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN-depleted head and neck cancer tumor cells.

PubMed

Liu, Zhiyong; Hartman, Yolanda E; Warram, Jason M; Knowles, Joseph A; Sweeny, Larissa; Zhou, Tong; Rosenthal, Eben L

2011-08-01

Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma-mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer, there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here, we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were cocultured with fibroblasts or inoculated with fibroblasts into severe combined immunodeficient mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Coculture experiments showed fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN-silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN-silenced cells compared with control vector-transfected cells, whereas inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast coculture, suggesting the importance of FGFR2 signaling in fibroblast-mediated tumor growth. Analysis of xenografted tumors revealed that EMMPRIN-silenced tumors had a larger stromal compartment compared with control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast-independent tumor growth.

Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN depleted head and neck cancer tumor cells

PubMed Central

Liu, Zhiyong; Hartman, Yolanda E.; Warram, Jason M.; Knowles, Joseph A.; Sweeny, Larrisa; Zhou, Tong; Rosenthal, Eben L.

2011-01-01

Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were co-cultured with fibroblasts or inoculated with fibroblasts into SCID mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Co-culture experiments demonstrated fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN silenced cells compared to control vector transfected cells, while inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast co-culture, suggesting the importance of FGFR2 signaling in fibroblast mediated tumor growth. Analysis of xenografted tumors revealed EMMPRIN silenced tumors had a larger stromal compartment compared to control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast independent tumor growth. PMID:21665938

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats

PubMed Central

Moreira, Veridiana Mota; da Silva Franco, Claudinéia Conationi; Prates, Kelly Valério; Gomes, Rodrigo Mello; de Moraes, Ana Maria Praxedes; Ribeiro, Tatiane Aparecida; Martins, Isabela Peixoto; Previate, Carina; Pavanello, Audrei; Matiusso, Camila Cristina Ianoni; Almeida, Douglas Lopes; Francisco, Flávio Andrade; Malta, Ananda; Tófolo, Laize Peron; da Silva Silveira, Sandra; Saavedra, Lucas Paulo Jacinto; Machado, Katia; da Silva, Paulo Henrique Olivieri; Fabrício, Gabriel S.; Palma-Rigo, Kesia; de Souza, Helenir Medri; de Fátima Silva, Flaviane; Biazi, Giuliana Regina; Pereira, Taís Susane; Vieira, Elaine; Miranda, Rosiane Aparecida; de Oliveira, Júlio Cezar; da Costa Lima, Luiz Delmar; Rinaldi, Wilson; Ravanelli, Maria Ida; de Freitas Mathias, Paulo Cezar

2018-01-01

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55–65% VO2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

PubMed

Moreira, Veridiana Mota; da Silva Franco, Claudinéia Conationi; Prates, Kelly Valério; Gomes, Rodrigo Mello; de Moraes, Ana Maria Praxedes; Ribeiro, Tatiane Aparecida; Martins, Isabela Peixoto; Previate, Carina; Pavanello, Audrei; Matiusso, Camila Cristina Ianoni; Almeida, Douglas Lopes; Francisco, Flávio Andrade; Malta, Ananda; Tófolo, Laize Peron; da Silva Silveira, Sandra; Saavedra, Lucas Paulo Jacinto; Machado, Katia; da Silva, Paulo Henrique Olivieri; Fabrício, Gabriel S; Palma-Rigo, Kesia; de Souza, Helenir Medri; de Fátima Silva, Flaviane; Biazi, Giuliana Regina; Pereira, Taís Susane; Vieira, Elaine; Miranda, Rosiane Aparecida; de Oliveira, Júlio Cezar; da Costa Lima, Luiz Delmar; Rinaldi, Wilson; Ravanelli, Maria Ida; de Freitas Mathias, Paulo Cezar

2018-01-01

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55-65% VO 2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO 2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training

Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities.

PubMed

Dao, Pascal; Jarray, Rafika; Smith, Nikaia; Lepelletier, Yves; Le Coq, Johanne; Lietha, Daniel; Hadj-Slimane, Réda; Herbeuval, Jean-Philippe; Garbay, Christiane; Raynaud, Françoise; Chen, Huixiong

2014-06-28

FAK and FGFR2 signaling pathways play important roles in cancer development, progression and tumor angiogenesis. PHM16 is a novel ATP competitive inhibitor of FAK and FGFR2. To evaluate the therapeutic efficacy of this agent, we examined its anti-angiogenic effect in HUVEC and its anti-tumor effect in different cancer cell lines. We showed PHM16 inhibited endothelial cell viability, adherence and tube formation along with the added ability to induce endothelial cell apoptosis. This compound significantly delayed tumor cell growth. Together, these data showed that inhibition of both FAK and FGFR2 signaling pathways can enhance anti-tumor and anti-angiogenic activities. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models.

PubMed

Irvin, David M; McNeill, Robert S; Bash, Ryan E; Miller, C Ryan

2017-01-01

The influence of cellular origin on glioma pathogenesis remains elusive. We previously showed that mutations inactivating Rb and Pten and activating Kras transform astrocytes and induce tumorigenesis throughout the adult mouse brain. However, it remained unclear whether astrocyte subpopulations were susceptible to these mutations. We therefore used genetic lineage tracing and fate mapping in adult conditional, inducible genetically engineered mice to monitor transformation of glial fibrillary acidic protein (GFAP) and glutamate aspartate transporter (GLAST) astrocytes and immunofluorescence to monitor cellular composition of the tumor microenvironment over time. Because considerable regional heterogeneity exists among astrocytes, we also examined the influence of brain region on tumor growth. GFAP astrocyte transformation induced uniformly rapid, regionally independent tumor growth, but transformation of GLAST astrocytes induced slowly growing tumors with significant regional bias. Transformed GLAST astrocytes had reduced proliferative response in culture and in vivo and malignant progression was delayed in these tumors. Recruited glial cells, including proliferating astrocytes, oligodendrocyte progenitors and microglia, were the majority of GLAST, but not GFAP astrocyte-derived tumors and their abundance dynamically changed over time. These results suggest that intrinsic astrocyte heterogeneity, and perhaps regional brain microenvironment, significantly contributes to glioma pathogenesis. © 2016 International Society of Neuropathology.

A new ODE tumor growth modeling based on tumor population dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oroji, Amin; Omar, Mohd bin; Yarahmadian, Shantia

2015-10-22

In this paper a new mathematical model for the population of tumor growth treated by radiation is proposed. The cells dynamics population in each state and the dynamics of whole tumor population are studied. Furthermore, a new definition of tumor lifespan is presented. Finally, the effects of two main parameters, treatment parameter (q), and repair mechanism parameter (r) on tumor lifespan are probed, and it is showed that the change in treatment parameter (q) highly affects the tumor lifespan.

Hepatic Radiofrequency Ablation–induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition

PubMed Central

Kumar, Gaurav; Moussa, Marwan; Wang, Yuanguo; Rozenblum, Nir; Galun, Eithan; Goldberg, S. Nahum

2016-01-01

VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met–negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment. Conclusion RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met–negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors. © RSNA, 2015 PMID:26418615

IK channel activation increases tumor growth and induces differential behavioral responses in two breast epithelial cell lines.

PubMed

Thurber, Amy E; Nelson, Michaela; Frost, Crystal L; Levin, Michael; Brackenbury, William J; Kaplan, David L

2017-06-27

Many potassium channel families are over-expressed in cancer, but their mechanistic role in disease progression is poorly understood. Potassium channels modulate membrane potential (Vmem) and thereby influence calcium ion dynamics and other voltage-sensitive signaling mechanisms, potentially acting as transcriptional regulators. This study investigated the differential response to over-expression and activation of a cancer-associated potassium channel, the intermediate conductance calcium-activated potassium channel (IK), on aggressive behaviors in mammary epithelial and breast cancer cell lines. IK was over-expressed in the highly metastatic breast cancer cell line MDA-MB-231 and the spontaneously immortalized breast epithelial cell line MCF-10A, and the effect on cancer-associated behaviors was assessed. IK over-expression increased primary tumor growth and metastasis of MDA-MB-231 in orthotopic xenografts, demonstrating for the first time in any cancer type that increased IK is sufficient to promote cancer aggression. The primary tumors had similar vascularization as determined by CD31 staining and similar histological characteristics. Interestingly, despite the increased in vivo growth and metastasis, neither IK over-expression nor activation with agonist had a significant effect on MDA-MB-231 proliferation, invasion, or migration in vitro. In contrast, IK decreased MCF-10A proliferation and invasion through Matrigel but had no effect on migration in a scratch-wound assay. We conclude that IK activity is sufficient to promote cell aggression in vivo. Our data provide novel evidence supporting IK and downstream signaling networks as potential targets for cancer therapies.

A tumor growth model with deformable ECM

NASA Astrophysics Data System (ADS)

Sciumè, G.; Santagiuliana, R.; Ferrari, M.; Decuzzi, P.; Schrefler, B. A.

2014-12-01

Existing tumor growth models based on fluid analogy for the cells do not generally include the extracellular matrix (ECM), or if present, take it as rigid. The three-fluid model originally proposed by the authors and comprising tumor cells (TC), host cells (HC), interstitial fluid (IF) and an ECM, considered up to now only a rigid ECM in the applications. This limitation is here relaxed and the deformability of the ECM is investigated in detail. The ECM is modeled as a porous solid matrix with Green-elastic and elasto-visco-plastic material behavior within a large strain approach. Jauman and Truesdell objective stress measures are adopted together with the deformation rate tensor. Numerical results are first compared with those of a reference experiment of a multicellular tumor spheroid (MTS) growing in vitro, then three different tumor cases are studied: growth of an MTS in a decellularized ECM, growth of a spheroid in the presence of host cells and growth of a melanoma. The influence of the stiffness of the ECM is evidenced and comparison with the case of a rigid ECM is made. The processes in a deformable ECM are more rapid than in a rigid ECM and the obtained growth pattern differs. The reasons for this are due to the changes in porosity induced by the tumor growth. These changes are inhibited in a rigid ECM. This enhanced computational model emphasizes the importance of properly characterizing the biomechanical behavior of the malignant mass in all its components to correctly predict its temporal and spatial pattern evolution.

A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors

NASA Astrophysics Data System (ADS)

Rubin, Joshua B.; Kung, Andrew L.; Klein, Robyn S.; Chan, Jennifer A.; Sun, Yanping; Schmidt, Karl; Kieran, Mark W.; Luster, Andrew D.; Segal, Rosalind A.

2003-11-01

The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology.

PubMed

Tilan, Jason; Kitlinska, Joanna

2016-02-01

Neuropeptide Y (NPY) is a sympathetic neurotransmitter with pleiotropic actions, many of which are highly relevant to tumor biology. Consequently, the peptide has been implicated as a factor regulating the growth of a variety of tumors. Among them, two pediatric malignancies with high endogenous NPY synthesis and release - neuroblastoma and Ewing sarcoma - became excellent models to investigate the role of NPY in tumor growth and progression. The stimulatory effect on tumor cell proliferation, survival, and migration, as well as angiogenesis in these tumors, is mediated by two NPY receptors, Y2R and Y5R, which are expressed in either a constitutive or inducible manner. Of particular importance are interactions of the NPY system with the tumor microenvironment, as hypoxic conditions commonly occurring in solid tumors strongly activate the NPY/Y2R/Y5R axis. This activation is triggered by hypoxia-induced up-regulation of Y2R/Y5R expression and stimulation of dipeptidyl peptidase IV (DPPIV), which converts NPY to a selective Y2R/Y5R agonist, NPY(3-36). While previous studies focused mainly on the effects of NPY on tumor growth and vascularization, they also provided insight into the potential role of the peptide in tumor progression into a metastatic and chemoresistant phenotype. This review summarizes our current knowledge of the role of NPY in neuroblastoma and Ewing sarcoma and its interactions with the tumor microenvironment in the context of findings in other malignancies, as well as discusses future directions and potential clinical implications of these discoveries. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Role of Oxygen in Avascular Tumor Growth

PubMed Central

Grimes, David Robert; Kannan, Pavitra; McIntyre, Alan; Kavanagh, Anthony; Siddiky, Abul; Wigfield, Simon; Harris, Adrian; Partridge, Mike

2016-01-01

The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model. PMID:27088720

Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bian, Yong, E-mail: drbiany@126.com; Yu, Yun; Wang, Shanshan

2015-08-07

Lipid metabolism is dysregulated in many human diseases including atherosclerosis, type 2 diabetes and cancers. Fatty acid synthase (FASN), a key lipogenic enzyme involved in de novo lipid biosynthesis, is significantly upregulated in multiple types of human cancers and associates with tumor progression. However, limited data is available to understand underlying biological functions and clinical significance of overexpressed FASN in pancreatic ductal adenocarcinoma (PDAC). Here, upregulated FASN was more frequently observed in PDAC tissues compared with normal pancreas in a tissue microarray. Kaplan–Meier survival analysis revealed that high expression level of FASN resulted in a significantly poor prognosis of PDACmore » patients. Knockdown or inhibition of endogenous FASN decreased cell proliferation and increased cell apoptosis in HPAC and AsPC-1 cells. Furthermore, we demonstrated that EGFR/ERK signaling accounts for elevated FASN expression in PDAC as ascertained by performing siRNA assays and using specific pharmacological inhibitors. Collectively, our results indicate that FASN exhibits important roles in tumor growth and EGFR/ERK pathway is responsible for upregulated expression of FASN in PDAC. - Highlights: • Increased expression of FASN indicates a poor prognosis in PDAC. • Elevated FASN favors tumor growth in PDAC in vitro. • Activation of EGFR signaling contributes to elevated FASN expression.« less

Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model.

PubMed

Gupta, Shishir Kumar; Yadav, Pavan Kumar; Gandham, Ravi Kumar; Sahoo, A P; Harish, D R; Singh, Arvind Kumar; Tiwari, A K

2016-02-02

Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity. Copyright © 2015 Elsevier B.V. All rights reserved.

The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

DTIC Science & Technology

2011-09-01

recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re-growth is triggered by shifting of...microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize that the balance of...dormancy and recurrence is determined by the ability of the tumor stem cells to recruit TAM which in turn promotes self-renewal of the stem cell . We

Brain tumor recurrence in children treated with growth hormone: the National Cooperative Growth Study experience.

PubMed

Moshang, T; Rundle, A C; Graves, D A; Nickas, J; Johanson, A; Meadows, A

1996-05-01

As of October 1993 the National Cooperative Growth Study included 1262 children with brain tumor who were treated with growth hormone. The type of brain tumor was specified in 947 (75%) of these children. The most common types were glioma, medulloblastoma, and craniopharyngioma, accounting for 91.3% of all those for which type was specified. Brain tumor recurred in 83 (6.6%) of the 1262 children over a total of 6115 patient-years at risk. The frequencies of tumor recurrence in children with low-grade glioma (18.1%), medulloblastoma (7.2%), and craniopharyngioma (6.4%) are lower than those in published reports of tumor recurrence in the general pediatric population with the same types of tumors. The analysis cannot conclusively show that no increased risk of tumor recurrence exists, however, because of the potential incompleteness of data reporting in the National Cooperative Growth Study. Nevertheless the findings are reassuring that children with the more common types of brain tumor who are treated with growth hormone do not seem to be at excessive risk for tumor recurrence.

Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.

PubMed

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-07-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models.

PubMed

Wu, Xiao Yu; Xu, Hao; Wu, Zhen Feng; Chen, Che; Liu, Jia Yun; Wu, Guan Nan; Yao, Xue Quan; Liu, Fu Kun; Li, Gang; Shen, Liang

2015-12-29

Most anti-angiogenic therapies currently being evaluated in clinical trials target vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified formononetin as a novel agent with potential anti-angiogenic and anti-cancer activities. Formononetin demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor 2 (FGF2). In ex vivo and in vivo angiogenesis assays, formononetin suppressed FGF2-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of formononetin on different molecular components in treated endothelial cell, and found that formononetin suppressed FGF2-triggered activation of FGFR2 and protein kinase B (Akt) signaling. Moreover, formononetin directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer, formononetin showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Moreover, formononetin enhanced the effect of VEGFR2 inhibitor sunitinib on tumor growth inhibition. Taken together, our results indicate that formononetin targets the FGFR2-mediated Akt signaling pathway, leading to the suppression of tumor growth and angiogenesis.

Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models

PubMed Central

Wu, Zhen Feng; Chen, Che; Liu, Jia Yun; Wu, Guan Nan; Yao, Xue Quan; Liu, Fu Kun; Li, Gang; Shen, Liang

2015-01-01

Most anti-angiogenic therapies currently being evaluated in clinical trials target vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified formononetin as a novel agent with potential anti-angiogenic and anti-cancer activities. Formononetin demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor 2 (FGF2). In ex vivo and in vivo angiogenesis assays, formononetin suppressed FGF2-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of formononetin on different molecular components in treated endothelial cell, and found that formononetin suppressed FGF2-triggered activation of FGFR2 and protein kinase B (Akt) signaling. Moreover, formononetin directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer, formononetin showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Moreover, formononetin enhanced the effect of VEGFR2 inhibitor sunitinib on tumor growth inhibition. Taken together, our results indicate that formononetin targets the FGFR2-mediated Akt signaling pathway, leading to the suppression of tumor growth and angiogenesis. PMID:26575424

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment.

PubMed

Michael, James V; Wurtzel, Jeremy G T; Goldfinger, Lawrence E

2016-10-01

The goal of this study was to develop combinatorial application of two drugs currently either in active use as anticancer agents (rapamycin) or in clinical trials (OTX008) as a novel strategy to inhibit Harvey RAS (HRAS)-driven tumor progression. HRAS anchored to the plasma membrane shuttles from the lipid ordered (L o ) domain to the lipid ordered/lipid disordered border upon activation, and retention of HRAS at these sites requires galectin-1. We recently showed that genetically enforced L o sequestration of HRAS inhibited mitogen-activated protein kinase (MAPK) signaling, but not phoshatidylinositol 3-kinase (PI3K) activation. Here we show that inhibition of galectin-1 with OTX008 sequestered HRAS in the L o domain, blocked HRAS-mediated MAPK signaling, and attenuated HRAS-driven tumor progression in mice. HRAS-driven tumor growth was also attenuated by treatment with mammalian target of rapamycin (mTOR) inhibitor rapamycin, and this effect was further enhanced in tumors driven by L o -sequestered HRAS. These drugs also revealed bidirectional cross-talk in HRAS pathways. Moreover, dual pathway inhibition with OTX008 and rapamycin resulted in nearly complete ablation of HRAS-driven tumor growth. These findings indicate that membrane microdomain sequestration of HRAS with galectin-1 inhibition, coupled with mTOR inhibition, may support a novel therapeutic approach to treat HRAS-mutant cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Cells competition in tumor growth poroelasticity

NASA Astrophysics Data System (ADS)

Fraldi, Massimiliano; Carotenuto, Angelo R.

2018-03-01

Growth of biological tissues has been recently treated within the framework of Continuum Mechanics, by adopting heterogeneous poroelastic models where the interaction between soft matrix and interstitial fluid flow is coupled with inelastic effects ad hoc introduced to simulate the macroscopic volumetric growth determined by cells division, cells growth and extracellular matrix changes occurring at the micro-scale level. These continuum models seem to overcome some limitations intrinsically associated to other alternative approaches based on mass balances in multiphase systems, because the crucial role played by residual stresses accompanying growth and nutrients walkway is preserved. Nevertheless, when these strategies are applied to analyze solid tumors, mass growth is usually assigned in a prescribed form that essentially copies the in vitro measured intrinsic growth rates of the cell species. As a consequence, some important cell-cell dynamics governing mass evolution and invasion rates of cancer cells, as well as their coupling with feedback mechanisms associated to in situ stresses, are inevitably lost and thus the spatial distribution and the evolution with time of the growth inside the tumor -which would be results rather than inputs- are forced to enter in the model simply as data. In order to solve this paradox, it is here proposed an enhanced multi-scale poroelastic model undergoing large deformations and embodying inelastic growth, where the net growth terms directly result from the "interspecific" predator-prey (Volterra/Lotka-like) competition occurring at the micro-scale level between healthy and abnormal cell species. In this way, a system of fully-coupled non-linear PDEs is derived to describe how the fight among cell species to grab the available common resources, stress field, pressure gradients, interstitial fluid flows driving nutrients and inhomogeneous growth all simultaneously interact to decide the tumor fate.

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

PubMed Central

Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M.; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

2017-01-01

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma. PMID:28696319

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.

PubMed

Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

2017-07-25

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3)

PubMed Central

2012-01-01

Background Signal transducer and activator of transcription 3 (STAT3) is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, to date the exact mechanism by which DIM induces growth suppressive effects has not been clear. In this report the mode of action of DIM is investigated. Methods Six human ovarian cancer cell lines and an ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination with cisplatin. Results Diindolylmethane treatment induced apoptosis in all six ovarian cancer cell lines. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. Interleukin (IL)-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, DIM treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. DIM treatment also inhibited cell invasion and angiogenesis by suppressing hypoxia-inducible factor 1α (HIF-1α) and vascular epithelial growth factor (VEGF). Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation. Conclusions These findings provide a rationale for further clinical investigation of DIM alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer. PMID:22280969

Brain tumor modeling: glioma growth and interaction with chemotherapy

NASA Astrophysics Data System (ADS)

Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

2011-10-01

In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

Trastuzumab inhibits pituitary tumor growth modulating the TGFB/Smad2/3 pathway.

PubMed

Petiti, Juan Pablo; Sosa, Liliana Del Valle; Picech, Florencia; Moyano Crespo, Gabriela Deisi; Arevalo Rojas, Jean Zander; Pérez, Pablo Anibal; Guido, Carolina Beatriz; Leimgruber, Carolina; Sabatino, María Eugenia; García, Pedro Emilio; Bengió, Verónica; Papalini, Francisco Roque; Estario, Paula; Bernhardt, Maria Celina; Villarreal, Marcos; Gutiérrez, Silvina; De Paul, Ana Lucía; Mukdsi, Jorge Humberto; Torres, Alicia I

2018-06-06

In pituitary adenomas, early recurrences and resistance to conventional pharmacotherapies are common, but the mechanisms involved are still not understood. The high expression of epidermal growth factor receptor 2 (HER2)/extracellular signal-regulated kinase (ERK1/2) signal observed in human pituitary adenomas, together with the low levels of the antimitogenic transforming growth factor beta receptor 2 (TBR2), encouraged us to evaluate the effect of the specific HER2 inhibition with trastuzumab on experimental pituitary tumor cell growth and its effect on the antiproliferative response to TGFB1. Trastuzumab decreased the pituitary tumor growth as well as the expression of ERK1/2 and the cell cycle regulators cyclin D1 and CDK4. The HER2/ERK1/2 pathway is an attractive therapeutic target, but its intricate relations with other signaling modulators still need to be unraveled. Thus, we investigated possible cross-talk with TGFB signaling, which has not yet been studied in pituitary tumors. In tumoral GH3 cells, co-incubation with trastuzumab and TGFB1 significantly decreased cell proliferation, an effect accompanied by a reduction in ERK1/2 phosphorylation, an increase of SMAD2/3 activation. In addition, through immunoprecipitation assays, a diminution of SMAD2/3-ERK1/2 and an increase SMAD2/3-TGFBR1 interactions were observed when cells were co-incubated with Trastuzumab and TGFB1. These findings indicate that blocking HER2 by trastuzumab inhibited pituitary tumor growth and modulated HER2/ERK1/2 signaling and consequently the anti-mitogenic TGFB1/TBRs/SMADs cascade. The imbalance between HER2 and TGFBRs expression observed in human adenomas and the response to trastuzumab on experimental tumor growth, may make the HER2/ERK1/2 pathway an attractive target for future pituitary adenoma therapy.

Tumor Biology of Vestibular Schwannoma: A Review of Experimental Data on the Determinants of Tumor Genesis and Growth Characteristics.

PubMed

de Vries, Maurits; van der Mey, Andel G L; Hogendoorn, Pancras C W

2015-08-01

Provide an overview of the literature on vestibular schwannoma biology with special attention to tumor behavior and targeted therapy. Vestibular schwannomas are benign tumors originating from the eighth cranial nerve and arise due to inactivation of the NF2 gene and its product merlin. Unraveling the biology of these tumors helps to clarify their growth pattern and is essential in identifying therapeutic targets. PubMed search for English-language articles on vestibular schwannoma biology from 1994 to 2014. Activation of merlin and its role in cell signaling seem as key aspects of vestibular schwannoma biology. Merlin is regulated by proteins such as CD44, Rac, and myosin phosphatase-targeting subunit 1. The tumor-suppressive functions of merlin are related to receptor tyrosine kinases, such as the platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Merlin mediates the Hippo pathway and acts within the nucleus by binding E3 ubiquiting ligase CRL4. Angiogenesis is an important mechanism responsible for the progression of these tumors and is affected by processes such as hypoxia and inflammation. Inhibiting angiogenesis by targeting vascular endothelial growth factor receptor seems to be the most successful pharmacologic strategy, but additional therapeutic options are emerging. Over the years, the knowledge on vestibular schwannoma biology has significantly increased. Future research should focus on identifying new therapeutic targets by investigating vestibular schwannoma (epi)genetics, merlin function, and tumor behavior. Besides identifying novel targets, testing new combinations of existing treatment strategies can further improve vestibular schwannoma therapy.

In silico modeling for tumor growth visualization.

PubMed

Jeanquartier, Fleur; Jean-Quartier, Claire; Cemernek, David; Holzinger, Andreas

2016-08-08

Cancer is a complex disease. Fundamental cellular based studies as well as modeling provides insight into cancer biology and strategies to treatment of the disease. In silico models complement in vivo models. Research on tumor growth involves a plethora of models each emphasizing isolated aspects of benign and malignant neoplasms. Biologists and clinical scientists are often overwhelmed by the mathematical background knowledge necessary to grasp and to apply a model to their own research. We aim to provide a comprehensive and expandable simulation tool to visualizing tumor growth. This novel Web-based application offers the advantage of a user-friendly graphical interface with several manipulable input variables to correlate different aspects of tumor growth. By refining model parameters we highlight the significance of heterogeneous intercellular interactions on tumor progression. Within this paper we present the implementation of the Cellular Potts Model graphically presented through Cytoscape.js within a Web application. The tool is available under the MIT license at https://github.com/davcem/cpm-cytoscape and http://styx.cgv.tugraz.at:8080/cpm-cytoscape/ . In-silico methods overcome the lack of wet experimental possibilities and as dry method succeed in terms of reduction, refinement and replacement of animal experimentation, also known as the 3R principles. Our visualization approach to simulation allows for more flexible usage and easy extension to facilitate understanding and gain novel insight. We believe that biomedical research in general and research on tumor growth in particular will benefit from the systems biology perspective.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

PubMed

Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Hedgehog signal inhibitor forskolin suppresses cell proliferation and tumor growth of human rhabdomyosarcoma xenograft.

PubMed

Yamanaka, Hiroaki; Oue, Takaharu; Uehara, Shuichiro; Fukuzawa, Masahiro

2011-02-01

We have previously reported that the Hedgehog (Hh) signaling pathway is activated in pediatric malignancies. In this study, we examined the effect of the Hh signal inhibitor forskolin on the growth of rhabdomyosarcoma (RMS) in vivo and in vitro and thereby elucidated the possibility of considering Hh signaling pathway as a therapeutic target for RMS. We evaluated the messenger RNA expressions of Hh signal mediators in 3 human RMS cell lines using reverse transcriptase-polymerase chain reaction method. The effect of forskolin on the tumor cell proliferation was investigated using WST-1 assay (Dojindo Co, Kumamoto, Japan). We inoculated 10(7) tumor cells into the back of nude mice to create RMS xenograft tumor models. Forskolin was subcutaneously administered in the region around the tumor, and the effect on the tumor growth was evaluated. The messenger RNA expression of glioma-associated oncogene homolog 1, the marker of Hh signaling activation, was expressed at various levels in RMS cell lines. The proliferation of RMS cells was inhibited in a dose-dependent fashion by forskolin. Similarly, in the xenograft model, tumor growth was also significantly reduced by forskolin treatment. Our findings suggest that the Hh signaling pathway plays an important role in the tumorigenesis of RMS and that this pathway can be considered to be a potential molecular target of new treatment strategies for RMS. Copyright © 2011 Elsevier Inc. All rights reserved.

Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

PubMed Central

Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

2015-01-01

Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.

PubMed

Pedersen, Line; Idorn, Manja; Olofsson, Gitte H; Lauenborg, Britt; Nookaew, Intawat; Hansen, Rasmus Hvass; Johannesen, Helle Hjorth; Becker, Jürgen C; Pedersen, Katrine S; Dethlefsen, Christine; Nielsen, Jens; Gehl, Julie; Pedersen, Bente K; Thor Straten, Per; Hojman, Pernille

2016-03-08

Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth. Copyright © 2016 Elsevier Inc. All rights reserved.

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

PubMed

Shukla, Surendra K; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V; Yu, Fang; Singh, Pankaj K

2015-12-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

PubMed Central

Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

2015-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID:26510913

Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

PubMed

Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

2016-12-01

Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.

PubMed

Sun, Xiujie; Gupta, Kshama; Wu, Bogang; Zhang, Deyi; Yuan, Bin; Zhang, Xiaowen; Chiang, Huai-Chin; Zhang, Chi; Curiel, Tyler J; Bendeck, Michelle P; Hursting, Stephen; Hu, Yanfen; Li, Rong

2018-02-23

Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1- KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro , and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.

PubMed

Roca, Hernan; Jones, Jacqueline D; Purica, Marta C; Weidner, Savannah; Koh, Amy J; Kuo, Robert; Wilkinson, John E; Wang, Yugang; Daignault-Newton, Stephanie; Pienta, Kenneth J; Morgan, Todd M; Keller, Evan T; Nör, Jacques E; Shea, Lonnie D; McCauley, Laurie K

2018-01-02

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.

Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

PubMed

Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

2015-10-12

Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer.

PubMed

Greenaway, James; Henkin, Jack; Lawler, Jack; Moorehead, Roger; Petrik, Jim

2009-01-01

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.

PubMed

Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L; Choi, Hyun-Jin; Hansen, Jean M; Dalton, Heather J; Stone, Rebecca L; Cho, Min Soon; Nick, Alpa M; Nagaraja, Archana S; Gutschner, Tony; Gharpure, Kshipra M; Mangala, Lingegowda S; Rupaimoole, Rajesha; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N; Wu, Sherry Y; Pecot, Chad V; Burns, Alan R; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K

2016-05-02

Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

PubMed Central

Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L.; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.

2016-01-01

Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

Emodin inhibits breast cancer growth by blocking the tumor-promoting feedforward loop between cancer cells and macrophages

PubMed Central

Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

2016-01-01

Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing anti-tumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2 related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration towards and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. PMID:27196773

Tumor Growth Increases Neuroinflammation, Fatigue and Depressive-like Behavior Prior to Alterations in Muscle Function

PubMed Central

Norden, Diana M.; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J.; Wold, Loren E.; Reiser, Peter J.; Godbout, Jonathan P.; McCarthy, Donna O.

2014-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. PMID:25102452

Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function.

PubMed

Norden, Diana M; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J; Wold, Loren E; Reiser, Peter J; Godbout, Jonathan P; McCarthy, Donna O

2015-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. Copyright © 2014 Elsevier Inc. All rights reserved.

The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

DTIC Science & Technology

2012-09-01

According to the recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re- growth is triggered by...shifting of microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize...the stem cell . We have established necessary mouse colonies and also developed the method to generate TAM. We have also shown that TAM indeed

Phase transition in tumor growth: I avascular development

NASA Astrophysics Data System (ADS)

Izquierdo-Kulich, E.; Rebelo, I.; Tejera, E.; Nieto-Villar, J. M.

2013-12-01

We propose a mechanism for avascular tumor growth based on a simple chemical network. This model presents a logistic behavior and shows a “second order” phase transition. We prove the fractal origin of the empirical logistics and Gompertz constant and its relation to mitosis and apoptosis rate. Finally, the thermodynamics framework developed demonstrates the entropy production rate as a Lyapunov function during avascular tumor growth.

Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.

PubMed

Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat

2011-05-01

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.

Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth

DTIC Science & Technology

2006-11-01

LN -Shh xenograft tumors is unabated after castration of the host mouse. However, castration of mice bearing LNCaP + Gli3-/- UGSM bi-clonal...canonical xenograft undergoes involution and growth arrest, growth of LN -Shh xenograft tumors is unabated after castration. As we have shown...signalingindependent of Shh ligand in tumor stroma accelerates tumor growth. We have identified potential stromal Shh target genes in xenograft tumors and have begun

A multiphase model for three-dimensional tumor growth

NASA Astrophysics Data System (ADS)

Sciumè, G.; Shelton, S.; Gray, W. G.; Miller, C. T.; Hussain, F.; Ferrari, M.; Decuzzi, P.; Schrefler, B. A.

2013-01-01

Several mathematical formulations have analyzed the time-dependent behavior of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the thermodynamically constrained averaging theory. A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TCs), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HCs); and an interstitial fluid for the transport of nutrients. The equations are solved by a finite element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTSs) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behavior: initially, the rapidly growing TCs tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable TCs whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case—mostly due to the relative adhesion of the TCs and HCs to the ECM, and the less favorable transport of nutrients. In particular, for HCs adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas TC

ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer

PubMed Central

Greenaway, James; Henkin, Jack; Lawler, Jack; Moorehead, Roger; Petrik, Jim

2012-01-01

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC. PMID:19139114

CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages.

PubMed

Ball, Michael S; Shipman, Emilie P; Kim, Hyunjung; Liby, Karen T; Pioli, Patricia A

2016-01-01

Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.

CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

PubMed Central

Ball, Michael S.; Shipman, Emilie P.; Kim, Hyunjung; Liby, Karen T.; Pioli, Patricia A.

2016-01-01

Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

PubMed Central

Watanabe, Akira; Ogiwara, Hideki; Ehata, Shogo; Mukasa, Akitake; Ishikawa, Shumpei; Maeda, Daichi; Ueki, Keisuke; Ino, Yasushi; Todo, Tomoki; Yamada, Yasuhiro; Fukayama, Masashi; Saito, Nobuhito; Miyazono, Kohei; Aburatani, Hiroyuki

2011-01-01

Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells. PMID:21750150

Anticancer activity of TTAC-0001, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR-2/KDR) monoclonal antibody, is associated with inhibition of tumor angiogenesis

PubMed Central

Kim, Dong Geon; Jin, Younggeon; Jin, Juyoun; Yang, Heekyoung; Joo, Kyeung Min; Lee, Weon Sup; Shim, Sang Ryeol; Kim, Sung-Woo; Yoo, Jinsang; Lee, Sang Hoon; Yoo, Jin-San; Nam, Do-Hyun

2015-01-01

Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft models. We were able to determine the relationship between PK and the efficacy of TTAC-0001 through in vivo single-dose PK study. Taken together, our data suggest that targeting VEGFR-2 with TTAC-0001 could be a promising approach for cancer treatment. PMID:26325365

Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

PubMed

Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

2016-08-01

Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. ©2016 American Association for Cancer Research.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

PubMed

Martín-Rodríguez, Juan F; Muñoz-Bravo, Jose L; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M; Castaño, Justo P; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A

2015-11-09

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

PubMed Central

Martín-Rodríguez, Juan F.; Muñoz-Bravo, Jose L.; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A.

2015-01-01

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. PMID:26549306

Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model1

PubMed Central

Dickerson, Erin B; Steinberg, Howard; Breen, Matthew; Auerbach, Robert; Helfand, Stuart C

2004-01-01

Abstract We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF) receptors 1 and 2, CD31, CD146, and αvβ3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL)-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy. PMID:15140399

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

PubMed

Markowitz, Geoffrey J; Yang, Pengyuan; Fu, Jing; Michelotti, Gregory A; Chen, Rui; Sui, Jianhua; Yang, Bin; Qin, Wen-Hao; Zhang, Zheng; Wang, Fu-Sheng; Diehl, Anna Mae; Li, Qi-Jing; Wang, Hongyang; Wang, Xiao-Fan

2016-04-15

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR. ©2016 American Association for Cancer Research.

Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.

Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloidmore » fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.« less

Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice.

PubMed

Kim, Sun-Jin; Uehara, Hisanori; Karashima, Takashi; Shepherd, David L; Killion, Jerald J; Fidler, Isaiah J

2003-03-01

We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice. Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry. Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions. These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.

Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis

PubMed Central

Henning, Susanne M.; Wang, Piwen; Said, Jonathan; Magyar, Clara; Castor, Brandon; Doan, Ngan; Tosity, Carmen; Moro, Aune; Gao, Kun; Li, Luyi; Heber, David

2011-01-01

It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis, and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi (GSTp1) to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 (DNMT1) mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice. PMID:22405694

Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis.

PubMed

Weng-Yew, Wong; Selvaduray, Kanga Rani; Ming, Cheng Hwee; Nesaretnam, Kalanithi

2009-01-01

Previous studies have revealed that tocotrienol-rich fractions (TRF) from palm oil inhibit the proliferation and the growth of solid tumors. The anticancer activity of TRF is said to be caused by several mechanisms, one of which is antiangiogenesis. In this study, we looked at the antiangiogenic effects of TRF. In vitro investigations of the antiangiogenic activities of TRF, delta-tocotrienol (deltaT3), and alpha-tocopherol (alphaToc) were carried out in human umbilical vein endothelial cells (HUVEC). TRF and deltaT3 significantly inhibited cell proliferation from 4 microg/ml onward (P < 0.05). Cell migration was inhibited the most by deltaT3 at 12 microg/ml. Anti-angiogenic properties of TRF were carried out further in vivo using the chick embryo chorioallantoic membrane (CAM) assay and BALB/c mice model. TRF at 200 microg/ml reduced the vascular network on CAM. TRF treatment of 1 mg/mouse significantly reduced 4T1 tumor volume in BALB/c mice. TRF significantly reduced serum vascular endothelial growth factor (VEGF) level in BALB/c mice. In conclusion, this study showed that palm tocotrienols exhibit anti-angiogenic properties that may assist in tumor regression.

Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

NASA Astrophysics Data System (ADS)

Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

2014-03-01

Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

S100A9 Interaction with TLR4 Promotes Tumor Growth

PubMed Central

Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

2012-01-01

By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies. PMID:22470535

Combined therapy with cyclophosphamide and DNA preparation inhibits the tumor growth in mice

PubMed Central

Alyamkina, Ekaterina A; Dolgova, Evgenia V; Likhacheva, Anastasia S; Rogachev, Vladimir A; Sebeleva, Tamara E; Nikolin, Valeriy P; Popova, Nelly A; Orishchenko, Konstantin E; Strunkin, Dmitriy N; Chernykh, Elena R; Zagrebelniy, Stanislav N; Bogachev, Sergei S; Shurdov, Mikhail A

2009-01-01

Background When cyclophosphamide and preparations of fragmented exogenous genomic double stranded DNA were administered in sequence, the regressive effect on the tumor was synergic: this combined treatment had a more pronounced effect than cyclophosphamide alone. Our further studies demonstrated that exogenous DNA stimulated the maturation and specific activities of dendritic cells. This suggests that cyclophosphamide, combined with DNA, leads to an immune response to the tumors that were grafted into the subjects post treatment. Methods Three-month old CBA/Lac mice were used in the experiments. The mice were injected with cyclosphamide (200 mkg per 1 kg body weight) and genomic DNA (of human, mouse or salmon sperm origin). The DNA was administered intraperitoneally or subcutaneously. After 23 to 60 days, one million tumor cells were intramuscularly grafted into the mice. In the final experiment, the mice were pre-immunized by subcutaneous injections of 20 million repeatedly thawed and frozen tumor cells. Changes in tumor growth were determined by multiplying the three perpendicular diameters (measured by caliper). Students' t-tests were used to determine the difference between tumor growth and average survival rate between the mouse groups and the controls. Results An analysis of varying treatments with cyclophosphamide and exogenous DNA, followed by tumor grafting, provided evidence that this combined treatment had an immunizing effect. This inhibitory effect in mice was analyzed in an experiment with the classical immunization of a tumor homogenate. The strongest inhibitory action on a transplanted graft was created through the following steps: cyclophosphamide at 200 mg/kg of body weight administered as a pretreatment; 6 mg fragmented exogenous DNA administered over the course of 3 days; tumor homogenate grafted 10 days following the final DNA injection. Conclusion Fragmented exogenous DNA injected with cyclophosphamide inhibits the growth of tumors that are

A High-Performance Cellular Automaton Model of Tumor Growth with Dynamically Growing Domains

PubMed Central

Poleszczuk, Jan; Enderling, Heiko

2014-01-01

Tumor growth from a single transformed cancer cell up to a clinically apparent mass spans many spatial and temporal orders of magnitude. Implementation of cellular automata simulations of such tumor growth can be straightforward but computing performance often counterbalances simplicity. Computationally convenient simulation times can be achieved by choosing appropriate data structures, memory and cell handling as well as domain setup. We propose a cellular automaton model of tumor growth with a domain that expands dynamically as the tumor population increases. We discuss memory access, data structures and implementation techniques that yield high-performance multi-scale Monte Carlo simulations of tumor growth. We discuss tumor properties that favor the proposed high-performance design and present simulation results of the tumor growth model. We estimate to which parameters the model is the most sensitive, and show that tumor volume depends on a number of parameters in a non-monotonic manner. PMID:25346862

Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

PubMed Central

2012-01-01

Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. Methods First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics. PMID:22857000

Naringin inhibits ovarian tumor growth by promoting apoptosis: An in vivo study.

PubMed

Cai, Liping; Wu, Heli; Tu, Chunhua; Wen, Xiaochun; Zhou, Bei

2018-07-01

The aim of the present study was to investigate the antitumor activities of naringin in ovarian cancer, and to assess the underlying mechanisms. Ovarian tumor cells were implanted into nude mice to produce ovarian tumors in vivo . The mice were divided into six groups: Control, low dose naringin [0.5 mg/kg, intraperitoneal (i.p.)], middle dose naringin (1 mg/kg, i.p.), high dose naringin (2 mg/kg, i.p.), positive control (cisplatin, 2 mg/kg, i.p.) and a combination of cisplatin and naringin (both 2 mg/kg). Following administration of naringin and/or cisplatin, the tumor size and weight were measured. Apoptosis of tumor cells was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-associated gene expression was detected using reverse transcription-polymerase chain reaction and immunohistochemistry. In the range of 0.5-2 mg/kg, naringin dose-dependently inhibited tumor growth, as demonstrated by a decrease in tumor size and weight. Naringin promoted apoptosis of the ovarian tumor cells. Additionally, naringin reduced the expression of B-cell lymphoma (Bcl)-2, Bcl-extra large (Bcl-xL), cyclin D1, c-Myc and survivin, while it increased the expression of caspase-3 and caspase-7. The data demonstrated that naringin inhibited ovarian tumor growth in vivo . Its mechanisms may be associated with caspase-7-, caspase-3-, Bcl-2- and Bcl-xL-mediated apoptosis. Nevertheless, the clinical application of naringin in the treatment of ovarian cancer requires further study.

Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsai, C.-S.; Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan; Chen, F.-H.

2007-06-01

Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNAmore » expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo.« less

Hypoestoxide inhibits tumor growth in the mouse CT26 colon tumor model

PubMed Central

Ojo-Amaize, Emmanuel A; Cottam, Howard B; Oyemade, Olusola A; Okogun, Joseph I; Nchekwube, Emeka J

2007-01-01

AIM: To evaluate the effect of the natural diterpenoid, hypoestoxide (HE) on the growth of established colon cancer in mice. METHODS: The CT26.WT mouse colon carcinoma cell line was grown and expanded in vitro. Following the expansion, BALB/c mice were inoculated s.c. with viable tumor cells. After the tumors had established and developed to about 80-90 mm3, the mice were started on chemotherapy by oral administration of HE, 5-fluorouracil (5-FU) or combination. RESULTS: The antiangiogenic HE has previously been shown to inhibit the growth of melanoma in the B16F1 tumor model in C57BL/6 mice. Our results demonstrate that mean volume of tumors in mice treated with oral HE as a single agent or in combination with 5-FU, were significantly smaller (> 60%) than those in vehicle control mice (471.2 mm3 vs 1542.8 mm3, P < 0.01). The significant reductions in tumor burden resulted in pronounced mean survival times (MST) and increased life spans (ILS) in the treated mice. CONCLUSION: These results indicate that HE is an effective chemotherapeutic agent for colorectal cancer in mice and that HE may be used alone or in combination with 5-FU. PMID:17729410

Stat3-induced S1PR1 expression is critical for persistent Stat3 activation in tumors

PubMed Central

Lee, Heehyoung; Deng, Jiehui; Kujawski, Maciej; Yang, Chunmei; Liu, Yong; Herrmann, Andreas; Kortylewski, Marcin; Horne, David; Somlo, George; Forman, Stephen; Jove, Richard; Yu, Hua

2011-01-01

IL-6/Jak2 signaling is viewed critical for persistent Stat3 activation in cancer. However, IL-6-induced Stat3 activity is transient in normal physiology. Here we identify a mechanism important for persistent Stat3 activation in tumor cells and the tumor microenvironment. We show that sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor for lysophospholipid sphingosine-1-phosphate (S1P), is elevated in Stat3-positive tumors. Stat3 is a transcription factor for the S1pr1 gene. Enhanced S1pr1 expression activates Stat3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis. Conversely, silencing S1pr1 in tumor cells or immune cells inhibits tumor Stat3 activity, tumor growth and metastasis. S1P/S1PR1-induced Stat3 activation is persistent, in contrast to transient Stat3 activation by IL-6. S1PR1 activates Stat3 in part by upregulating Jak2 tyrosine kinase activity. We demonstrate that Stat3-induced S1pr1 expression, as well as S1P/S1PR1 pathway, is important for persistent Stat3 activation in cancer cells and the tumor microenvironment and for malignant progression. PMID:21102457

Action of hexachlorobenzene on tumor growth and metastasis in different experimental models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pontillo, Carolina Andrea, E-mail: caroponti@hotmail.com; Rojas, Paola, E-mail: parojas2010@gmail.com; Chiappini, Florencia, E-mail: florenciachiappini@hotmail.com

Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR-dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5 μM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30 mg/kg b.w.) on tumor growth, MMP2more » and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5 μM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3 mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30 mg/kg b.w.) activated c-Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression. - Highlights: ► HCB enhances MMP2 and MMP9 expression and cell invasion in MDA-MB-231, in vitro. ► HCB-effects are mediated through AhR, HER1 and/or c-Src. ► HCB increases subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. ► HCB activates c-Src/HER1 pathway and increases MMPs levels in MDA-MB-231 tumors. ► HCB stimulates lung metastasis in C4-HI and LM3 in vivo models.« less

A frightening thought: Neuronal activity enhances tumor growth.

PubMed

Thompson, Emily G; Sontheimer, Harald

2015-08-01

Stem cells present in the adult brain are regulated by neuronal activity; malignant gliomas, which most likely originate from this population of cells, could also be regulated in this manner. A recent study by Venkatesh et al. published in Cell has identified Neuroligin-3 (NLGN3) as a mitogen promoting high-grade glioma growth.

Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer

PubMed Central

Forghani, Parvin; Khorramizadeh, Mohammad R; Waller, Edmund K

2014-01-01

Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b+ Gr-1+ MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b+Gr-1+ MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs. PMID:24574320

Ecto-5’-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model

PubMed Central

Cappellari, Angélica R.; Pillat, Micheli M.; Souza, Hellio D. N.; Dietrich, Fabrícia; Oliveira, Francine H.; Figueiró, Fabrício; Abujamra, Ana L.; Roesler, Rafael; Lecka, Joanna; Sévigny, Jean; Battastini, Ana Maria O.; Ulrich, Henning

2015-01-01

Background Ecto-5’-nucleotidase/CD73 (ecto-5’-NT) participates in extracellular ATP catabolism by converting adenosine monophosphate (AMP) into adenosine. This enzyme affects the progression and invasiveness of different tumors. Furthermore, the expression of ecto-5’-NT has also been suggested as a favorable prognostic marker, attributing to this enzyme contradictory functions in cancer. Medulloblastoma (MB) is the most common brain tumor of the cerebellum and affects mainly children. Materials and Methods The effects of ecto-5’-NT overexpression on human MB tumor growth were studied in an in vivo model. Balb/c immunodeficient (nude) 6 to 14-week-old mice were used for dorsal subcutaneous xenograph tumor implant. Tumor development was evaluated by pathophysiological analysis. In addition, the expression patterns of adenosine receptors were verified. Results The human MB cell line D283, transfected with ecto-5’-NT (D283hCD73), revealed reduced tumor growth compared to the original cell line transfected with an empty vector. D283hCD73 generated tumors with a reduced proliferative index, lower vascularization, the presence of differentiated cells and increased active caspase-3 expression. Prominent A1 adenosine receptor expression rates were detected in MB cells overexpressing ecto-5’-NT. Conclusion This work suggests that ecto-5’-NT promotes reduced tumor growth to reduce cell proliferation and vascularization, promote higher differentiation rates and initiate apoptosis, supposedly by accumulating adenosine, which then acts through A1 adenosine receptors. Therefore, ecto-5’-NT might be considered an important prognostic marker, being associated with good prognosis and used as a potential target for therapy. PMID:26491983

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

PubMed Central

Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E.; Henning, Susanne M.; Vadgama, Jaydutt V.

2017-01-01

The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo.

PubMed

Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E; Henning, Susanne M; Vadgama, Jaydutt V

2017-06-01

The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa , has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo , which provides a high promise in its translation to human application.

CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma.

PubMed

Gao, Xiaohua; Deeb, Dorrah; Liu, Yongbo; Liu, Patricia; Zhang, Yiguan; Shaw, Jiajiu; Gautam, Subhash C

2015-12-01

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) has shown potent antitumorigenic activity against a wide range of cancer cell lines in vitro and inhibited the growth of liver, lung and prostate cancer in vivo. In the present study, we examined the antitumor activity of CDDO-Me for pancreatic ductal adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with CDDO-Me elicited strong antiproliferative and proapoptopic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-кB and p-mTOR signaling proteins. For testing efficacy of CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with CDDO-Me prolonged the survival of mice when administered following the surgical resection of tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of tumors. These preclinical data demonstrate the potential of CDDO-Me for treating primary PDAC tumors and for preventing relapse/recurrence through the destruction of residual disease.

Poly (I:C) enhances the anti-tumor activity of canine parvovirus NS1 protein by inducing a potent anti-tumor immune response.

PubMed

Gupta, Shishir Kumar; Yadav, Pavan Kumar; Tiwari, A K; Gandham, Ravi Kumar; Sahoo, A P

2016-09-01

The canine parvovirus NS1 (CPV2.NS1) protein selectively induces apoptosis in the malignant cells. However, for an effective in vivo tumor treatment strategy, an oncolytic agent also needs to induce a potent anti-tumor immune response. In the present study, we used poly (I:C), a TLR3 ligand, as an adjuvant along with CPV2.NS1 to find out if the combination can enhance the oncolytic activity by inducing a potent anti-tumor immune response. The 4T1 mammary carcinoma cells were used to induce mammary tumor in Balb/c mice. The results suggested that poly (I:C), when given along with CPV2.NS1, not only significantly reduced the tumor growth but also augmented the immune response against tumor antigen(s) as indicated by the increase in blood CD4+ and CD8+ counts and infiltration of immune cells in the tumor tissue. Further, blood serum analysis of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were significantly upregulated in the treatment group indicating activation of cell-mediated immune response. The present study reports the efficacy of CPV2.NS1 along with poly (I:C) not only in inhibiting the mammary tumor growth but also in generating an active anti-tumor immune response without any visible toxicity. The results of our study may help in developing CPV2.NS1 and poly (I: C) combination as a cancer therapeutic regime to treat various malignancies.

P-selectin deficiency attenuates tumor growth and metastasis

PubMed Central

Kim, Young J.; Borsig, Lubor; Varki, Nissi M.; Varki, Ajit

1998-01-01

Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals. PMID:9689079

Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis

PubMed Central

Jin, Kideok; Pandey, Niranjan B.; Popel, Aleksander S.

2017-01-01

Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB-231-CXCR2−/− tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231-CXCR2−/− tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDA-MB-231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components. PMID:28947965

Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

PubMed

Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

2015-01-01

Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. Copyright © 2014 by The American Association of Immunologists, Inc.

SU-E-T-751: Three-Component Kinetic Model of Tumor Growth and Radiation Response for Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Y; Dahlman, E; Leder, K

Purpose: To develop and study a kinetic model of tumor growth and its response to stereotactic radiosurgery (SRS) by assuming that the cells in irradiated tumor volume were made of three types. Methods: A set of ordinary differential equations (ODEs) were derived for three types of cells and a tumor growth rate. It is assumed that the cells were composed of actively proliferating cells, lethally damaged-dividing cells, and non-dividing cells. We modeled the tumor volume growth with a time-dependent growth rate to simulate the saturation of growth. After SRS, the proliferating cells were permanently damaged and converted to the lethallymore » damaged cells. The amount of damaged cells were estimated by the LQ-model. The damaged cells gradually stopped dividing/proliferating and died with a constant rate. The dead cells were cleared from their original location with a constant rate. The total tumor volume was the sum of the three components. The ODEs were numerically solved with appropriate initial conditions for a given dosage. The proposed model was used to model an animal experiment, for which the temporal change of a rhabdomyosarcoma tumor volume grown in a rat was measured with time resolution sufficient to test the model. Results: To fit the model to the experimental data, the following characteristics were needed with the model parameters. The α-value in the LQ-model was smaller than the commonly used value; furthermore, it decreased with increasing dose. At the same time, the tumor growth rate after SRS had to increase. Conclusions: The new 3-component model of tumor could simulate the experimental data very well. The current study suggested that the radiation sensitivity and the growth rate of the proliferating tumor cells may change after irradiation and it depended on the dosage used for SRS. These preliminary observations must be confirmed by future animal experiments.« less

A Big Bang model of human colorectal tumor growth

PubMed Central

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A.; Salomon, Matthew P.; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F.; Shibata, Darryl; Curtis, Christina

2015-01-01

What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. PMID:25665006

The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners

PubMed Central

Li, Yang; Lv, Zhaohui; Zhu, Jie; Lin, Jing; Ding, Lihua; Ye, Qinong

2016-01-01

The DEK oncogene is overexpressed in various cancers and overexpression of DEK correlates with poor clinical outcome. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis, a process essential for tumor growth and metastasis. However, whether DEK enhances tumor angiogenesis remains unclear. Here, we show that DEK is a key regulator of VEGF expression and tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that DEK promoted VEGF transcription in breast cancer cells (MCF7, ZR75-1 and MDA-MB-231) by directly binding to putative DEK-responsive element (DRE) of the VEGF promoter and indirectly binding to hypoxia response element (HRE) upstream of the DRE through its interaction with the transcription factor hypoxia-inducible factor 1α (HIF-1α), a master regulator of tumor angiogenesis and growth. DEK is responsible for recruitment of HIF-1α and the histone acetyltransferase p300 to the VEGF promoter. DEK-enhanced VEGF increases vascular endothelial cell proliferation, migration and tube formation as well as angiogenesis in the chick chorioallantoic membrane. DEK promotes tumor angiogenesis and growth in nude mice in HIF-1α-dependent and -independent manners. Immunohistochemical staining showed that DEK expression positively correlates with the expression of VEGF and microvessel number in 58 breast cancer patients. Our data establish DEK as a sequence-specific binding transcription factor, a novel coactivator for HIF-1α in regulation of VEGF transcription and a novel promoter of angiogenesis. PMID:26988756

Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis*

PubMed Central

Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

2015-01-01

The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1−/−) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4−/− mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID:26475855

Ellagitannin-rich cloudberry inhibits hepatocyte growth factor induced cell migration and phosphatidylinositol 3-kinase/AKT activation in colon carcinoma cells and tumors in Min mice

PubMed Central

Pajari, Anne-Maria; Päivärinta, Essi; Paavolainen, Lassi; Vaara, Elina; Koivumäki, Tuuli; Garg, Ritu; Heiman-Lindh, Anu; Mutanen, Marja; Marjomäki, Varpu; Ridley, Anne J.

2016-01-01

Berries have been found to inhibit colon carcinogenesis in animal models, and thus represent a potential source of compounds for prevention and treatment of colorectal cancer. The mechanistic basis for their effects is not well understood. We used human colon carcinoma cells and Min mice to investigate the effects of ellagitannin-rich cloudberry (Rubus chamaemorus) extract on cancer cell migration and underlying cell signaling. Intrinsic and hepatocyte growth factor (HGF) -induced cell motility in human HT29 and HCA7 colon carcinoma cells was assessed carrying out cell scattering and scratch wound healing assays using time-lapse microscopy. Activation of Met, AKT, and ERK in cell lines and tumors of cloudberry-fed Min mice were determined using immunoprecipitation, Western blot and immunohistochemical analyses. Cloudberry extract significantly inhibited particularly HGF-induced cancer cell migration in both cell lines. Cloudberry extract inhibited the Met receptor tyrosine phosphorylation by HGF and strongly suppressed HGF-induced AKT and ERK activation in both HT29 and HCA7 cells. Consistently, cloudberry feeding (10% w/w freeze-dried berries in diet for 10 weeks) reduced the level of active AKT and prevented phosphoMet localization at the edges in tumors of Min mice. These results indicate that cloudberry reduces tumor growth and cancer cell motility by inhibiting Met signaling and consequent activation of phosphatidylinositol 3-kinase/AKT in vitro and in tumors in vivo. As the Met receptor is recognized to be a major target in cancer treatment, our results suggest that dietary phytochemicals may have therapeutic value in reducing cancer progression and metastasis. PMID:27270323

Basic fibroblast growth factor in an animal model of spontaneous mammary tumor progression.

PubMed

Kao, Steven; Mo, Jeffrey; Baird, Andrew; Eliceiri, Brian P

2012-06-01

Although basic fibroblast growth factor (FGF2) was the first pro-angiogenic molecule discovered, it has numerous activities on the growth and differentiation of non-vascular cell types. FGF2 is both stimulatory and inhibitory, depending on the cell type evaluated, the experimental design used and the context in which it is tested. Here, we investigated the effects of manipulating endogenous FGF2 on the development of mammary cancer to determine whether its endogenous contribution in vivo is pro- or anti-tumorigenic. Specifically, we examined the effects of FGF2 gene dosing in a cross between a spontaneous breast tumor model (PyVT+ mice) and FGF2-/- (FGF KO) mice. Using these mice, the onset and progression of mammary tumors was determined. As predicted, female FGF2 WT mice developed mammary tumors starting around 60 days after birth and by 80 days, 100% of FGF2 WT female mice had mammary tumors. In contrast, 80% of FGF2 KO female mice had no palpable tumors until nearly three weeks later (85 days) at times when 100% of the WT cohort was tumor positive. All FGF KO mice were tumor-bearing by 115 days. When we compared the onset of mammary tumor development and the tumor progression curves between FGF het and FGF KO mice, we observed a difference, which suggested a gene dosing effect. Analysis of the tumors demonstrated that there were significant differences in tumor size depending on FGF2 status. The delay in tumor onset supports a functional role for FGF2 in mammary tumor progression, but argues against an essential role for FGF2 in overall mammary tumor progression.

A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

PubMed Central

Jiménez-Medina, Eva; Garcia-Lora, Angel; Paco, Laura; Algarra, Ignacio; Collado, Antonia; Garrido, Federico

2006-01-01

Background Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). Methods An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. Results The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. Conclusion These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented

Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.

PubMed

Kim, Ha; Sin, Jeong-Im

2012-11-01

Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.

Biodegradable polymeric micelles encapsulated JK184 suppress tumor growth through inhibiting Hedgehog signaling pathway

NASA Astrophysics Data System (ADS)

Zhang, Nannan; Liu, Shichang; Wang, Ning; Deng, Senyi; Song, Linjiang; Wu, Qinjie; Liu, Lei; Su, Weijun; Wei, Yuquan; Xie, Yongmei; Gong, Changyang

2015-01-01

JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity.JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in

SOCS3 Deficiency in Myeloid Cells Promotes Tumor Development: Involvement of STAT3 Activation and Myeloid-Derived Suppressor Cells

PubMed Central

Yu, Hao; Liu, Yudong; McFarland, Braden C.; Deshane, Jessy S.; Hurst, Douglas R.; Ponnazhagan, Selvarangan; Benveniste, Etty N.; Qin, Hongwei

2015-01-01

Suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing antitumor immunity. We report for the first time that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T-cell infiltration in tumors. The importance of MDSCs in promoting tumor growth is documented by reduced tumor growth upon depletion of MDSCs. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte colony-stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSCs via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSCs and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation. PMID:25649351

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment.

PubMed

Deguchi, A; Tomita, T; Ohto, U; Takemura, K; Kitao, A; Akashi-Takamura, S; Miyake, K; Maru, Y

2016-03-17

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.

PubMed

Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin P; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T; Zhang, Wentao; Marlowe, Charles K; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T; Dale, Stephanie; Yturralde, Olivia; Matthews, David J; Lamb, Peter; Laird, A Douglas

2015-04-01

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. ©2015 American Association for Cancer Research.

Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice.

PubMed

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.

Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer.

PubMed

Forghani, Parvin; Khorramizadeh, Mohammad R; Waller, Edmund K

2014-04-01

Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b(+) Gr-1(+) MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b(+) Gr-1(+) MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The strange connection between epidermal growth factor receptor tyrosine kinase inhibitors and dapsone: from rash mitigation to the increase in anti-tumor activity.

PubMed

Boccellino, Mariarosaria; Quagliuolo, Lucio; Alaia, Concetta; Grimaldi, Anna; Addeo, Raffaele; Nicoletti, Giovanni Francesco; Kast, Richard Eric; Caraglia, Michele

2016-11-01

The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion.

The milk protein α-casein functions as a tumor suppressor via activation of STAT1 signaling, effectively preventing breast cancer tumor growth and metastasis

PubMed Central

Bonuccelli, Gloria; Castello-Cros, Remedios; Capozza, Franco; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Tsirigos, Aristotelis; Xuanmao, Jiao; Whitaker-Menezes, Diana; Howell, Anthony; Lisanti, Michael P.; Sotgia, Federica

2012-01-01

Here, we identified the milk protein α-casein as a novel suppressor of tumor growth and metastasis. Briefly, Met-1 mammary tumor cells expressing α-casein showed a ~5-fold reduction in tumor growth and a near 10-fold decrease in experimental metastasis. To identify the molecular mechanism(s), we performed genome-wide transcriptional profiling. Interestingly, our results show that α-casein upregulates gene transcripts associated with interferon/STAT1 signaling and downregulates genes associated with “stemness.” These findings were validated by immunoblot and FACS analysis, which showed the upregulation and hyperactivation of STAT1 and a decrease in the number of CD44(+) “cancer stem cells.” These gene signatures were also able to predict clinical outcome in human breast cancer patients. Thus, we conclude that a lactation-based therapeutic strategy using recombinant α-casein would provide a more natural and non-toxic approach to the development of novel anticancer therapies. PMID:23047602

Emergent Behaviors from a Cellular Automaton Model for Invasive Tumor Growth in Heterogeneous Microenvironments

PubMed Central

Jiao, Yang; Torquato, Salvatore

2011-01-01

Understanding tumor invasion and metastasis is of crucial importance for both fundamental cancer research and clinical practice. In vitro experiments have established that the invasive growth of malignant tumors is characterized by the dendritic invasive branches composed of chains of tumor cells emanating from the primary tumor mass. The preponderance of previous tumor simulations focused on non-invasive (or proliferative) growth. The formation of the invasive cell chains and their interactions with the primary tumor mass and host microenvironment are not well understood. Here, we present a novel cellular automaton (CA) model that enables one to efficiently simulate invasive tumor growth in a heterogeneous host microenvironment. By taking into account a variety of microscopic-scale tumor-host interactions, including the short-range mechanical interactions between tumor cells and tumor stroma, degradation of the extracellular matrix by the invasive cells and oxygen/nutrient gradient driven cell motions, our CA model predicts a rich spectrum of growth dynamics and emergent behaviors of invasive tumors. Besides robustly reproducing the salient features of dendritic invasive growth, such as least-resistance paths of cells and intrabranch homotype attraction, we also predict nontrivial coupling between the growth dynamics of the primary tumor mass and the invasive cells. In addition, we show that the properties of the host microenvironment can significantly affect tumor morphology and growth dynamics, emphasizing the importance of understanding the tumor-host interaction. The capability of our CA model suggests that sophisticated in silico tools could eventually be utilized in clinical situations to predict neoplastic progression and propose individualized optimal treatment strategies. PMID:22215996

Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis

PubMed Central

Pratheeshkumar, Poyil; Son, Young-Ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-Chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

2012-01-01

Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PMID:23300633

Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma

PubMed Central

Haxho, Fiona; Allison, Stephanie; Alghamdi, Farah; Brodhagen, Lacey; Kuta, Victoria EL; Abdulkhalek, Samar; Neufeld, Ronald J; Szewczuk, Myron R

2014-01-01

Background Triple-negative breast cancers (TNBCs) lack the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors. Patients with TNBC have typical high grading, more frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes of breast cancers. Currently, there are no targeted therapies that are effective for TNBC. Preclinical antitumor activity of oseltamivir phosphate (OP) therapy was investigated to identify its role in tumor neovascularization, growth, invasiveness, and long-term survival in a mouse model of human TNBC. Methods Live cell sialidase, water soluble tetrazolium, WST-1 cell viability, and immunohistochemistry assays were used to evaluate sialidase activity, cell survival, and the expression levels of tumor E-cadherin, N-cadherin, and host endothelial CD31+/PECAM-1 cells in archived paraffin-embedded TNBC MDA-MB-231 tumors grown in RAGxCγ double mutant mice. Results OP, anti-Neu1 antibodies, and matrix metalloproteinase-9-specific inhibitor blocked Neu1 activity associated with EGF-stimulated TNBC MDA-MB-231 cells. OP treatment of MDA-MB-231 and MCF-7 cells and their long-term tamoxifen-resistant clones reproducibly and dose-dependently reduced the sialidase activity associated with EGF-stimulated live cells and the cell viability after 72 hours of incubation. Combination of 1 μM cisplatin, 5-FU, paclitaxel, gemcitabine, or tamoxifen with OP dosages ≥300 μg/mL significantly reduced cell viability at 24, 48, and 72 hours when compared to the chemodrug alone. Heterotopic xenografts of MDA-MB-231 tumors developed robust and bloody tumor vascularization in RAG2xCγ double mutant mice. OP treatment at 30 mg/kg daily intraperitoneally reduced tumor vascularization and growth rate as well as significantly reduced tumor weight and spread to the lungs compared with the untreated cohorts. OP treatment at 50 mg/kg completely ablated tumor vascularization, tumor growth and spread to the

RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations.

PubMed

Fischer, Marcus M; Yeung, V Pete; Cattaruzza, Fiore; Hussein, Rajaa; Yen, Wan-Ching; Murriel, Christopher; Evans, James W; O'Young, Gilbert; Brunner, Alayne L; Wang, Min; Cain, Jennifer; Cancilla, Belinda; Kapoun, Ann; Hoey, Timothy

2017-11-10

Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

PubMed Central

Sugahara, Kazuyuki; Thimmaiah, Kuntebommanahalli N.; Bid, Hemant K.; Houghton, Peter J.; Rangappa, Kanchugarakoppal S.

2012-01-01

The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF) pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl)-3H-imidazole-4-carbaldehyde) was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS), which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7) which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor. PMID:22916091

Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect.

PubMed

Renaud, Stéphanie; Corcé, Vincent; Cannie, Isabelle; Ropert, Martine; Lepage, Sylvie; Loréal, Olivier; Deniaud, David; Gaboriau, François

2015-08-01

Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Zone-specific remodeling of tumor blood vessels affects tumor growth.

PubMed

Tilki, Derya; Kilic, Nerbil; Sevinc, Sema; Zywietz, Friedrich; Stief, Christian G; Ergun, Suleyman

2007-11-15

Chaotic organization, abnormal leakiness, and structural instability are characteristics of tumor vessels. However, morphologic events of vascular remodeling in relation to tumor growth are not sufficiently studied yet. By using the rat rhabdomyosarcoma tumor model vascular morphogenesis was studied by light and electron microscopy and immunohistochemistry in relation to tumor regions such as tumor surrounding (TSZ), marginal (TMZ), intermediate (TIZ), and center (TCZ) zones. The analyses revealed that blood vessels of TSZ display a regular ultrastructure, whereas blood vessels of TMZ showed a chaotic organization and unstable structure with a diffuse or even lacking basal lamina, and missing or irregular assembled periendothelial cells. In contrast, blood vessels of TIZ and TCZ exhibited a more or less stabilized vessel structure with increased diameter. Correspondingly, normal assembly of alpha-smooth-muscle-actin (alpha-SMA)-positive cells into the vessel wall was observed in blood vessels of TSZ, TIZ, and TCZ. Also, Ang1 immunostaining was strongest in large vessels of TIZ and TCZ, whereas Ang2 staining was prominent in small vessels of TIZ. Tie2 staining was detectable in small and large vessels of all tumor zones. Immunostaining for alpha(v)beta(3)-integrin was strongest in small vessels of TMZ, whereas large vessels of TIZ and TCZ were almost negative. The results indicate a zone-specific remodeling of tumor blood vessels by stabilization of vessels in TIZ and TCZ, whereas small vessels of these zones obviously undergo regression leading to tumor necrosis. Thus, a better understanding of vascular remodeling and stabilization in tumors would enable new strategies in tumor therapy and imaging. (c) 2007 American Cancer Society.

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

PubMed

Takakusagi, Yoichi; Matsumoto, Shingo; Saito, Keita; Matsuo, Masayuki; Kishimoto, Shun; Wojtkowiak, Jonathan W; DeGraff, William; Kesarwala, Aparna H; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Munasinghe, Jeeva P; Gillies, Robert J; Mitchell, James B; Hart, Charles P; Krishna, Murali C

2014-01-01

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth. Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors

PubMed Central

Papageorgis, Panagiotis; Odysseos, Andreani D.; Stylianopoulos, Triantafyllos

2014-01-01

Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion. PMID:25111061

Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.

PubMed

Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

2015-12-11

The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

PubMed

Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

2015-02-01

Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.

PubMed

Yoshiji, Hitoshi; Kuriyama, Shigeki; Noguchi, Ryuichi; Yoshii, Junichi; Ikenaka, Yasuhide; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Akahane, Takemi; Asada, Kiyoshi; Tsujimoto, Tatsuhito; Uemura, Masahito; Fukui, Hiroshi

2006-01-01

Recent studies have revealed that angiogenesis plays a pivotal role in carcinogenesis and tumor growth. We previously reported that the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) exerted potent anti-angiogenic activities. The aim of our current study was to examine the combination effect of VK and ACE-I on hepatocarcinogenesis induced by diethyl-nitrosamine, and orthotopic hepatocellular carcinoma (HCC) growth in rats. When used individually, both VK and ACE-I at clinically comparable low doses exerted significant inhibitory effects on tumor development in the liver. A combination treatment of VK and ACE-I showed a more potent suppressive effect against hepatocarcinogenesis. Neovascularization increased during hepatocarcinogenesis, and VK and ACE-I significantly attenuated angiogenesis in the tumor. In orthotopic HCC transplantation, VK and ACE-I also showed marked suppressive effects against HCC development similar to those against hepatocarcinogenesis. In both experiments, the suppressive effects of VK and ACE-I against angiogenesis were similar in magnitude to their inhibitory effects against hepatocarcinogenesis and orthotopic HCC development. In the orthotopic model, VK and ACE-I treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. Since both VK and ACE-I are widely used in clinical practice without serious side effects, this combination therapy may be an effective new therapeutic strategy against hepatocarcinogenesis and HCC growth in the future.

A Big Bang model of human colorectal tumor growth.

PubMed

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

2015-03-01

What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads.

PubMed

Ruddell, Alanna; Croft, Alexandra; Kelly-Spratt, Karen; Furuya, Momoko; Kemp, Christopher J

2014-05-21

Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes.

Ultrasound Targeted Microbubble Destruction-Mediated Delivery of a Transcription Factor Decoy Inhibits STAT3 Signaling and Tumor Growth

PubMed Central

Kopechek, Jonathan A.; Carson, Andrew R.; McTiernan, Charles F.; Chen, Xucai; Hasjim, Bima; Lavery, Linda; Sen, Malabika; Grandis, Jennifer R.; Villanueva, Flordeliza S.

2015-01-01

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble destruction (UTMD) has been shown to enhance image-guided local delivery of molecular therapeutics to a target site. The objective of this study was to deliver STAT3 decoy to squamous cell carcinoma (SCC) tumors using UTMD to disrupt STAT3 signaling and inhibit tumor growth. Studies performed demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles inhibited STAT3 signaling in SCC cells in vitro. Studies performed in vivo demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles induced significant tumor growth inhibition (31-51% reduced tumor volume vs. controls, p < 0.05) in mice bearing SCC tumors. Furthermore, expression of STAT3 downstream target genes (Bcl-xL and cyclin D1) was significantly reduced (34-39%, p < 0.05) in tumors receiving UTMD treatment with STAT3 decoy-loaded microbubbles compared to controls. In addition, the quantity of radiolabeled STAT3 decoy detected in tumors eight hours after treatment was significantly higher with UTMD treatment compared to controls (70-150%, p < 0.05). This study demonstrates that UTMD can increase delivery of a transcription factor decoy to tumors in vivo and that the decoy can inhibit STAT3 signaling and tumor growth. These results suggest that UTMD treatment holds potential for clinical use to increase the concentration of a transcription factor signaling inhibitor in the tumor. PMID:26681983

GM-CSF production by glioblastoma cells has a functional role in eosinophil survival, activation and growth factor production for enhanced tumor cell proliferation

PubMed Central

Curran, Colleen S.; Evans, Michael D.; Bertics, Paul J.

2011-01-01

Medicinal interventions of limited efficacy are currently available for the treatment of glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults. The eosinophil is a pivotal immune cell in the pathobiology of atopic disease that is also found to accumulate in certain tumor tissues. Inverse associations between atopy and GBM risk suggest that the eosinophil may play a functional role in certain tumor immune responses. To assess the potential interactions between eosinophils and GBM, human primary blood eosinophils were cultured with two separate human GBM-derived cell lines (A172, U87-MG) or conditioned media generated in the presence or absence of TNF-α. Results revealed differential eosinophil adhesion and increased survival in response to co-culture with GBM cell lines. Eosinophil responses to GBM cell line-conditioned media included increased survival, activation, CD11b expression and S100A9 release. Addition of GM-CSF neutralizing antibodies to GBM cell cultures or conditioned media reduced eosinophil adhesion, survival and activation, linking tumor cell-derived GM-CSF to the functions of eosinophils in the tumor microenvironment. Dexamethasone, which has been reported to inhibit eosinophil recruitment and shrink GBM lesions on contrast enhanced scans, reduced the production of tumor cell-derived GM-CSF. Furthermore, culture of GBM cells in eosinophil-conditioned media increased tumor cell viability, and generation of eosinophil-conditioned media in the presence of GM-CSF enhanced the effect. These data support the idea of a paracrine loop between GM-CSF producing tumors and eosinophil-derived growth factors in tumor promotion/progression. PMID:21705618

The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth: Different administration routes.

PubMed

Fasehee, Hamidreza; Zarrinrad, Ghazaleh; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamidollah; Faghihi, Shahab

2016-06-01

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models.

PubMed

Higgins, Brian; Kolinsky, Kenneth; Smith, Melissa; Beck, Gordon; Rashed, Mohammad; Adames, Violeta; Linn, Michael; Wheeldon, Eric; Gand, Laurent; Birnboeck, Herbert; Hoffmann, Gerhard

2004-06-01

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar

Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model.

PubMed

Morscher, Raphael Johannes; Aminzadeh-Gohari, Sepideh; Feichtinger, René Gunther; Mayr, Johannes Adalbert; Lang, Roland; Neureiter, Daniel; Sperl, Wolfgang; Kofler, Barbara

2015-01-01

Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer's oxidative phosphorylation system. Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content). Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention. Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose

Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis.

PubMed

Amirkhosravi, A; Amaya, M; Siddiqui, F; Biggerstaff, J P; Meyer, T V; Francis, J L

1999-01-01

Evidence that platelets play a role in tumor metastasis includes the observation of circulating tumor cell-platelet aggregates and the anti-metastatic effect of thrombocytopenia and anti-platelet drugs. Platelets have recently been shown to contain vascular endothelial growth factor (VEGF) which is released during clotting. We therefore studied the effects of (1) tumor cell-platelet adherence and tumor cell TF activity on platelet VEGF release; and (2) the effects of GpIIb/IIIa blockade on tumor cell-induced platelet VEGF release, tumor cell-induced thrombocytopenia and experimental metastasis. Adherent A375 human melanoma cells (TF+) and KG1 myeloid leukemia (TF-) cells were cultured in RPMI containing 10% fetal bovine serum. Platelet-rich plasma was obtained from normal citrated whole blood and the presence of VEGF (34 and 44 kDa isoforms) confirmed by immunoblotting. Platelet-rich plasma with or without anti-GpIIb/IIIa (Abciximab) was added to A375 monolayers and supernatant VEGF measured by ELISA. Tumor cell-induced platelet activation and release were determined by CD62P expression and serotonin release respectively. In vitro, tumor cell-platelet adherence was evaluated by flow cytometry. In vivo, thrombocytopenia and lung seeding were assessed 30 min and 18 days, respectively, after i.v. injection of Lewis Lung carcinoma (LL2) cells into control or murine 7E3 F(ab')(2) (6 mg/ kg) athymic rats. Maximal in vitro platelet activation (72% serotonin release) occurred 30 min after adding platelets to tumor cells. At this time, 87% of the A375 cells had adhered to platelets. Abciximab significantly (P<0.05) reduced platelet adherence to tumor cells as evidenced by flow cytometry. Incubation of A375 cells with platelets induced VEGF release in a time-dependent manner. This release was significantly inhibited by Abciximab (81% at 30 min; P<0.05). In the presence of fibrinogen and FII, VEGF release induced by A375 (TF+) cells was significantly higher than that induced

Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.

PubMed

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A; Fournier, Michelle; Vrionis, Frank D; Tran, Nam; Chan, Jennifer A; Kenchappa, Rajappa S; Forsyth, Peter A

2015-02-06

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Neurotrophin Signaling via TrkB and TrkC Receptors Promotes the Growth of Brain Tumor-initiating Cells*

PubMed Central

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A.; Fournier, Michelle; Vrionis, Frank D.; Tran, Nam; Chan, Jennifer A.; Kenchappa, Rajappa S.; Forsyth, Peter A.

2015-01-01

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. PMID:25538243

Vascular CD39/ENTPD1 Directly Promotes Tumor Cell Growth by Scavenging Extracellular Adenosine Triphosphate12

PubMed Central

Feng, Lili; Sun, Xiaofeng; Csizmadia, Eva; Han, Lihui; Bian, Shu; Murakami, Takashi; Wang, Xin; Robson, Simon C; Wu, Yan

2011-01-01

Extracellular adenosine triphosphate (ATP) is known to boost immune responses in the tumor microenvironment but might also contribute directly to cancer cell death. CD39/ENTPD1 is the dominant ectonucleotidase expressed by endothelial cells and regulatory T cells and catalyzes the sequential hydrolysis of ATP to AMP that is further degraded to adenosine by CD73/ecto-5′-nucleotidase. We have previously shown that deletion of Cd39 results in decreased growth of transplanted tumors in mice, as a result of both defective angiogenesis and heightened innate immune responses (secondary to loss of adenosinergic immune suppression). Whether alterations in local extracellular ATP and adenosine levels as a result of CD39 bioactivity directly affect tumor growth and cytotoxicity has not been investigated to date. We show here that extracellular ATP exerts antitumor activity by directly inhibiting cell proliferation and promoting cancer cell death. ATP-induced antiproliferative effects and cell death are, in large part, mediated through P2X7 receptor signaling. Tumors in Cd39 null mice exhibit increased necrosis in association with P2X7 expression. We further demonstrate that exogenous soluble NTPDase, or CD39 expression by cocultured liver sinusoidal endothelial cells, stimulates tumor cell proliferation and limits cell death triggered by extracellular ATP. Collectively, our findings indicate that local expression of CD39 directly promotes tumor cell growth by scavenging extracellular ATP. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy in cancer management. PMID:21390184

Third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice.

PubMed

Nakatake, Richi; Kaibori, Masaki; Nakamura, Yusuke; Tanaka, Yoshito; Matushima, Hideyuki; Okumura, Tadayoshi; Murakami, Takashi; Ino, Yasushi; Todo, Tomoki; Kon, Masanori

2018-03-01

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited, as was the case for contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors.

PubMed

Honkanen, Hanne-Kaisa; Izzi, Valerio; Petäistö, Tiina; Holopainen, Tanja; Harjunen, Vanessa; Pihlajaniemi, Taina; Alitalo, Kari; Heljasvaara, Ritva

2016-07-01

Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4(+) T-cells and an increase of cytotoxic CD8(+) T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Selection, calibration, and validation of models of tumor growth.

PubMed

Lima, E A B F; Oden, J T; Hormuth, D A; Yankeelov, T E; Almeida, R C

2016-11-01

This paper presents general approaches for addressing some of the most important issues in predictive computational oncology concerned with developing classes of predictive models of tumor growth. First, the process of developing mathematical models of vascular tumors evolving in the complex, heterogeneous, macroenvironment of living tissue; second, the selection of the most plausible models among these classes, given relevant observational data; third, the statistical calibration and validation of models in these classes, and finally, the prediction of key Quantities of Interest (QOIs) relevant to patient survival and the effect of various therapies. The most challenging aspects of this endeavor is that all of these issues often involve confounding uncertainties: in observational data, in model parameters, in model selection, and in the features targeted in the prediction. Our approach can be referred to as "model agnostic" in that no single model is advocated; rather, a general approach that explores powerful mixture-theory representations of tissue behavior while accounting for a range of relevant biological factors is presented, which leads to many potentially predictive models. Then representative classes are identified which provide a starting point for the implementation of OPAL, the Occam Plausibility Algorithm (OPAL) which enables the modeler to select the most plausible models (for given data) and to determine if the model is a valid tool for predicting tumor growth and morphology ( in vivo ). All of these approaches account for uncertainties in the model, the observational data, the model parameters, and the target QOI. We demonstrate these processes by comparing a list of models for tumor growth, including reaction-diffusion models, phase-fields models, and models with and without mechanical deformation effects, for glioma growth measured in murine experiments. Examples are provided that exhibit quite acceptable predictions of tumor growth in laboratory

Antibody-directed neutralization of annexin II (ANX II) inhibits neoangiogenesis and human breast tumor growth in a xenograft model.

PubMed

Sharma, Meena; Blackman, Marc R; Sharma, Mahesh C

2012-02-01

Activation of the fibrinolytic pathway has long been associated with human breast cancer. Plasmin is the major end product of the fibrinolytic pathway and is critical for normal physiological functions. The mechanism by which plasmin is generated in breast cancer is not yet fully described. We previously identified annexin II (ANX II), a fibrinolytic receptor, in human breast tumor tissue samples and observed a strong positive correlation with advanced stage cancer (Sharma et al., 2006a). We further demonstrated that tissue plasminogen activator (tPA) binds to ANX II in invasive breast cancer MDA-MB231cells, which leads to plasmin generation (Sharma et al., 2010). We hypothesize that ANX II-dependent plasmin generation in breast tumor is necessary to trigger the switch to neoangiogenesis, thereby stimulating a more aggressive cancer phenotype. Our immunohistochemical studies of human breast tumor tissues provide compelling evidence of a strong positive correlation between ANX II expression and neoangiogenesis, and suggest that ANX II is a potential target to slow or inhibit breast tumor growth by inhibiting neoangiogenesis. We now report that administration of anti-ANX II antibody potently inhibits the growth of human breast tumor in a xenograft model. Inhibition of tumor growth is at least partly due to attenuation of neoangiogenic activity within the tumor. In vitro studies demonstrate that anti-ANX II antibody inhibits angiogenesis on three dimensional matrigel cultures by eliciting endothelial cell (EC) death likely due to apoptosis. Taken together, these data suggest that selective disruption of the fibrinolytic activity of ANX II may provide a novel strategy for specific inhibition of neoangiogenesis in human breast cancer. Published by Elsevier Inc.

14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases

PubMed Central

Luo, Chao; Wang, Yu; Li, Dong; Shu, Yu; Wang, Shan-Shan; Qin, Jian; Li, Yong-Chao; Zou, Jiu-Ming; Tian, De-An; Zhang, Gui-Mei; Feng, Zuo-Hua

2016-01-01

Infiltrating neutrophils are known to promote in thedevelopment of tumor. However, it is unclear whether and how neutrophils areinvolved in triggering the growth of dormant metastases. Here we show that14,15-epoxyeicosatrienoic acid (14,15-EET) can trigger the growth of dormantmicrometastases by inducing neutrophilic infiltration and converting neutrophilfunction. 14,15-EET triggered neutrophil infiltration in metastatic lesions byactivating STAT3 and JNK pathways to induce the expression of human IL-8 andmurine CXCL15 in corresponding tumor cells. The continuous expression ofhIL-8/mCXCL15 was maintained by the sustained and enhanced activation of JNKpathway. 14,15-EET up-regulated miR-155 expression by activating STAT3 and JNKpathways. miR-155 in turn down-regulated the expression of SHIP1 and DET1, thusaugmenting the activation of JNK and c-Jun. Moreover, the function ofneutrophils was converted from tumor-suppressing to tumor-promoting by14,15-EET in vivo. By inducing the production of G-CSF/IL-6 in vivo, 14,15-EET induced the enhancement of STAT3 activation in neutrophilsto increase MMP-9 expression and decrease TRAIL expression. Neutrophil-derivedMMP-9 was required for 14,15-EET to induce angiogenesis during the growth ofdormant micrometastases. Depleting neutrophils or inhibiting hIL-8/mCXCL15up-regulation resulted in the failure of 14,15-EET to promote the developmentof micrometastases. These findings reveal a mechanism through which theinfiltration and tumor-promoting function of neutrophils could be induced totrigger the growth of dormant metastases, which might be a driving force forthe tumor recurrence based on dormant metastases. PMID:27270316

Polysaccharides from Epimedium koreanum Nakai with immunomodulatory activity and inhibitory effect on tumor growth in LLC-bearing mice.

PubMed

Wang, Chengcheng; Feng, Liang; Su, Jiayan; Cui, Li; Dan Liu; Yan, Jun; Ding, Chuanlin; Tan, Xiaobin; Jia, Xiaobin

2017-07-31

, CD4 T-cell differentiation and increased INF-γ production stimulated by EPS-activated macrophages were observed in the research. Furthermore, EPS exhibited prominent antitumor activities through regulating host immune system function in LLC-bearing mice. Taken together, experimental findings suggested EPS could be regarded as a potential immune-stimulating modifier for cancer therapy. Our studies demonstrated the polysaccharide (180 × 10 4 Da) purified from Epimedium koreanum Nakai could promote maturation and Ag presentation function of DCs, increase the level of immunomodulatory cytokines and activate CD4 T-cell differentiation. Furthermore, it may inhibit the tumor growth in LLC-bearing mice through regulating host immune system function. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

PubMed Central

Obrador, Elena; Benlloch, María; Pellicer, José A.; Asensi, Miguel; Estrela, José M.

2011-01-01

B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci. PMID:21393247

Energy Balance Modulates Colon Tumor Growth: Interactive Roles of Insulin and Estrogen

PubMed Central

Rondini, Elizabeth A.; Harvey, Alison E.; Steibel, Juan Pedro; Hursting, Stephen D.; Fenton, Jenifer I.

2011-01-01

Obesity increases colorectal cancer (CRC) risk and progression. However, the impact of obesity on CRC in women is dependent on ovarian hormone status. The purpose of this study was to determine the interactive roles of obesity and ovarian hormones on serum markers of inflammation, cell signaling and transplanted colon tumor growth. Female C57BL/6 mice (6 weeks) were either ovariectomized (OVX) or ovaries left intact (NOVX) and randomized to receive a 1) control, 2) 30% calorie-restricted (CR), or 3) diet-induced obese (DIO) diet regimen for 20 weeks to induce differing levels of adiposity. Serum was collected and inflammatory and metabolic markers were measured using an antibody array (62 proteins) and ELISAs. Mice were subcutaneously injected with syngeneic MC38 colon cancer cells after 20 weeks and sacrificed 4 weeks later. CR mice had the smallest tumors irrespective of hormone status, whereas the largest tumors were observed in DIO-OVX mice. Glucose tolerance was impaired in ovariectomized mice, being most severe in the DIO-OVX group. Cytokine arrays suggested that in CR animals, inhibition of tumor growth paralleled insulin sensitivity and associated changes in leptin, adiponectin, and IGF-BPs. Conversely, in DIO-OVX animals, tumor growth was associated with insulin and leptin resistance as well as higher levels of pro-inflammatory proteins. In vitro, leptin and adiponectin had no effect, whereas insulin induced MC38 cell proliferation and MAPK activation. Co-treatment with estrogen blocked the stimulatory effects of insulin. Thus, our in vitro and in vivo data indicate female reproductive hormones have a modulating effect on obesity-induced insulin resistance and inflammation, which may directly or indirectly influence CRC progression. PMID:21480390

Associated relaxation time and the correlation function for a tumor cell growth system subjected to color noises

NASA Astrophysics Data System (ADS)

Wang, Can-Jun; Wei, Qun; Mei, Dong-Cheng

2008-03-01

The associated relaxation time T and the normalized correlation function C(s) for a tumor cell growth system subjected to color noises are investigated. Using the Novikov theorem and Fox approach, the steady probability distribution is obtained. Based on them, the expressions of T and C(s) are derived by means of projection operator method, in which the effects of the memory kernels of the correlation function are taken into account. Performing the numerical computations, it is found: (1) With the cross-correlation intensity |λ|, the additive noise intensity α and the multiplicative noise self-correlation time τ increasing, the tumor cell numbers can be restrained; And the cross-correlation time τ, the multiplicative noise intensity D can induce the tumor cell numbers increasing; However, the additive noise self-correlation time τ cannot affect the tumor cell numbers; The relaxation time T is a stochastic resonant phenomenon, and the distribution curves exhibit a single-maximum structure with D increasing. (2) The cross-correlation strength λ weakens the related activity between two states of the tumor cell numbers at different time, and enhances the stability of the tumor cell growth system in the steady state; On the contrast, τ and τ enhance the related activity between two states at different time; However, τ has no effect on the related activity between two states at different time.

Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects.

PubMed

Otsuki, Noriko; Dang, Nam H; Kumagai, Emi; Kondo, Akira; Iwata, Satoshi; Morimoto, Chikao

2010-02-17

Various parts of Carica papaya Linn. (CP) have been traditionally used as ethnomedicine for a number of disorders, including cancer. There have been anecdotes of patients with advanced cancers achieving remission following consumption of tea extract made from CP leaves. However, the precise cellular mechanism of action of CP tea extracts remains unclear. The aim of the present study is to examine the effect of aqueous-extracted CP leaf fraction on the growth of various tumor cell lines and on the anti-tumor effect of human lymphocytes. In addition, we attempted to identify the functional molecular weight fraction in the CP leaf extract. The effect of CP extract on the proliferative responses of tumor cell lines and human peripheral blood mononuclear cells (PBMC), and cytotoxic activities of PBMC were assessed by [(3)H]-thymidine incorporation. Flow cytometric analysis and measurement of caspase-3/7 activities were performed to confirm the induction of apoptosis on tumor cells. Cytokine productions by PBMC were measured by ELISA. Gene profiling of the effect of CP extract treatment was performed by microarray analysis and real-time RT-PCR. We observed significant growth inhibitory activity of the CP extract on tumor cell lines. In PBMC, the production of IL-2 and IL-4 was reduced following the addition of CP extract, whereas that of IL-12p40, IL-12p70, IFN-gamma and TNF-alpha was enhanced without growth inhibition. In addition, cytotoxicity of activated PBMC against K562 was enhanced by the addition of CP extract. Moreover, microarray analyses showed that the expression of 23 immunomodulatory genes, classified by gene ontology analysis, was enhanced by the addition of CP extract. In this regard, CCL2, CCL7, CCL8 and SERPINB2 were representative of these upregulated genes, and thus may serve as index markers of the immunomodulatory effects of CP extract. Finally, we identified the active components of CP extract, which inhibits tumor cell growth and stimulates anti-tumor

On a Nonlinear Model for Tumor Growth: Global in Time Weak Solutions

NASA Astrophysics Data System (ADS)

Donatelli, Donatella; Trivisa, Konstantina

2014-07-01

We investigate the dynamics of a class of tumor growth models known as mixed models. The key characteristic of these type of tumor growth models is that the different populations of cells are continuously present everywhere in the tumor at all times. In this work we focus on the evolution of tumor growth in the presence of proliferating, quiescent and dead cells as well as a nutrient. The system is given by a multi-phase flow model and the tumor is described as a growing continuum Ω with boundary ∂Ω both of which evolve in time. Global-in-time weak solutions are obtained using an approach based on penalization of the boundary behavior, diffusion and viscosity in the weak formulation.

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

PubMed Central

Nokin, Marie-Julie; Durieux, Florence; Peixoto, Paul; Chiavarina, Barbara; Peulen, Olivier; Blomme, Arnaud; Turtoi, Andrei; Costanza, Brunella; Smargiasso, Nicolas; Baiwir, Dominique; Scheijen, Jean L; Schalkwijk, Casper G; Leenders, Justine; De Tullio, Pascal; Bianchi, Elettra; Thiry, Marc; Uchida, Koji; Spiegel, David A; Cochrane, James R; Hutton, Craig A; De Pauw, Edwin; Delvenne, Philippe; Belpomme, Dominique; Castronovo, Vincent; Bellahcène, Akeila

2016-01-01

Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment. DOI: http://dx.doi.org/10.7554/eLife.19375.001 PMID:27759563

Impact of pneumoperitoneum on tumor growth.

PubMed

Lécuru, F; Agostini, A; Camatte, S; Robin, F; Aggerbeck, M; Jaïs, J P; Vilde, F; Taurelle, R

2002-08-01

To compare intraperitoneal tumor growth after CO2 laparoscopy (L), gasless laparoscopy (GL), midline laparotomy (ML), and general anesthesia (GA) as a control. A prospective randomized trial was carried out in nude rats. A carcinomatosis was obtained by intraperitoneal injection of either one of the two human ovarian cancer cell lines IGR-OV1 or NIH:OVCAR-3. Rats secondly underwent randomly different kind of procedures: CO2 L (8 mmHg, 60 min), GL (traction by a balloon for 60 min), ML (bowel removed and let on a mesh for 60 min), or GA. The rats were finally killed 10 or 35 days after surgery (respectively in IGR-OV1, or NIH:OVCAR-3 models). Tumor growth was assessed by the weight of the omental metastasis and MIB1 immunostaining. Peritoneal dissemination as well as abdominal wall metastases were assessed by pathological examination. Statistical analysis used the chi-square test (or Fisher exact test) and Bonferroni method for multiple comparison between groups. Fifteen rats were included in each group. Mean omental weight was significantly increased after surgery (3.1 to 5.6 g), when compared to control (2.4 g), but no significant difference was recorded between the three surgical accesses. MIB1 immunostaining was poor in the PNP group (37%), whereas it was higher after midline laparotomy (51%), but the difference was not significant (p = 0.07). Similarly, no significant variation was recorded in the NIH:OVCAR-3 model for omental weight or MIB1 staining. CO2 pneumoperitoneum significantly increased right diaphragmatic dome involvement in the NIH:OVCAR-3 model. Abdominal wall metastases were significantly more frequent after surgery when compared to the control group, but no significant difference could be demonstrated between surgical groups in each model. In these solid tumor models, CO2 pneumoperitoneum had no deleterious effect on tumor growth when compared to gasless laparoscopy or midline laparotomy.

The Initial Immune Reaction to a New Tumor Antigen Is Always Stimulatory and Probably Necessary for the Tumor's Growth

PubMed Central

Prehn, Richmond T.

2010-01-01

All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse-skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin. PMID:20811480

The initial immune reaction to a new tumor antigen is always stimulatory and probably necessary for the tumor's growth.

PubMed

Prehn, Richmond T

2010-01-01

All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse-skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin.

Computational Modeling of 3D Tumor Growth and Angiogenesis for Chemotherapy Evaluation

PubMed Central

Tang, Lei; van de Ven, Anne L.; Guo, Dongmin; Andasari, Vivi; Cristini, Vittorio; Li, King C.; Zhou, Xiaobo

2014-01-01

Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID:24404145

Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.

PubMed

Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

2010-07-09

Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.

[Clinical and etiopathogenetic role of plasminogen and metaloproteinase systems in the tumor growth. Pericellular proteolysis of extracellular matrix and tumor growth].

PubMed

Cosić, Sanda Jelisavac; Kovac, Zdenko

2011-01-01

Pericellular proteolysis is a cascade process involved in degradation of extracellular matrix. This process is included in various physiological and pathological processes. Pericellullar proteolysis has major functions like degradation of tissue stroma and weakening of intercellular connections but it also has a function in the synthesis of bioactive molecules (cytokines, growth factors and inhibitory factors). Plasminogen system is involved in fibrinolysis and starts metalloproteinase activation. Activity of proteolytic molecules is controlled by the rate of zymogenic activation, half-life of molecules, and action of inhibitory molecules. Inhibition is achieved through direct binding of inhibitor and enzyme and takes a few steps. Pericellular proteolysis is involved in tumor invasion and metastasis, inflammatory reaction, degenerative diseases and other diseases. Pathophysiological regulation of pericellular proteolysis in mentioned diseases contributes to clinical properties of diseases and has diagnostic and therapeutic importance.

Masked Chimeric Antigen Receptor for Tumor-Specific Activation.

PubMed

Han, Xiaolu; Bryson, Paul D; Zhao, Yifan; Cinay, Gunce E; Li, Si; Guo, Yunfei; Siriwon, Natnaree; Wang, Pin

2017-01-04

Adoptive cellular therapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a powerful form of cancer immunotherapy. CAR-T cells can be redirected to specifically recognize tumor-associated antigens (TAAs) and induce high levels of antitumor activity. However, they may also display "on-target off-tumor" toxicities, resulting from low-level expression of TAAs in healthy tissues. These adverse effects have raised considerable safety concerns and limited the clinical application of this otherwise promising therapeutic modality. To minimize such side effects, we have designed an epidermal growth factor receptor (EGFR)-specific masked CAR (mCAR), which consists of a masking peptide that blocks the antigen-binding site and a protease-sensitive linker. Proteases commonly active in the tumor microenvironment can cleave the linker and disengage the masking peptide, thereby enabling CAR-T cells to recognize target antigens only at the tumor site. In vitro mCAR showed dramatically reduced antigen binding and antigen-specific activation in the absence of proteases, but normal levels of binding and activity upon treatment with certain proteases. Masked CAR-T cells also showed antitumor efficacy in vivo comparable to that of unmasked CAR. Our study demonstrates the feasibility of improving the safety profile of conventional CARs and may also inspire future design of CAR molecules targeting broadly expressed TAAs. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity

PubMed Central

Grossman, Craig E.; Carter, Shirron L.; Czupryna, Julie; Wang, Le; Putt, Mary E.; Busch, Theresa M.

2016-01-01

Photodynamic therapy (PDT) of the thoracic cavity can be performed in conjunction with surgery to treat cancers of the lung and its pleura. However, illumination of the cavity results in tissue exposure to a broad range of fluence rates. In a murine model of intrathoracic PDT, we studied the efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH; Photochlor®)-mediated PDT in reducing the burden of non-small cell lung cancer for treatments performed at different incident fluence rates (75 versus 150 mW/cm). To better understand a role for growth factor signaling in disease progression after intrathoracic PDT, the expression and activation of epidermal growth factor receptor (EGFR) was evaluated in areas of post-treatment proliferation. The low fluence rate of 75 mW/cm produced the largest reductions in tumor burden. Bioluminescent imaging and histological staining for cell proliferation (anti-Ki-67) identified areas of disease progression at both fluence rates after PDT. However, increased EGFR activation in proliferative areas was detected only after treatment at the higher fluence rate of 150 mW/cm. These data suggest that fluence rate may affect the activation of survival factors, such as EGFR, and weaker activation at lower fluence rate could contribute to a smaller tumor burden after PDT at 75 mW/cm. PMID:26784170

Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity.

PubMed

Grossman, Craig E; Carter, Shirron L; Czupryna, Julie; Wang, Le; Putt, Mary E; Busch, Theresa M

2016-01-14

Photodynamic therapy (PDT) of the thoracic cavity can be performed in conjunction with surgery to treat cancers of the lung and its pleura. However, illumination of the cavity results in tissue exposure to a broad range of fluence rates. In a murine model of intrathoracic PDT, we studied the efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH; Photochlor(®))-mediated PDT in reducing the burden of non-small cell lung cancer for treatments performed at different incident fluence rates (75 versus 150 mW/cm). To better understand a role for growth factor signaling in disease progression after intrathoracic PDT, the expression and activation of epidermal growth factor receptor (EGFR) was evaluated in areas of post-treatment proliferation. The low fluence rate of 75 mW/cm produced the largest reductions in tumor burden. Bioluminescent imaging and histological staining for cell proliferation (anti-Ki-67) identified areas of disease progression at both fluence rates after PDT. However, increased EGFR activation in proliferative areas was detected only after treatment at the higher fluence rate of 150 mW/cm. These data suggest that fluence rate may affect the activation of survival factors, such as EGFR, and weaker activation at lower fluence rate could contribute to a smaller tumor burden after PDT at 75 mW/cm.

Anti-hepatoma activity and mechanism of corn silk polysaccharides in H22 tumor-bearing mice.

PubMed

Yang, Jingyue; Li, Xiao; Xue, Yan; Wang, Nan; Liu, Wenchao

2014-03-01

Corn silk is a well known traditional Chinese herbal medicine and corn silk polysaccharides (CSP) possess multiple pharmacological activities. However, the antitumor effect of CSP on hepatocarcinoma has not been studied. This study aimed to investigate the effects of CSP on tumor growth and immune functions in H22 hepatocarcinoma tumor-bearing mice. The results demonstrated that CSP could not only inhibit the tumor growth, but also extended the survival time of H22 tumor-bearing mice. Besides, CSP administration could increase the body weight, peripheral white blood cells (WBC) count, thymus index and spleen index of H22 tumor-bearing mice. Furthermore, the production of serum cytokines in H22 tumor-bearing mice, such as IL-2, IL-6 and TNF-α, was enhanced by CSP treatment. In addition, no toxicological effects were observed on hepatic function and renal function in CSP-treated mice transplanted H22 tumor cells. In summary, this experimental finding indicated that CSP could elevate the immune functions in H22 tumor-bearing mice to enhance its antitumor activity and CSP seems to be a safe and effective agent for the treatment of hepatocellular carcinoma. Copyright © 2013 Elsevier B.V. All rights reserved.

Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

PubMed Central

Babich, Polina S.; Skvortsov, Alexey N; Rusconi, Paolo; Tsymbalenko, Nadezhda V.; Mutanen, Marja; Puchkova, Ludmila V.; Broggini, Massimo

2013-01-01

To assess the statistical relationship between tumor growth and copper metabolism, we performed a metaanalysis of studies in which patients with neoplasms were characterized according to any of the copper status indexes (atomic copper serum concentration, serum oxidase activity, ceruloplasmin protein content). Our metaanalysis shows that in the majority of cases (more than 3100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nu/nu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and ApcMin mice with spontaneously developing adenomas throughout the intestinal tract were studied to experimentally determine the relationship between tumor progression, liver copper metabolism, and copper status indexes. We showed that the copper status indexes increased significantly during tumor growth. In the liver tissue of tumor-bearing mice, ceruloplasmin gene expression, as well as the expression of genes related to ceruloplasmin metallation (CTR1 and ATP7B), increased significantly. Moreover, the presence of an mRNA splice variant encoding a form of ceruloplasmin anchored to the plasma membrane by glycosylphosphatidyl inositol, which is atypical for hepatocytes, was also detected. The ATP7A copper transporter gene, which is normally expressed in the liver only during embryonic copper metabolism, was also activated. Depletion of holo-ceruloplasmin resulted in retardation of human HCT116 colon carcinoma cell growth in nude mice and induced DNA fragmentation in tumor cells. In addition, the concentration of cytochrome c increased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver. PMID:23792645

Growth of melanoma brain tumors monitored by photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Staley, Jacob; Grogan, Patrick; Samadi, Abbas K.; Cui, Huizhong; Cohen, Mark S.; Yang, Xinmai

2010-07-01

Melanoma is a primary malignancy that is known to metastasize to the brain and often causes death. The ability to image the growth of brain melanoma in vivo can provide new insights into its evolution and response to therapies. In our study, we use a reflection mode photoacoustic microscopy (PAM) system to detect the growth of melanoma brain tumor in a small animal model. The melanoma tumor cells are implanted in the brain of a mouse at the beginning of the test. Then, PAM is used to scan the region of implantation in the mouse brain, and the growth of the melanoma is monitored until the death of the animal. It is demonstrated that PAM is capable of detecting and monitoring the brain melanoma growth noninvasively in vivo.

mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer

PubMed Central

Cash, Harrison; Shah, Sujay; Moore, Ellen; Caruso, Andria; Uppaluri, Ravindra; Van Waes, Carter; Allen, Clint

2015-01-01

We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer. PMID:26506415

Early tumor growth in metastatic organs influenced by the microenvironment is an important factor which provides organ specificity of colon cancer metastasis.

PubMed

Hara, Y; Ogata, Y; Shirouzu, K

2000-12-01

We have previously demonstrated that liver metastases in nude mice and lung metastases in nude rats occurred specifically, when KM12SM human colon carcinoma cells were inoculated orthotopically into the cecal wall of nude mice and rats. To clarify the relationship between the tumor growth potential in the metastatic organs and the metastatic organ preference in these two metastatic models, we have evaluated the in vitro cell growth activities affected by the organ conditioned medium (CM) from the liver and lung, and the in vivo growth activities of the ectopic implanted tumors in the liver and lung. The tumorigenicity of the ectopic implanted tumors was 100% in mouse liver, 33% in rat liver, 50% in mouse lung, and 75% in rat lung. The crude liver CM of the animals showed inhibitory activities for KM12SM cell growth in a dosage-dependent manner, and the crude lung CM stimulated KM12SM cell growth. The liver CM of nude mice inhibited the KM12SM cell growth more strongly compared with the CM of nude rats, and the lung CM of nude rats was more strongly stimulated compared with the CM of nude mice. The liver CM of nude mice had non-heparin binding factors, which stimulated or inhibited KM12SM cell growth, in a molecular weight range of 50 to 100 kDa. By contrast, the liver CM of nude rats showed no growth stimulating activity for KM12SM cells. These results suggest that the metastatic organ specificity of KM12SM cells may depend on the early tumor growth influenced by the microenvironment in metastatic organs.

Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death.

PubMed

Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana Pratap; Singh, Sukh Mahendra

2018-01-15

Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts.

PubMed

Yttersian Sletta, Kristine; Tveitarås, Maria K; Lu, Ning; Engelsen, Agnete S T; Reed, Rolf K; Garmann-Johnsen, Annette; Stuhr, Linda

2017-01-01

Tumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model. 5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU). HBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model. Despite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the

CD200-expressing human basal cell carcinoma cells initiate tumor growth.

PubMed

Colmont, Chantal S; Benketah, Antisar; Reed, Simon H; Hawk, Nga V; Telford, William G; Ohyama, Manabu; Udey, Mark C; Yee, Carole L; Vogel, Jonathan C; Patel, Girish K

2013-01-22

Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200(+) CD45(-) BCC subpopulation that represents 1.63 ± 1.11% of all BCC cells resides in small clusters at the tumor periphery. By using reproducible in vivo xenograft growth assays, we determined that tumor initiating cell frequencies approximate one per 1.5 million unsorted BCC cells. The CD200(+) CD45(-) BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200(+) CD45(-) cells, representing ~1,500-fold enrichment. CD200(-) CD45(-) BCC cells were unable to form tumors. These findings establish a platform to study the effects of Smoothened antagonists on BCC tumor initiating cell and also suggest that currently available anti-CD200 therapy be considered, either as monotherapy or an adjunct to Smoothened antagonists, in the treatment of inoperable BCC.

S100A8/A9 activate key genes and pathways in colon tumor progression

PubMed Central

Ichikawa, Mie; Williams, Roy; Wang, Ling; Vogl, Thomas; Srikrishna, Geetha

2011-01-01

The tumor microenvironment plays an important role in modulating tumor progression. We earlier showed that S100A8/A9 proteins secreted by myeloid-derived suppressor cells (MDSC) present within tumors and metastatic sites promote an autocrine pathway for accumulation of MDSC. In a mouse model of colitis-associated colon cancer, we also showed that S100A8/A9 positive cells accumulate in all regions of dysplasia and adenoma. Here we present evidence that S100A8/A9 interact with RAGE and carboxylated glycans on colon tumor cells and promote activation of MAPK and NF-κB signaling pathways. Comparison of gene expression profiles of S100A8/A9-activated colon tumor cells versus unactivated cells led us to identify a small cohort of genes upregulated in activated cells, including Cxcl1, Ccl5 and Ccl7, Slc39a10, Lcn2, Zc3h12a, Enpp2 and other genes, whose products promote leukocyte recruitment, angiogenesis, tumor migration, wound healing, and formation of premetastatic niches in distal metastatic organs. Consistent with this observation, in murine colon tumor models we found that chemokines were up-regulated in tumors, and elevated in sera of tumor-bearing wild-type mice. Mice lacking S100A9 showed significantly reduced tumor incidence, growth and metastasis, reduced chemokine levels, and reduced infiltration of CD11b+Gr1+ cells within tumors and premetastatic organs. Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis. PMID:21228116

G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

PubMed Central

Petrie, Whitney K.; Dennis, Megan K.; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R.

2013-01-01

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth. PMID:24379833

G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.

PubMed

Petrie, Whitney K; Dennis, Megan K; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B; Smith, Harriet O; Hathaway, Helen J; Prossnitz, Eric R

2013-01-01

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the "ERα-selective" agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of "ER-targeted" therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.

β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation.

PubMed

Sayeed, Aejaz; Lu, Huimin; Liu, Qin; Deming, David; Duffy, Alexander; McCue, Peter; Dicker, Adam P; Davis, Roger J; Gabrilovich, Dmitry; Rodeck, Ulrich; Altieri, Dario C; Languino, Lucia R

2016-08-16

Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (β1wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1pc-/- /TRAMP). Since JNK is known to be suppressed by β1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in β1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the β1/IGF-IR crosstalk and report that β1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that β1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.

Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma.

PubMed

Mazzocca, Antonio; Fransvea, Emilia; Dituri, Francesco; Lupo, Luigi; Antonaci, Salvatore; Giannelli, Gianluigi

2010-02-01

Tumor-stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor beta (TGF-beta) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-beta-dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-beta1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-beta1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-beta-dependent CTGF expression may offer clinical benefits. Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials.

Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity.

PubMed

Novosyadlyy, Ruslan; Leroith, Derek

2012-06-01

Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity.

Growth analysis of pulmonary metastases from salivary gland tumors.

PubMed

Twardzik, F G; Sklaroff, D M

1976-03-01

Three cases of primary salivary gland tumors with lung metastasis are presented with extremely long survival (six, ten, and twelve years). The tumor doubling time was calculated and the growth rate of the pulmonary metastasis was found to be slow and erratic. A simplified table was devised, which permits rapid calculation of the tumor doubling time without the use of graphs. The presence of lung metastasis from some primary malignant salivary tumor is not necessarily an ominous sign: a long survival without symtoms is possible.

Extravascular red blood cells and hemoglobin promote tumor growth and therapeutic resistance as endogenous danger signals.

PubMed

Yin, Tao; He, Sisi; Liu, Xiaoling; Jiang, Wei; Ye, Tinghong; Lin, Ziqiang; Sang, Yaxiong; Su, Chao; Wan, Yang; Shen, Guobo; Ma, Xuelei; Yu, Min; Guo, Fuchun; Liu, Yanyang; Li, Ling; Hu, Qiancheng; Wang, Yongsheng; Wei, Yuquan

2015-01-01

Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1β release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance. Copyright © 2014 by The American Association of Immunologists, Inc.

IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

PubMed

Zhang, Yu; Davis, Celestia; Shah, Sapana; Hughes, Daniel; Ryan, James C; Altomare, Diego; Peña, Maria Marjorette O

2017-01-01

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b + GR1 + and CD11b + F4/80 + myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Integrative models of vascular remodeling during tumor growth

PubMed Central

Rieger, Heiko; Welter, Michael

2015-01-01

Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.

PubMed

Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried

2010-04-01

Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.

Comparative activation states of tumor-associated and peritoneal macrophages from mice bearing an induced fibrosarcoma.

PubMed

Valdez, J C; de Alderete, N; Meson, O E; Sirena, A; Perdigon, G

1990-11-01

Balb/c mice bearing a methylcholanthrene-induced fibrosarcoma were used to compare the activation levels of tumor-associated and peritoneal macrophages. Two stages of tumor growth were examined, namely "small" and "large" tumors, with average diameters of 10 and 30 mm, respectively. The activation state, determined by measurement of both phagocytic index and beta-glucuronidase content, was found to be markedly higher in tumor-associated macrophages than in their peritoneal counterparts and it was, in addition, independent of tumor progression. The percentage of tumor-associated macrophages, which were detected on the basis of Fc receptor expression, remained constant in the growing neoplasm, at approximately 23% of total cell population. None of these parameters were affected by inoculation with an immunopotentiating dose of heat-killed Candida albicans which, on the other hand, seemed not to alter the course of the tumor. These data suggest that within the tumor microenvironment macrophages would somehow be maintained at a constant proportion and at a highly activated state, while outside the tumor they would be at a lower activation level. Our results also suggest that TAM would not possess antitumor activity in vivo, although we have found this activity in vitro.

Single Institutional Experience with Observing 564 Vestibular Schwannomas: Factors Associated with Tumor Growth

PubMed Central

Hunter, Jacob B.; Francis, David O.; O’Connell, Brendan P.; Kabagambe, Edmond K.; Bennett, Marc L.; Wanna, George B.; Rivas, Alejandro; Thompson, Reid C.; Haynes, David S.

2016-01-01

Objective To characterize the risk and predictors of growth during observation of vestibular schwannomas (VS). Study Design Retrospective case series. Setting Single academic, tertiary care center. Patients 564 consecutive VS patients who underwent at least two MRI studies prior to intervention. Intervention(s) Serial MRI studies Main outcome measure(s) Tumor growth, defined as a ≥2 mm increase in the maximum tumor diameter between consecutive MRI studies, or between the first and last study. Results A total of 1,296 patients (1995–2015) with VS were identified. Of those, 564 patients (median age 59.2 years; 53.5% female) were initially observed and underwent multiple MRI studies (median follow-up 22.9 months, interquartile range [IQR] 11.7 – 42.7). The median maximum tumor diameter at presentation was 1.00 cm (IQR 0.6 – 1.51 cm). In all, 40.8% of tumors demonstrated growth and 32.1% underwent intervention (21.5% microsurgery, 10.5% radiation) during the surveillance period. Multivariable Cox regression analysis showed that for each tumor, the risk of growth or intervention was significantly increased for larger initial VS diameters (HR=2.22; 95% CI: 1.90 – 2.61) and when disequilibrium was a presenting symptom (HR=1.70; 95% CI: 1.30 – 2.23). Patient age, gender, aspirin use and presenting symptoms of asymmetric hearing loss, tinnitus, and vertigo, were not associated with tumor growth. Conclusions To date, this is the largest series of observed VS reported in the literature. Risk of VS growth is significantly increased among patients who present with larger tumors and who have concomitant disequilibrium. IRB 151481 Define Professional Practice Gap & Educational Need No cohort with this sample size has assessed vestibular schwannoma growth rates in conjunction with this number of variables. Learning Objective To characterize vestibular schwannoma growth rates and predictors of growth. PMID:27668793

Nucleoprotein Changes in Plant Tumor Growth

PubMed Central

Rasch, Ellen; Swift, Hewson; Klein, Richard M.

1959-01-01

Tumor cell transformation and growth were studied in a plant neoplasm, crown gall of bean, induced by Agrobacterium rubi. Ribose nucleic acid (RNA), deoxyribose nucleic acid (DNA), histone, and total protein were estimated by microphotometry of nuclei, nucleoli, and cytoplasm in stained tissue sections. Transformation of normal cells to tumor cells was accompanied by marked increases in ribonucleoprotein content of affected tissues, reaching a maximum 2 to 3 days after inoculation with virulent bacteria. Increased DNA levels were in part associated with increased mitotic frequency, but also with progressive accumulation of nuclei in the higher DNA classes, formed by repeated DNA doubling without intervening reduction by mitosis. Some normal nuclei of the higher DNA classes (with 2, 4, or 8 times the DNA content of diploid nuclei) were reduced to diploid levels by successive cell divisions without intervening DNA synthesis. The normal relation between DNA synthesis and mitosis was thus disrupted in tumor tissue. Nevertheless, clearly defined DNA classes, as found in homologous normal tissues, were maintained in the tumor at all times. PMID:13673042

Big Bang Tumor Growth and Clonal Evolution.

PubMed

Sun, Ruping; Hu, Zheng; Curtis, Christina

2018-05-01

The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Effects of tibolone on sulfatase pathway of estrogens metabolism and on growth of MCF-7 human breast tumors implanted in ovariectomized nude mice.

PubMed

Desreux, Joëlle; Kloosterboer, Helenius; Noël, Agnès; Frankenne, Francis; Lemaire, Madeleine; Putman, Monique; Foidart, Jean-Michel

2007-01-01

The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17beta-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors.

PubMed

Florio, Tullio

2008-01-01

The current treatment of neuroendocrine tumors include the use of somatostatin (SST) agonists. These compounds are able to control most of the symptoms caused by the hypersecretory activity of the tumor cells, and for this reason, they provide a significant improvement in the well-being of the patients. Although, several reports also showed a possible direct antiproliferative activity of SST agonists in different neuroendocrine tumors, the therapeutic potential of an in vivo antiproliferative activity mediated by SST receptors is still debated. In recent years, there has been great insights on understanding the molecular basis of the antitumoral activity of SST that appears to be exerted via both direct and indirect mechanisms. Direct mechanisms require the activation of SST receptors in tumor cells and the induction of cell cycle arrest or apoptosis, mainly through the regulation of phosphotyrosine phosphatase (PTP) and MAP kinase activities. The indirect mechanisms involve the inhibition of tumor angiogenesis and the inhibition of the secretion of factors which are required for tumor growth. Here, we will review the molecular mechanisms which are implicated in the antiproliferative activity of SST. Such an understanding is necessary for improving the antitumoral efficacy of SSTR agonists as well as for the development of novel therapeutic strategies.

Opposite Effects of Coinjection and Distant Injection of Mesenchymal Stem Cells on Breast Tumor Cell Growth.

PubMed

Zheng, Huilin; Zou, Weibin; Shen, Jiaying; Xu, Liang; Wang, Shu; Fu, Yang-Xin; Fan, Weimin

2016-09-01

: Mesenchymal stem cells (MSCs) usually promote tumor growth and metastasis. By using a breast tumor 4T1 cell-based animal model, this study determined that coinjection and distant injection of allogeneic bone marrow-derived MSCs with tumor cells could exert different effects on tumor growth. Whereas the coinjection of MSCs with 4T1 cells promoted tumor growth, surprisingly, the injection of MSCs at a site distant from the 4T1 cell inoculation site suppressed tumor growth. We further observed that, in the distant injection model, MSCs decreased the accumulation of myeloid-derived suppressor cells and regulatory T cells in tumor tissues by enhancing proinflammatory factors such as interferon-γ, tumor necrosis factor-α, Toll-like receptor (TLR)-3, and TLR-4, promoting host antitumor immunity and inhibiting tumor growth. Unlike previous reports, this is the first study reporting that MSCs may exert opposite roles on tumor growth in the same animal model by modulating the host immune system, which may shed light on the potential application of MSCs as vehicles for tumor therapy and other clinical applications. Mesenchymal stem cells (MSCs) have been widely investigated for their potential roles in tissue engineering, autoimmune diseases, and tumor therapeutics. This study explored the impact of coinjection and distant injection of allogeneic bone marrow-derived MSCs on mouse 4T1 breast cancer cells. The results showed that the coinjection of MSCs and 4T1 cells promoted tumor growth. MSCs might act as the tumor stromal precursors and cause immunosuppression to protect tumor cells from immunosurveillance, which subsequently facilitated tumor metastasis. Interestingly, the distant injection of MSCs and 4T1 cells suppressed tumor growth. Together, the results of this study revealed the dual functions of MSCs in immunoregulation. ©AlphaMed Press.

Apigenin sensitizes colon cancer cells to anti-tumor activity of ABT-263

PubMed Central

Shao, Huanjie; Jing, Kai; Mahmoud, Esraa; Huang, Haihong; Fang, Xianjun; Yu, Chunrong

2013-01-01

Apigenin is an edible plant-derived flavonoid that shows modest anti-tumor activities in vitro and in vivo. Apigenin treatment resulted in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between apigenin and ABT-263 in colon cancer cells. We observed a synergistic effect between apigenin and ABT-263 on apoptosis of colon cancer cells. ABT-263 alone induced limited cell death while upregulating expression of Mcl-1, a potential mechanism for the acquired resistance to ABT-263. The presence of apigenin antagonized ABT-263-induced Mcl-1 upregulation and dramatically enhanced ABT-263-induced cell death. Meanwhile, apigenin suppressed AKT and ERK activation. Inactivation of either AKT or ERK by lentivirus-transduced shRNA or treatment with specific small molecule inhibitors of these pathways enhanced ABT-263-induced cell death, mirroring the effect of apigenin. Moreover, the combination response was associated with upregulation of Bim and activation of Bax. Downregulation of Bax eliminated the synergistic effect of apigenin and ABT-263 on cell death. Xenograft studies in SCID mice showed that the combined treatment with apigenin and ABT-263 inhibited tumor growth by up to 70% without obvious adverse effects, while either agent only inhibited around 30%. Our results demonstrate a novel strategy to enhance ABT-263 induced anti-tumor activity in human colon cancer cells by apigenin via inhibition of the Mcl-1, AKT and ERK pro-survival regulators. PMID:24126433

Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

PubMed Central

Olson, Terrah J. Paul; Hadac, Jamie N.; Sievers, Chelsie K.; Leystra, Alyssa A.; Deming, Dustin A.; Zahm, Christopher D.; Albrecht, Dawn M.; Nomura, Alice; Nettekoven, Laura A.; Plesh, Lauren K.; Clipson, Linda; Sullivan, Ruth; Newton, Michael A.; Schelman, William R.; Halberg, Richard B.

2014-01-01

Colorectal cancer (CRC) often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which progress and which remain benign is difficult. We developed a novel long-lived murine model of CRC with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk-stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas as compared to those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to CRC. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progression to CRC and potentially guide prevention strategies. PMID:24196829

Dietary rice component, Oryzanol, inhibits tumor growth in tumor-bearing Mice

USDA-ARS?s Scientific Manuscript database

Scope: We investigated the effects of rice bran and components on tumor growth in mice. Methods and results: Mice fed standard diets supplemented with rice bran, '-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet fo...

Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice1

PubMed Central

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

Abstract We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy. PMID:12659668

Growth of Malignant Non-CNS Tumors Alters Brain Metabolome

PubMed Central

Kovalchuk, Anna; Nersisyan, Lilit; Mandal, Rupasri; Wishart, David; Mancini, Maria; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga

2018-01-01

Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as “tumor brain.” Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraft™ mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID:29515623

YB-1, the E2F Pathway, and Regulation of Tumor Cell Growth

PubMed Central

Samuel, Weini; Cao, Helen; Patel, Rachna; Mehta, Reena; Stern, J. Lewis; Reid, Glen; Woolley, Adele G.; Miller, Lance D.; Black, Michael A; Shelling, Andrew N.; Print, Cristin G.; Braithwaite, Antony W.

2012-01-01

Background Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear. Methods YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis–free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests. Results YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis–free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter–reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= −2.64, 95% confidence interval = −3.57 to −1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes. Conclusion YB-1 expression is associated with the

Modified Gompertz equation for electrotherapy murine tumor growth kinetics: predictions and new hypotheses

PubMed Central

2010-01-01

Background Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed and perturbed tumors through use of the modified Gompertz equation in order to generate useful insight into the mechanisms that underpin this devastating disease. Methods The complete tumor growth kinetics for control and treated groups are obtained by interpolation and extrapolation methods with different time steps, using experimental data of fibrosarcoma Sa-37. In the modified Gompertz equation, a delay time is introduced to describe the tumor's natural history before treatment. Different graphical strategies are used in order to reveal new information in the complete kinetics of this tumor type. Results The first stage of complete tumor growth kinetics is highly non linear. The model, at this stage, shows different aspects that agree with those reported theoretically and experimentally. Tumor reversibility and the proportionality between regions before and after electrotherapy are demonstrated. In tumors that reach partial remission, two antagonistic post-treatment processes are induced, whereas in complete remission, two unknown antitumor mechanisms are induced. Conclusion The modified Gompertz equation is likely to lead to insights within cancer research. Such insights hold promise for increasing our understanding of tumors as self-organizing systems and, the possible existence of phase transitions in tumor growth kinetics, which, in turn, may have significant impacts both on cancer research and on clinical practice. PMID:21029411

Modified Gompertz equation for electrotherapy murine tumor growth kinetics: predictions and new hypotheses.

PubMed

Cabrales, Luis E Bergues; Nava, Juan J Godina; Aguilera, Andrés Ramírez; Joa, Javier A González; Ciria, Héctor M Camué; González, Maraelys Morales; Salas, Miriam Fariñas; Jarque, Manuel Verdecia; González, Tamara Rubio; Mateus, Miguel A O'Farril; Brooks, Soraida C Acosta; Palencia, Fabiola Suárez; Zamora, Lisset Ortiz; Quevedo, María C Céspedes; Seringe, Sarah Edward; Cuitié, Vladimir Crombet; Cabrales, Idelisa Bergues; González, Gustavo Sierra

2010-10-28

Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed and perturbed tumors through use of the modified Gompertz equation in order to generate useful insight into the mechanisms that underpin this devastating disease. The complete tumor growth kinetics for control and treated groups are obtained by interpolation and extrapolation methods with different time steps, using experimental data of fibrosarcoma Sa-37. In the modified Gompertz equation, a delay time is introduced to describe the tumor's natural history before treatment. Different graphical strategies are used in order to reveal new information in the complete kinetics of this tumor type. The first stage of complete tumor growth kinetics is highly non linear. The model, at this stage, shows different aspects that agree with those reported theoretically and experimentally. Tumor reversibility and the proportionality between regions before and after electrotherapy are demonstrated. In tumors that reach partial remission, two antagonistic post-treatment processes are induced, whereas in complete remission, two unknown antitumor mechanisms are induced. The modified Gompertz equation is likely to lead to insights within cancer research. Such insights hold promise for increasing our understanding of tumors as self-organizing systems and, the possible existence of phase transitions in tumor growth kinetics, which, in turn, may have significant impacts both on cancer research and on clinical practice.

A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

PubMed

Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

2016-09-07

Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: tumor growth promotion or suppression?

PubMed

Ayroldi, Emira; Cannarile, Lorenza; Delfino, Domenico V; Riccardi, Carlo

2018-04-26

Glucocorticoids (GCs), important therapeutic tools to treat inflammatory and immunosuppressive diseases, can also be used as part of cancer therapy. In oncology, GCs are used as anticancer drugs for lymphohematopoietic malignancies, while in solid neoplasms primarily to control the side effects of chemo/radiotherapy treatments. The molecular mechanisms underlying the effects of GCs are numerous and often overlapping, but not all have been elucidated. In normal, cancerous, and inflammatory tissues, the response to GCs differs based on the tissue type. The effects of GCs are dependent on several factors: the tumor type, the GC therapy being used, the expression level of the glucocorticoid receptor (GR), and the presence of any other stimuli such as signals from immune cells and the tumor microenvironment. Therefore, GCs may either promote or suppress tumor growth via different molecular mechanisms. Stress exposure results in dysregulation of the hypothalamic-pituitary-adrenal axis with increased levels of endogenous GCs that promote tumorigenesis, confirming the importance of GCs in tumor growth. Most of the effects of GCs are genomic and mediated by the modulation of GR gene transcription. Moreover, among the GR-induced genes, glucocorticoid-induced leucine zipper (GILZ), which was cloned and characterized primarily in our laboratory, mediates many GC anti-inflammatory effects. In this review, we analyzed the possible role for GILZ in the effects GCs have on tumors cells. We also suggest that GILZ, by affecting the immune system, tumor microenvironment, and directly cancer cell biology, has a tumor-promoting function. However, it may also induce apoptosis or decrease the proliferation of cancer cells, thus inhibiting tumor growth. The potential therapeutic implications of GILZ activity on tumor cells are discussed here.

Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth.

PubMed

Kock, Anna; Larsson, Karin; Bergqvist, Filip; Eissler, Nina; Elfman, Lotta H M; Raouf, Joan; Korotkova, Marina; Johnsen, John Inge; Jakobsson, Per-Johan; Kogner, Per

2018-06-01

Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E 2 (PGE 2 )-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE 2 . However, clinical targeting of PGE 2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE 2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chinese Red Yeast Rice Inhibition of Prostate Tumor Growth in SCID mice

PubMed Central

Hong, Mee Young; Henning, Susanne; Moro, Aune; Seeram, Navindra P.; Zhang, Yanjun; Heber, David

2011-01-01

Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but lovastatin unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and AR-overexpressing androgen-independent prostate cancer cell proliferation in vitro. The present study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared to animals receiving vehicle alone (P<0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR demonstrating that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P<0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3 and SRD5A1) in both type of tumors (P<0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. PMID:21278313

Repeated Administration of Inhibitors for Ion Pumps Reduce Markedly Tumor Growth in Vivo

PubMed Central

Hrgovic, Igor; Glavic, Zeljko; Kovacic, Zeljko; Mulic, Smaila; Zunic, Lejla; Hrgovic, Zlatko

2014-01-01

ABSTRACT Introduction: Measurements of extracellular pH show that the micro environment of malignant tumors is more acidic than that of normal cells, whereas pH does not differ appreciable in normal and malignant cells. The acid micro environment of tumors is created by the secretion of tumor factors and ATP hydrolysis in hypoxic tumor tissue. In order to survive in a low pH-environment tumor cells develop regulatory mechanisms which keep their intracellular pH stable. Two of the most important systems are the Na+/H+ ion pump and the Na-dependent HCO3-/Cl- pump of stilbenian derivatives. Material and methods: Experiments were carried out on DBA mice of both sexes at the age of 4 month. Laboratory animals were grown in our institute and supplied with food and aqua ad libitum. Results: After termination of the experiments the mean tumor diameter in the control group was 12.4±0.8mm, in group A it was 6.9±0.6mm, and in group B we measured 6.6±3.1mm. At the final day the tumor size in treated animals was twice as small as in the control group. In addition we observed the rate of survival. In the control group only 18% of the animals were still alive at day 18. Considering the rate of survival a statistically significant difference between treated and untreated animals was observed. The survival of tumor cells is dependent on the function of these ion pumps which keep their intracellular pH values constant in the setting of an acid extracellular environment. Conclusion: The activity of the ion pump is especially important at the beginning of cell division and in cell proliferation. Our in vivo experiments demonstrate that prolonged administration of intratumoral ion pump inhibitors suppresses tumor growth as well as enhances survival of tumor-bearing animals. Research of inhibitors of ion pumps and their action in tumor growth opens new perspectives into pathophysiology of malignant tumors and may create new therapeutic options. PMID:24937925

Early treatment with metformin induces resistance against tumor growth in adult rats

PubMed Central

Trombini, Amanda B; Franco, Claudinéia CS; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane AS; Fabricio, Gabriel S; de Sant’Anna, Juliane R; Castro-Prado, Marialba AA; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo CF

2015-01-01

It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer. PMID:26024008

Influence of pulsed electromagnetic and pulsed vector magnetic potential field on the growth of tumor cells.

PubMed

Loja, Tomas; Stehlikova, Olga; Palko, Lukas; Vrba, Kamil; Rampl, Ivan; Klabusay, Martin

2014-09-01

Tumor diseases cause 20% of deaths in Europe and they are the second most common cause of death and morbidity after cardiovascular diseases. Thus, tumor cells are target of many therapeutic strategies and tumor research is focused on searching more efficient and specific drugs as well as new therapeutic approaches. One of the areas of tumor research is an issue of external fields. In our work, we tested influence of a pulsed electromagnetic field (PEMF) and a hypothetic field of the pulsed vector magnetic potential (PVMP) on the growth of tumor cells; and further the possible growth inhibition effect of the PVMP. Both unipolar and bipolar PEMF fields of 5 mT and PVMP fields of 0 mT at frequencies of 15 Hz, 125 Hz and 625 Hz were tested on cancer cell lines derived from various types of tumors: CEM/C2 (acute lymphoblastic leukemia), SU-DHL-4 (B-cell lymphoma), COLO-320DM (colorectal adenocarcinoma), MDA-BM-468 (breast adenocarcinoma), and ZR-75-1 (ductal carcinoma). Cell morphology was observed, proliferation activity using WST assay was measured and simultaneous proportion of live, early apoptotic and dead cells was detected using flow cytometry. A PEMF of 125 Hz and 625 Hz for 24 h-48 h increased proliferation activity in the 2 types of cancer cell lines used, i.e. COLO-320DM and ZR-75-1. In contrast, any of employed methods did not confirm a significant inhibitory effect of hypothetic PVMP field on tumor cells.

Change of tumor vascular reactivity during tumor growth and postchemotherapy observed by near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Lee, Songhyun; Jeong, Hyeryun; Seong, Myeongsu; Kim, Jae Gwan

2017-12-01

Breast cancer is one of the most common cancers in females. To monitor chemotherapeutic efficacy for breast cancer, medical imaging systems such as x-ray mammography, computed tomography, magnetic resonance imaging, and ultrasound imaging have been used. Currently, it can take up to 3 to 6 weeks to see the tumor response from chemotherapy by monitoring tumor volume changes. We used near-infrared spectroscopy (NIRS) to predict breast cancer treatment efficacy earlier than tumor volume changes by monitoring tumor vascular reactivity during inhalational gas interventions. The results show that the amplitude of oxy-hemoglobin changes (vascular reactivity) during hyperoxic gas inhalation is well correlated with tumor growth and responded one day earlier than tumor volume changes after chemotherapy. These results may imply that NIRS with respiratory challenges can be useful in early detection of tumor and in the prediction of tumor response to chemotherapy.

Influence of Anti-Mouse Interferon Serum on the Growth and Metastasis of Tumor Cells Persistently Infected with Virus and of Human Prostatic Tumors in Athymic Nude Mice

NASA Astrophysics Data System (ADS)

Reid, Lola M.; Minato, Nagahiro; Gresser, Ion; Holland, John; Kadish, Anna; Bloom, Barry R.

1981-02-01

Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF--NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.

Altered tumor cell growth and tumorigenicity in models of microgravity

NASA Astrophysics Data System (ADS)

Yamauchi, K.; Taga, M.; Furian, L.; Odle, J.; Sundaresan, A.; Pellis, N.; Andrassy, R.; Kulkarni, A.

Spaceflight environment and microgravity (MG) causes immune dysfunction and is a major health risk to humans, especially during long-term space missions. The effects of microgravity environment on tumor growth and carcinogenesis are yet unknown. Hence, we investigated the effects of simulated MG (SMG) on tumor growth and tumorigenicity using in vivo and in vitro models. B16 melanoma cells were cultured in static flask (FL) and rotating wall vessel bioreactors (BIO) to measure growth and properties, melanin production and apoptosis. BIO cultures had 50% decreased growth (p<0.01), increased doubling time and a 150% increase in melanin production (p<0.05). Flow cytometric analysis showed increased apoptosis in BIO. When BIO cultured melanoma cells were inoculated sc in mice there was a significant increase in tumorigenicity as compared to FL cells. Thus SMG may have supported &selected highly tumorigenic cells and it is pos sible that in addition to decreased immune function MG may alter tumor cell characteristics and invasiveness. Thus it is important to study effects of microgravity environment and its stressors using experimental tumors and SMG to understand and evaluate carcinogenic responses to true microgravity. Further studies on carcinogenic events and their mechanisms will allow us develop and formulate countermeasures and protect space travelers. Additional results will be presented. (Supported by NASA NCC8-168 grant, ADK)

Modified model of VX2 tumor overexpressing vascular endothelial growth factor.

PubMed

Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre

2012-06-01

To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (ρ = .883, P = .012). The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model.

PubMed

Roel, María; Rubiolo, Juan A; Guerra-Varela, Jorge; Silva, Siguara B L; Thomas, Olivier P; Cabezas-Sainz, Pablo; Sánchez, Laura; López, Rafael; Botana, Luis M

2016-12-13

The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo.Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools.

Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model

PubMed Central

Roel, María; Rubiolo, Juan A.; Guerra-Varela, Jorge; Silva, Siguara B. L.; Thomas, Olivier P.; Cabezas-Sainz, Pablo; Sánchez, Laura; López, Rafael; Botana, Luis M.

2016-01-01

The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo. Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools. PMID:27825113

Enhanced In Vivo Tumor Detection by Active Tumor Cell Targeting Using Multiple Tumor Receptor-Binding Peptides Presented on Genetically Engineered Human Ferritin Nanoparticles.

PubMed

Kwon, Koo Chul; Ko, Ho Kyung; Lee, Jiyun; Lee, Eun Jung; Kim, Kwangmeyung; Lee, Jeewon

2016-08-01

Human ferritin heavy-chain nanoparticle (hFTH) is genetically engineered to present tumor receptor-binding peptides (affibody and/or RGD-derived cyclic peptides, named 4CRGD here) on its surface. The affibody and 4CRGD specifically and strongly binds to human epidermal growth factor receptor I (EGFR) and human integrin αvβ3, respectively, which are overexpressed on various tumor cells. Through in vitro culture of EGFR-overexpressing adenocarcinoma (MDA-MB-468) and integrin-overexpressing glioblastoma cells (U87MG), it is clarified that specific interactions between receptors on tumor cells and receptor-binding peptides on engineered hFTH is critical in active tumor cell targeting. After labeling with the near-infrared fluorescence dye (Cy5.5) and intravenouse injection into MDA-MB-468 or U87MG tumor-bearing mice, the recombinant hFTHs presenting either peptide or both of affibody and 4CRGD are successfully delivered to and retained in the tumor for a prolonged period of time. In particular, the recombinant hFTH presenting both affibody and 4CRGD notably enhances in vivo detection of U87MG tumors that express heterogeneous receptors, integrin and EGFR, compared to the other recombinant hFTHs presenting either affibody or 4CRGD only. Like affibody and 4CRGD used in this study, other multiple tumor receptor-binding peptides can be also genetically introduced to the hFTH surface for actively targeting of in vivo tumors with heterogenous receptors. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor

PubMed Central

Wang, Lihong; Liu, Liping; Shi, Yan; Cao, Hanwei; Chaturvedi, Rupesh; Calcutt, M. Wade; Hu, Tianhui; Ren, Xiubao; Wilson, Keith T.; Polk, D. Brent; Yan, Fang

2012-01-01

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc min mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth. PMID:22574158

Long acting propranolol and HSP-70 rich tumor lysate reduce tumor growth and enhance immune response against fibrosarcoma in Balb/c mice.

PubMed

Khalili, Ahmad; Hassan, Zuhair Muhammad; Shahabi, Shahram; Pourfathollah, Ali Akbar; Ostad, Seyed Nasser; Noori, Shokoofe; Mahdavi, Mehdi; Haybar, Habib; Langroudi, Ladan

2013-06-01

Noradrenaline (NA), the principal neurotransmitter released from sympathetic nerve terminals, influences T-cell maturation, not only directly in developing T cells, but also indirectly, by acting on the thymic nonlymphoid cells. In vitro and in vivo studies have demonstrated the anti-proliferative, anti-migratory, anti-angiogenic and cytotoxic properties of propranolol, β-AR blocker, against various cancers. To evaluate the effect of propranolol on efficacy of HSP-70 rich lysate vaccine in immunotherapy of fibrosarcoma. Mouse fibrosarcoma WEHI-164 cells were used to immunize tumor-bearing mice with or without propranolol and HSP-70. Splenocytes proliferation, cytotoxicity activity of the splenocytes, naturally occurring CD4+ CD25high T-reg cells and IFN-γ and IL-4 secretion as well as tumor size, were assessed to describe the anti-tumor immune response. A significant increase in the level of IFN-γ in the mice vaccinated with WEHI-164 cells enriched with HSP-70 and co-treated with propranolol was observed compared to controls. However, HSP enrichment or propranolol treatment alone did not enhance the immune response as measured by the level of IFN-γ. Likewise, a decrease in tumor growth in the test group (p<0.01) and a significant increase in CTL activity (p<0.05) was observed. HSP enriched vaccine shows anti-tumor activity, probably due to the modulation of immune responses.

Anti-tumor activity of staurosporine in the tumor microenvironment of cervical cancer: An in vitro study.

PubMed

Yadav, Suresh Singh; Prasad, Chandra Bhushan; Prasad, Shyam Babu; Pandey, Lakshmi Kant; Singh, Sunita; Pradhan, Satyajit; Narayan, Gopeshwar

2015-07-15

The fundamental events for cancer progression and metastases include loss of cell adhesion, cell proliferation, anchorage-independent cell growth (evading anoikis), cell migration and cell invasion. All these events leading to cancer progression happen in a favorable nurturing tumor microenvironment. This study was designed to explore the anti-tumor activity of staurosporine (a nonspecific protein kinase inhibitor) in the tumor microenvironment of cervical cancer. The anti-tumor activity of staurosporine was investigated by cell adhesion assay, colony formation assay, apoptosis assay and quantitative real-time polymerase chain reaction (PCR) in cervical cancer cell lines. The cell adhesion assay showed that staurosporine induces adhesion of cervical cancer cells to the extracellular matrix (ECM) protein fibronectin. The soft agar colony formation assay showed that staurosporine inhibits both the number and size of colony formation in a dose dependent manner and also induces adherent tendency in the cancer cells. Staurosporine also induces prominent apoptosis in single cell suspensions compared to adherent cells. Stroma cell induced transcription of matrix metalloprotease 1 (MMP1) and matrix metalloprotease 2 (MMP2) in cervical cancer cells was inhibited by staurosporine. Our results indicate that staurosporine induces anti-tumor response in the cervical tumor microenvironment by inhibiting the fundamental events for cancer progression and metastases. The present study represents an attractive area for further research and opens up new avenues towards the understanding of cervical cancer therapeutics. Copyright © 2015 Elsevier Inc. All rights reserved.

Anti-tumor activity of three ginsenoside derivatives in lung cancer is associated with Wnt/β-catenin signaling inhibition.

PubMed

Bi, Xiuli; Xia, Xichun; Mou, Teng; Jiang, Bowen; Fan, Dongdong; Wang, Peng; Liu, Yafei; Hou, Yue; Zhao, Yuqing

2014-11-05

Numerous compounds isolated from Ginseng have been shown to exhibit various biological activities, including antioxidant, anti-carcinogenic, anti-mutagenic, and anti-tumor activities. Recent research has focused on the potential values of these compounds in the prevention and treatment of human cancers. The anti-tumor activity of 25-hydroxyprotopanaxadiol (25-OH-PPD), a natural compound isolated from Panax ginseng, has been established in previous study. In the current study, we investigated the anti-tumor activity of three derivatives of 25-OH-PPD, namely xl, 1c, and 8b with respect to lung cancer. All three compounds significantly inhibited the growth of the human lung cancer cells A549 and H460. Oral administration of these compounds significantly inhibited the growth of xenograft tumors in mice without affecting body weight. Further mechanistic study demonstrated that these compounds could decrease the expression levels of β-catenin and its downstream targets Cyclin D1, CDK4, and c-myc in lung cancer cells. Taken together, the results suggested that the anti-growth activity exerted by these 25-OH-PPD derivatives against lung cancer cells probably involved β-catenin-mediated signaling pathway, a finding that could have important implication for chemotherapeutic strategy aiming at the treatment of lung cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

Interfacial properties in a discrete model for tumor growth

NASA Astrophysics Data System (ADS)

Moglia, Belén; Guisoni, Nara; Albano, Ezequiel V.

2013-03-01

We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent β=0.32(2) that governs the early time regime, (ii) the roughness exponent α=0.49(2) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z=α/β≃1.49(2), which measures the propagation of correlations in the direction parallel to the interface, e.g., ξ∝t1/z, where ξ is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.

Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.

PubMed

Dey, Julien H; Bianchi, Fabrizio; Voshol, Johannes; Bonenfant, Debora; Oakeley, Edward J; Hynes, Nancy E

2010-05-15

Members of the fibroblast growth factor receptor (FGFR) family have essential roles in normal physiology and in cancer where they control diverse processes. FGFRs have been associated with breast cancer development. Thus, models to study the role of FGFR in breast cancer and their targeting potential are important. We present an in vitro and in vivo analysis of FGFRs in the breast cancer model cell lines 67NR and 4T1. We show that both tumor cell lines coexpress FGFRs and ligands and display autocrine FGFR signaling activity. Fibroblast growth factor receptor substrate 2 (FRS2), a downstream mediator of FGFR, is constitutively tyrosine phosphorylated and multiple signaling pathways are active. Treatment of 67NR and 4T1 cultures with TKI258, an FGFR tyrosine kinase inhibitor (TKI), caused a rapid decrease in FRS2 phosphorylation; decreased the activity of extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and phospholipase Cgamma; and blocked proliferation of both tumor lines. Furthermore, TKI258 induced 4T1 apoptotic cell death via blockade of the phosphoinositide 3-kinase/AKT pathway. In vivo, one dose of TKI258 rapidly lowered FRS2 phosphorylation and ERK1/2 and AKT activity in mammary tumors. Long-term TKI258 treatment of 4T1 tumor- and 67NR tumor-bearing mice had a significant effect on primary tumor outgrowth and 4T1 tumor-induced lung metastases. A microarray analysis was carried out to identify targets with roles in TKI258 antitumor activity and potential prognostic markers in human breast tumors. Of interest are the downregulated matrix metalloproteases (MMP), in particular MMP9, which is essential for metastatic spread of 4T1 tumors. (c)2010 AACR.

Plantamajoside, a potential anti-tumor herbal medicine inhibits breast cancer growth and pulmonary metastasis by decreasing the activity of matrix metalloproteinase-9 and -2.

PubMed

Pei, Shimin; Yang, Xu; Wang, Huanan; Zhang, Hong; Zhou, Bin; Zhang, Di; Lin, Degui

2015-12-16

Metastasis is the major cause of death in breast cancers. MMPs play a key role in tumor microenvironment that facilitates metastasis. The existing researches suggest that the high expression of gelatinase A and B (MMP2 and MMP9) promote the metastasis of breast cancer. Therefore, gelatinase inhibitor can effectively suppress tumor metastasis. However, at present, there is no dramatically effective gelatinase inhibitor against breast cancer. We screened gelatinase inhibitor among Chinese herbal medicine by molecular docking technology; investigated the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line in response to the treatment with the screened inhibitor by wound assay, invasion assay and gelatin zymography; then further examined the effects of inhibitor on allograft mammary tumors of mice by immunohistochemistry. We successfully screened an Chinese herbal medicine-Plantamajoside(PMS)-which can reduce the gelatinase activity of MMP9 and MMP2. In vitro, PMS can inhibit the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line by decreasing MMP9 and MMP2 activity. In vivo, oral administration of PMS to the mice bearing 4T1 cells induced tumors resulted in significant reduction in allograft tumor volume and weights, significant decrease in microvascular density and significant lower lung metastasis rate. Our results indicate that as a promising anti-cancer agent, PMS may inhibit growth and metastasis of breast cancer by inhibiting the activity of MMP9 and MMP2.

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

PubMed Central

Hennenberg, Eva Maria; Eyking, Annette; Reis, Henning

2017-01-01

Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC. PMID:28686677

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis.

PubMed

Hennenberg, Eva Maria; Eyking, Annette; Reis, Henning; Cario, Elke

2017-01-01

Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.

A flavonoid component from Docynia delavayi (Franch.) Schneid represses transplanted H22 hepatoma growth and exhibits low toxic effect on tumor-bearing mice.

PubMed

Zhao, Xiangpei; Shu, Guangwen; Chen, Lvyi; Mi, Xue; Mei, Zhinan; Deng, Xukun

2012-09-01

The fruit of Docynia delavayi (Franch.) Schneid is a kind of popular food in southwestern areas of China. Additionally, its rhizome has been long used as a folk medicine in the treatment of liver cancer by local people. Chrysin is a kind of flavonoid which induces cancer cell death in vitro. However, its anti-tumor activity in vivo and toxicological effects on the tumor-bearing animals still remain poorly understood. In this study, we obtained four flavonoids from this herb. Among them, chrysin showed the strongest cytotoxic effect on an array of cultured tumor cells. Further investigations revealed that it significantly repressed transplanted H22 ascitic hepatic tumor cell growth in vivo. Moreover, this compound displayed little toxic effects. Additionally, we demonstrated that in transplanted tumor tissues, chrysin not only activated caspase-3 and induced apoptosis, but also inhibited the production of vascular endothelial growth factor (VEGF) and suppressed angiogenesis. These data showed that chrysin exhibited prominent anti-tumor activities and low toxic effects in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

Tumor growth model for atlas based registration of pathological brain MR images

NASA Astrophysics Data System (ADS)

Moualhi, Wafa; Ezzeddine, Zagrouba

2015-02-01

The motivation of this work is to register a tumor brain magnetic resonance (MR) image with a normal brain atlas. A normal brain atlas is deformed in order to take account of the presence of a large space occupying tumor. The method use a priori model of tumor growth assuming that the tumor grows in a radial way from a starting point. First, an affine transformation is used in order to bring the patient image and the brain atlas in a global correspondence. Second, the seeding of a synthetic tumor into the brain atlas provides a template for the lesion. Finally, the seeded atlas is deformed combining a method derived from optical flow principles and a model for tumor growth (MTG). Results show that an automatic segmentation method of brain structures in the presence of large deformation can be provided.

An enteric pathogen Salmonella enterica serovar Typhimurium suppresses tumor growth by downregulating CD44high and CD4T regulatory (Treg) cell expression in mice: the critical role of lipopolysaccharide and Braun lipoprotein in modulating tumor growth.

PubMed

Liu, T; Chopra, A K

2010-02-01

An antitumor activity associated with several bacterial pathogens, including Salmonella enterica serovar Typhimurium, has been reported; however, the underlying immunological mechanism(s) that lead to an antitumor effect are currently unclear. Furthermore, such pathogens cannot be used to suppress tumor growth because of their potential for causing sepsis. Recently, we reported the characterization of S. Typhimurium isogenic mutants from which Braun lipoprotein genes (lppA and B) and the multicopy repressor of high temperature requirement (msbB) gene were deleted. In a mouse infection model, two mutants, namely, lppB/msbB and lppAB/msbB, minimally induced proinflammatory cytokine production at high doses and were nonlethal to animals. We showed that immunization of mice with these mutants, followed by challenge with the wild-type S. Typhimurium, could significantly suppress tumor growth, as evidenced by an 88% regression in tumor size in lppB/msbB mutant-immunized animals over a 24-day period. However, the lppAB/msbB mutant alone was not effective in modulating tumor growth in mice, although the lppB/msbB mutant alone caused marginal regression in tumor size. Importantly, we showed that CD44(+) cells grew much faster than CD44(-) cells from human liver tumors in mice, leading us to examine the possibility that S. Typhimurium might downregulate CD44 in tumors and splenocytes of mice. Consequently, we found in S. Typhimurium-infected mice that tumor size regression could indeed be related to the downregulation of CD44(high) and CD4(+)CD25(+) T(reg) cells. Importantly, the role of lipopolysaccharide and Braun lipoprotein was critical in S. Typhimurium-induced antitumor immune responses. Taken together, we have defined new immune mechanisms leading to tumor suppression in mice by S. Typhimurium.

Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model.

PubMed

Guerrero-Vargas, Natalí N; Navarro-Espíndola, Raful; Guzmán-Ruíz, Mara A; Basualdo, María Del Carmen; Espitia-Bautista, Estefania; López-Bago, Ana; Lascurain, Ricardo; Córdoba-Manilla, Cinthya; Buijs, Ruud M; Escobar, Carolina

2017-09-06

Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells. Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet. We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the

Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3.

PubMed

Thomas, Margaret Lois; de Antueno, Roberto; Coyle, Krysta Mila; Sultan, Mohammad; Cruickshank, Brianne Marie; Giacomantonio, Michael Anthony; Giacomantonio, Carman Anthony; Duncan, Roy; Marcato, Paola

2016-11-01

Breast cancer stem cells (CSCs) can be identified by increased Aldefluor fluorescence caused by increased expression of aldehyde dehydrogenase 1A3 (ALDH1A3), as well as ALDH1A1 and ALDH2. In addition to being a CSC marker, ALDH1A3 regulates gene expression via retinoic acid (RA) signaling and plays a key role in the progression and chemotherapy resistance of cancer. Therefore, ALDH1A3 represents a druggable anti-cancer target of interest. Since to date, there are no characterized ALDH1A3 isoform inhibitors, drugs that were previously described as inhibiting the activity of other ALDH isoforms were tested for anti-ALDH1A3 activity. Twelve drugs (3-hydroxy-dl-kynurenine, benomyl, citral, chloral hydrate, cyanamide, daidzin, DEAB, disulfiram, gossypol, kynurenic acid, molinate, and pargyline) were compared for their efficacy in inducing apoptosis and reducing ALDH1A3, ALDH1A1 and ALDH2-associated Aldefluor fluorescence in breast cancer cells. Citral was identified as the best inhibitor of ALDH1A3, reducing the Aldefluor fluorescence in breast cancer cell lines and in a patient-derived tumor xenograft. Nanoparticle encapsulated citral specifically reduced the enhanced tumor growth of MDA-MB-231 cells overexpressing ALDH1A3. To determine the potential mechanisms of citral-mediated tumor growth inhibition, we performed cell proliferation, clonogenic, and gene expression assays. Citral reduced ALDH1A3-mediated colony formation and expression of ALDH1A3-inducible genes. In conclusion, citral is an effective ALDH1A3 inhibitor and is able to block ALDH1A3-mediated breast tumor growth, potentially via blocking its colony forming and gene expression regulation activity. The promise of ALDH1A3 inhibitors as adjuvant therapies for patients with tumors that have a large population of high-ALDH1A3 CSCs is discussed. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation.

PubMed

Unkelbach, Jan; Menze, Bjoern H; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A

2014-02-07

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

NASA Astrophysics Data System (ADS)

Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

2014-02-01

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Optimization of a therapeutic electromagnetic field (EMF) to retard breast cancer tumor growth and vascularity.

PubMed

Cameron, Ivan L; Markov, Marko S; Hardman, W Elaine

2014-01-01

This study provided additional data on the effects of a therapeutic electromagnetic field (EMF) device on growth and vascularization of murine 16/C mammary adenocarcinoma cells implanted in C3H/HeJ mice. The therapeutic EMF device generated a defined 120 Hz semi sine wave pulse signal of variable intensity. Murine 16/C mammary adenocarcinoma tumor fragments were implanted subcutaneously between the scapulae of syngeneic C3H mice. Once the tumor grew to 100 mm(3), daily EMF treatments were started by placing the cage of mice within the EMF field. Treatment ranged from 10 to 20 milli-Tesla (mT) and was given for 3 to 80 minutes either once or twice a day for 12 days. Tumors were measured and volumes calculated each 3-4 days. Therapeutic EMF treatment significantly suppressed tumor growth in all 7 EMF treated groups. Exposure to 20mT for 10 minutes twice a day was the most effective tumor growth suppressor. The effect of EMF treatment on extent of tumor vascularization, necrosis and viable area was determined after euthanasia. The EMF reduced the vascular (CD31 immunohistochemically positive) volume fraction and increased the necrotic volume of the tumor. Treatment with 15 mT for 10 min/d gave the maximum anti-angiogenic effect. Lack of a significant correlation between tumor CD 31 positive area and tumor growth rate indicates a mechanism for suppression of tumor growth in addition to suppression of tumor vascularization. It is proposed that EMF therapy aimed at suppression of tumor growth and vascularization may prove a safe alternative for patients whether they are or are not candidates for conventional cancer therapy.

Measurement of telomerase activity in dog tumors.

PubMed

Yazawa, M; Okuda, M; Setoguchi, A; Nishimura, R; Sasaki, N; Hasegawa, A; Watari, T; Tsujimoto, H

1999-10-01

Telomeres are specific structures present at the end of liner chromosomes. DNA polymerase can not synthesize the end of liner DNA and, as a result, the telomeres become progressively shortened by successive cell divisions. To overcome the end replication problem, telomerase adds new telomeric sequences to the end of chromosomal DNA. The enzyme activity is undetectable in most normal human adult somatic cells, in which shortening of the telomere is thought to limit the somatic-cell life span. In contrast to normal somatic cells, many human tumors possess telomerase activity. The present study looked at whether telomerase activity might serve as a marker for canine tumors. Telomerase activity was measured using the telomeric repeat amplification protocol assay. Normal dog somatic tissues showed little or no telomerase activity, while normal testis exhibited a high level of telomerase activity. We measured telomerase activity in tumor samples from 45 dogs; 21 mammary gland tumors, 16 tumors developed in the skin and oral cavity, 7 vascular tumors and 1 Sertoli cell tumor. Greater than 95% of the tumor samples contained telomerase activity (3-924 U/2 micrograms protein). The results obtained in this study indicated that telomerase should be a useful diagnostic marker for a variety of dog tumors, and it may serve as a target for antitumor chemotherapy.

Macrophages inhibit human osteosarcoma cell growth after activation with the bacterial cell wall derivative liposomal muramyl tripeptide in combination with interferon-γ.

PubMed

Pahl, Jens H W; Kwappenberg, Kitty M C; Varypataki, Eleni M; Santos, Susy J; Kuijjer, Marieke L; Mohamed, Susan; Wijnen, Juul T; van Tol, Maarten J D; Cleton-Jansen, Anne-Marie; Egeler, R Maarten; Jiskoot, Wim; Lankester, Arjan C; Schilham, Marco W

2014-03-10

In osteosarcoma, the presence of tumor-infiltrating macrophages positively correlates with patient survival in contrast to the negative effect of tumor-associated macrophages in patients with other tumors. Liposome-encapsulated muramyl tripeptide (L-MTP-PE) has been introduced in the treatment of osteosarcoma patients, which may enhance the potential anti-tumor activity of macrophages. Direct anti-tumor activity of human macrophages against human osteosarcoma cells has not been described so far. Hence, we assessed osteosarcoma cell growth after co-culture with human macrophages. Monocyte-derived M1-like and M2-like macrophages were polarized with LPS + IFN-γ, L-MTP-PE +/- IFN-γ or IL-10 and incubated with osteosarcoma cells. Two days later, viable tumor cell numbers were analyzed. Antibody-dependent effects were investigated using the therapeutic anti-EGFR antibody cetuximab. M1-like macrophages inhibited osteosarcoma cell growth when activated with LPS + IFN-γ. Likewise, stimulation of M1-like macrophages with liposomal muramyl tripeptide (L-MTP-PE) inhibited tumor growth, but only when combined with IFN-γ. Addition of the tumor-reactive anti-EGFR antibody cetuximab did not further improve the anti-tumor activity of activated M1-like macrophages. The inhibition was mediated by supernatants of activated M1-like macrophages, containing TNF-α and IL-1β. However, specific blockage of these cytokines, nitric oxide or reactive oxygen species did not inhibit the anti-tumor effect, suggesting the involvement of other soluble factors released upon macrophage activation. While LPS + IFN-γ-activated M2-like macrophages had low anti-tumor activity, IL-10-polarized M2-like macrophages were able to reduce osteosarcoma cell growth in the presence of the anti-EGFR cetuximab involving antibody-dependent tumor cell phagocytosis. This study demonstrates that human macrophages can be induced to exert direct anti-tumor activity against osteosarcoma cells. Our

Influence of histamine and serotonin antagonists on the growth of xenografted human colorectal tumors.

PubMed

Barkla, D H; Tutton, P J

1981-12-01

Four lines of human colorectal cancer were established and serially propagated as subcutaneous xenographs in immunosuppressed inbred CBA/Lac mice. Established xenografts were then used to investigate the influence of a serotonin antagonist (BW 501c) and a histamine H2 receptor antagonists (Cimetidine) on xenograft growth. The growth of each of the four tumor lines was significantly inhibited by BW 501c throughout the treatment, whereas the growth of only two tumor lines was significantly inhibited by Cimetidine treatment. The response of individual tumor lines was not predictable on the basis of either tumor histopathology or the natural growth rate of the untreated xenograft. A number of alternative, but not mutually exclusive, hypotheses are suggested to explain the results. One hypothesis proposes that colorectal tumors are composed of subpopulations of tumor cells that are variously dependent on or independent of amine hormones. Another hypothesis is that tumor cells exhibit temporal changes in hormone sensitivity to amine hormones during treatment. Finally, it is suggested that serotonin and/or histamine H2 antagonists may be useful in preventing the repopulation of colorectal carcinomas following antineoplastic therapy with the use of conventional drugs.

The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

PubMed Central

Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav; Pomerantz, Jason H

2015-01-01

The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species’ regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF –p53 axis activation. DOI: http://dx.doi.org/10.7554/eLife.07702.001 PMID:26575287

Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeda, Tomoya; Tsubaki, Masanobu; Sakamoto, Kotar

Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa Bmore » kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma. - Highlights: • Mangiferin prolongs survival in mice by inhibiting metastasis and tumor growth • Mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation • Mangiferin regulates the expression of MMPs, VLAs, and apoptosis regulatory proteins.« less

Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells.

PubMed

Yin, Xuyuan; Zhang, Yu; Su, Jingna; Hou, Yingying; Wang, Lixia; Ye, Xiantao; Zhao, Zhe; Zhou, Xiuxia; Li, Yali; Wang, Zhiwei

2016-10-11

Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2 enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer.

Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Wei; Chai, Hongyan; Li, Ying

2012-10-01

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressingmore » cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP

Proton-sensing G protein-coupled receptors as regulators of cell proliferation and migration during tumor growth and wound healing.

PubMed

Weiß, Katharina T; Fante, Matthias; Köhl, Gudrun; Schreml, Julia; Haubner, Frank; Kreutz, Marina; Haverkampf, Sonja; Berneburg, Mark; Schreml, Stephan

2017-02-01

Dysregulation of pH is a feature of both tumor growth and tissue repair. In tumors, microenvironmental changes, like in lactate metabolism, lead to altered intra- and extracellular pH (pH i , pH e ) and vice versa. In wounds, barrier disruption results in extensive variations in pH e on the wound surface. It is known that altered extracellular proton concentrations have a major impact on cell turnover and migration as well as on the metabolic activity of cells involved in tumor spread and wound closure. The proton-sensing G protein-coupled receptors (GPCRs) GPR4, GPR65 (TDAG8), GPR68 (OGR1) and GPR132 (G2A) are activated via a decrease in pH e and transduce this signal to molecular intracellular pathways. Based on the current knowledge, we speculate on the role of proton-sensing GPCRs in wound healing and on their potential as mechanistic linkers of tumor growth and tissue repair. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase.

PubMed

Chitambar, Christopher R; Al-Gizawiy, Mona M; Alhajala, Hisham S; Pechman, Kimberly R; Wereley, Janine P; Wujek, Robert; Clark, Paul A; Kuo, John S; Antholine, William E; Schmainda, Kathleen M

2018-06-01

Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMEC) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) in vitro After 24 hours of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). IHC staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2, and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control ( P = 0.0159) and reduced tumor mitotic figures ( P = 0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals, thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted. Mol Cancer Ther; 17(6); 1240-50. ©2018 AACR . ©2018 American Association for Cancer Research.

Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth.

PubMed

Tu, Shui Ping; Jin, Huanyu; Shi, Jin Dong; Zhu, Li Ming; Suo, Ya; Lu, Gang; Liu, Anna; Wang, Timothy C; Yang, Chung S

2012-02-01

Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis, and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells, and related tumor growth. Treatment with curcumin in the diet or by intraperitoneal injection significantly inhibited tumorigenicity and tumor growth, decreased the percentages of MDSCs in the spleen, blood, and tumor tissues, reduced interleukin (IL)-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine IL-6 by MDSCs in a coculture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs, when MDSCs were cultured in the presence of IL-1β, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results show that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy. ©2011 AACR.

Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth

PubMed Central

Tu, Shui Ping; Jin, Huanyu; Shi, Jin Dong; Zhu, Li Ming; Suo, Ya; Lu, Gang; Liu, Anna; Wang, Timothy C.; Yang, Chung S.

2011-01-01

Myeloid-derived suppressor cells (MDSCs) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells and related tumor growth. Treatment with curcumin in the diet or by i.p. injection significantly inhibited tumorigenecity and tumor growth, decreased the percentages of MDSCs in the spleen, blood and tumor tissues, reduced IL-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine interleukin (IL)-6 by MDSCs in a co-culture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs when MDSCs were cultured in the presence of IL-1β, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results demonstrate that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy. PMID:22030090

DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer.

PubMed

Huang, Lin; Chen, Keng; Cai, Zhao-Peng; Chen, Fu-Chao; Shen, Hui-Yong; Zhao, Wei-Hua; Yang, Song-Jie; Chen, Xu-Biao; Tang, Guo-Xue; Lin, Xi

2017-08-26

DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Acanthus ebracteatus Vahl on tumor angiogenesis and on tumor growth in nude mice implanted with cervical cancer

PubMed Central

Mahasiripanth, Taksanee; Hokputsa, Sanya; Niruthisard, Somchai; Bhattarakosol, Parvapan; Patumraj, Suthiluk

2012-01-01

Purpose The aim of this study was to examine the effects of the crude extract of Acanthus ebracteatus Vahl (AE) on tumor growth and angiogenesis by utilizing a tumor model in which nude mice were implanted with cervical cancer cells containing human papillomavirus 16 DNA (HPV-16 DNA). Materials and methods The growth-inhibitory effect of AE was investigated in four different cell types: CaSki (HPV-16 positive), HeLa (HPV-18 positive), hepatocellular carcinoma cells (HepG2), and human dermal fibroblast cells (HDFs). The cell viabilities and IC50 values of AE were determined in cells incubated with AE for different lengths of time. To conduct studies in vivo, female BALB/c nude mice (aged 6–7 weeks, weighing 20–25 g) were used. A cervical cancer-derived cell line (CaSki) with integrated HPV-16 DNA was injected subcutaneously (1 × 107 cells/200 μL) in the middle dorsum of each animal (HPV group). One week after injection, mice were fed orally with AE crude extract at either 300 or 3000 mg/kg body weight/day for 14 or 28 days (HPV-AE groups). Tumor microvasculature and capillary vascularity were determined using laser scanning confocal microscopy. Tumor tissue was collected from each mouse to evaluate tumor histology and vascular endothelial growth factor (VEGF) immunostaining. Results The time-response curves of AE and the dose-dependent effect of AE on growth inhibition were determined. After a 48-hour incubation period, the IC50 of AE in CaSki was discovered to be significantly different from that of HDFs (P < 0.05). A microvascular network was observed around the tumor area in the HPV group on days 21 and 35. Tumor capillary vascularity in the HPV group was significantly increased compared with the control group (P < 0.001). High-dose treatment of AE extract (HPV-3000AE group) significantly attenuated the increase in VEGF expression and tumor angiogenesis in mice that received either the 14- or 28-day treatment period (P < 0.001). Conclusion Our novel

N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins.

PubMed

Zhao, Guoping; Neely, Aaron M; Schwarzer, Christian; Lu, Huayi; Whitt, Aaron G; Stivers, Nicole S; Burlison, Joseph A; White, Carl; Machen, Terry E; Li, Chi

2016-02-02

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells.

N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins

PubMed Central

Zhao, Guoping; Neely, Aaron M.; Schwarzer, Christian; Lu, Huayi; Whitt, Aaron G.; Stivers, Nicole S.; Burlison, Joseph A.; White, Carl; Machen, Terry E.; Li, Chi

2016-01-01

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells. PMID:26758417

Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth