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Sample records for reducing tumor growth

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

    SciTech Connect

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

    1988-01-01

    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. Keloid 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.

  2. Reduced Tumor Growth after Low-Dose Irradiation or Immunization against Blastic Suppressor T Cells

    NASA Astrophysics Data System (ADS)

    Tilkin, A. F.; Schaaf-Lafontaine, N.; van Acker, A.; Boccadoro, M.; Urbain, J.

    1981-03-01

    Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

  3. Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma

    PubMed Central

    Tham, Muly; Khoo, Karen; Yeo, Kim Pin; Kato, Masashi; Prevost-Blondel, Amelle; Angeli, Veronique; Abastado, Jean-Pierre

    2015-01-01

    Surgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection. PMID:25762633

  4. Inhibition of melanocortin 1 receptor slows melanoma growth, reduces tumor heterogeneity and increases survival.

    PubMed

    Kansal, Rita G; McCravy, Matthew S; Basham, Jacob H; Earl, Joshua A; McMurray, Stacy L; Starner, Chelsey J; Whitt, Michael A; Albritton, Lorraine M

    2016-05-01

    Melanoma risk is increased in patients with mutations of melanocortin 1 receptor (MC1R) yet the basis for the increased risk remains unknown. Here we report in vivo evidence supporting a critical role for MC1R in regulating melanoma tumor growth and determining overall survival time. Inhibition of MC1R by its physiologically relevant competitive inhibitor, agouti signaling protein (ASIP), reduced melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. In the lungs of syngeneic C57BL/6 mice, mCherry-marked, ASIP-secreting lung tumors inhibited MC1R on neighboring tumors lacking ASIP in a dose dependent manner as evidenced by a proportional loss of pigment in tumors from mice injected with 1:1, 3:1 and 4:1 mixtures of parental B16-F10 to ASIP-expressing tumor cells. ASIP-expressing B16-F10 cells formed poorly pigmented tumors in vivo that correlated with a 20% longer median survival than those bearing parental B16-F10 tumors (p=0.0005). Mice injected with 1:1 mixtures also showed survival benefit (p=0.0054), whereas injection of a 4:1 mixture showed no significant difference in survival. The longer survival time of mice bearing ASIP-expressing tumors correlated with a significantly slower growth rate than parental B16-F10 tumors as judged by quantification of numbers of tumors and total tumor load (p=0.0325), as well as a more homogeneous size and morphology of ASIP-expressing lung tumors. We conclude that MC1R plays an important role in regulating melanoma growth and morphology. Persistent inhibition of MC1R provided a significant survival advantage resulting in part from slower tumor growth, establishing MC1R as a compelling new molecular target for metastatic melanoma. PMID:27028866

  5. Inhibition of melanocortin 1 receptor slows melanoma growth, reduces tumor heterogeneity and increases survival

    PubMed Central

    Kansal, Rita G.; McCravy, Matthew S.; Basham, Jacob H.; Earl, Joshua A.; McMurray, Stacy L.; Starner, Chelsey J.

    2016-01-01

    Melanoma risk is increased in patients with mutations of melanocortin 1 receptor (MC1R) yet the basis for the increased risk remains unknown. Here we report in vivo evidence supporting a critical role for MC1R in regulating melanoma tumor growth and determining overall survival time. Inhibition of MC1R by its physiologically relevant competitive inhibitor, agouti signaling protein (ASIP), reduced melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. In the lungs of syngeneic C57BL/6 mice, mCherry-marked, ASIP-secreting lung tumors inhibited MC1R on neighboring tumors lacking ASIP in a dose dependent manner as evidenced by a proportional loss of pigment in tumors from mice injected with 1:1, 3:1 and 4:1 mixtures of parental B16-F10 to ASIP-expressing tumor cells. ASIP-expressing B16-F10 cells formed poorly pigmented tumors in vivo that correlated with a 20% longer median survival than those bearing parental B16-F10 tumors (p=0.0005). Mice injected with 1:1 mixtures also showed survival benefit (p=0.0054), whereas injection of a 4:1 mixture showed no significant difference in survival. The longer survival time of mice bearing ASIP-expressing tumors correlated with a significantly slower growth rate than parental B16-F10 tumors as judged by quantification of numbers of tumors and total tumor load (p=0.0325), as well as a more homogeneous size and morphology of ASIP-expressing lung tumors. We conclude that MC1R plays an important role in regulating melanoma growth and morphology. Persistent inhibition of MC1R provided a significant survival advantage resulting in part from slower tumor growth, establishing MC1R as a compelling new molecular target for metastatic melanoma. PMID:27028866

  6. Adiponectin deficiency promotes tumor growth in mice by reducing macrophage infiltration.

    PubMed

    Sun, Yutong; Lodish, Harvey F

    2010-08-05

    Adiponectin is an adipocyte-derived plasma protein that has been implicated in regulating angiogenesis, but the role of adiponectin in regulating this process is still controversial. In this study, in order to determine whether adiponectin affects tumor growth and tumor induced vascularization, we implanted B16F10 melanoma and Lewis Lung Carcinoma cells subcutaneously into adiponectin knockout and wild-type control mice, and found that adiponectin deficiency markedly promoted the growth of both tumors. Immunohistochemical analyses indicated that adiponectin deficiency reduced macrophage recruitment to the tumor, but did not affect cancer cell mitosis, apoptosis, or tumor-associated angiogenesis. In addition, treatment with recombinant adiponectin did not affect the proliferation of cultured B16F10 tumor cells. Importantly, the restoration of microphage infiltration at an early stage of tumorigenesis by means of co-injection of B16F10 cells and macrophages reversed the increased tumor growth in adiponectin knockout mice. Thus, we conclude that the enhanced tumor growth observed in adiponectin deficient mice is likely due to the reduction of macrophage infiltration rather than enhanced angiogenesis.

  7. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice

    PubMed Central

    Esteva-Font, Cristina; Jin, Byung-Ju; Verkman, A. S.

    2014-01-01

    Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1+/+ MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm3 (se, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm3, 12 mice) were greatly reduced in AQP1−/− MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1−/− MMTV-PyVT mice, with reduced vessel density. HIF-1α expression was increased in tumors in AQP1−/− MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1+/+ MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.—Esteva-Font, C., Jin, B.-J., Verkman, A. S. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. PMID:24334548

  8. A ribonuclease inhibitor expresses anti-angiogenic properties and leads to reduced tumor growth in mice.

    PubMed Central

    Polakowski, I. J.; Lewis, M. K.; Muthukkaruppan, V. R.; Erdman, B.; Kubai, L.; Auerbach, R.

    1993-01-01

    Our experiments were designed to determine whether recombinant ribonuclease inhibitor (RNasin) could inhibit angiogenesis and reduce tumor growth in adult mice. We used the Fajardo disc angiogenesis assay as the primary means of measuring new blood vessel growth. This assay measures the penetration of cells into a polyvinyl alcohol sponge with a central core of ELVAX-coated sponge containing test substances. Cell penetration was reduced to 29.3% of control (phosphate-buffered saline; heat-inactivated RNasin) values. Endothelial cell influx was measured by lectin staining and confirmed by culturing cells isolated from sponges by collagenase treatment. RNasin also reduced the augmented reaction evoked by either basic fibroblast growth factor (bFGF) or sodium orthovanadate. To confirm the anti-angiogenic activity of RNasin, Hydron-coated polyvinyl sponges containing bFGF or bFGF plus RNasin were implanted into adult mouse corneas. bFGF induced a strong angiogenic response that was almost completely inhibited by RNasin. RNasin-containing ELVAX-coated sponges implanted subcutaneously underneath an intradermal inoculum of C755 mammary tumor cells caused significant reduction in tumor growth (P < 0.005). The antitumor effect of RNasin correlated with its effect on tumor-induced neovascularization, suggesting that the ability of RNasin to affect tumor growth was due to its ability to inhibit angiogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:7688185

  9. 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. PMID:27435926

  10. Chronic supplementation with shark liver oil for reducing tumor growth and cachexia in walker 256 tumor-bearing rats.

    PubMed

    Iagher, Fabíola; de Brito Belo, Sérgio Ricardo; Naliwaiko, Katya; Franzói, Andressa Machado; de Brito, Gleisson Alisson Pereira; Yamazaki, Ricardo Key; Muritiba, Ana Lúcia; Muehlmann, Luis Alexandre; Steffani, Jovani Antonio; Fernandes, Luiz Cláudio

    2011-11-01

    We investigated the effect of chronic supplementation with shark liver oil (SLO), an antitumor supplement source of n-3 fatty acids and 1-O-alkylglycerols, alone and combined with coconut fat (CF), a source of saturated fatty acids, on Walker 256 tumor growth and cachexia. Male rats were supplemented daily and orally with SLO and/or CF (1 g per kg body weight) for 7 wk. After 7 wk, 50% of animals were subcutaneously inoculated with 3 × 10(7) Walker 256 tumor cells. After 14 days, the rats were killed, the tumors were removed for lipid peroxidation measurement, and blood was collected for glycemia, triacylglycerolemia, and lacticidemia evaluation. Liver samples were obtained for glycogen measurement. Unlike CF, supplementation with SLO promoted gain in body weight, reduction of tumor weight, and maintained glycemia, triacylglycerolemia, lacticidemia, and liver glycogen content to values similar to non-tumor-bearing rats. Combined supplementation of SLO with CF also showed a reversion of cachexia with gain in body mass, reduction of lacticidemia, maintaining the liver glycogen store, and reduction in tumor weight. SLO, alone or combined with CF, promoted increase of tumor lipid peroxidation. In conclusion, SLO supplemented chronically, alone or associated with CF, was able to reduce tumor growth and cachexia.

  11. 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

  12. In vivo Cytokine Gene Transfer by Gene Gun Reduces Tumor Growth in Mice

    NASA Astrophysics Data System (ADS)

    Sun, Wenn H.; Burkholder, Joseph K.; Sun, Jian; Culp, Jerilyn; Turner, Joel; Lu, Xing G.; Pugh, Thomas D.; Ershler, William B.; Yang, Ning-Sun

    1995-03-01

    Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investigators to result in potent in vivo antitumor activities in mice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumorbearing animals by particle-mediated gene transfer. In vivo transfection of the human interleukin 6 gene into the tumor site reduced methylcholanthrene-induced fibrosarcoma growth, and a combination of murine tumor necrosis factor α and interferon γ genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin 2 and interferon γ genes prolonged the survival of Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was demonstrated in treated tissues by ELISA and immunohistochemical analysis. Significant serum levels of interleukin 6 and interferon γ were detected, demonstrating effective secretion of transgenic proteins from treated skin into the bloodstream. This in vivo cytokine gene therapy approach provides a system for evaluating the antitumor properties of various cytokines in different tumor models and has potential utility for human cancer gene therapy.

  13. Mammary tumor growth and metastasis are reduced in c-Kit mutant Sash mice.

    PubMed

    He, Licai; Zhu, Zhenfeng; Chen, Shang; Wang, Yongping; Gu, Haihua

    2016-06-01

    Besides its well-known function in allergic response, mast cell, one of the key immune cells present in tumor microenvironment, plays important roles in cancer progression. However, the functional role of mast cells in breast cancer development and metastasis is not well understood. To test the involvement of mast cells in breast cancer, we examined the effects of loss of mast cells on mammary tumor development by crossing the well-known mast cell deficient mouse strain sash (Kit(W-sh/W-sh) ) with the mammary tumor transgenic mouse strain MMTV-Polyoma Middle T antigen (PyMT). Although mammary tumor onset was not affected in the absence of mast cells, mammary growth and metastasis were reduced in PyMT/Kit(W-sh/W-sh) mice compared with PyMT/wild-type mice (WT). Histological and immunofluorescent analyses showed that tumors from PyMT/Kit(W-sh/W-sh) mice showed largely differentiated morphology with reduced angiogenesis compared with MMTV-PyMT/WT mice. Our results suggest that mast cells may promote breast cancer growth and metastasis. Agents that can block mast cells growth are potential new therapies to treat metastatic breast cancer. PMID:26992445

  14. TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation

    PubMed Central

    Atretkhany, Kamar-Sulu N.; Nosenko, Maxim A.; Gogoleva, Violetta S.; Zvartsev, Ruslan V.; Qin, Zhihai; Nedospasov, Sergei A.; Drutskaya, Marina S.

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo. PMID:27148266

  15. Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis.

    PubMed

    Merk, Henriette; Zhang, Siwei; Lehr, Thorsten; Müller, Christoph; Ulrich, Melanie; Bibb, James A; Adams, Ralf H; Bracher, Franz; Zahler, Stefan; Vollmar, Angelika M; Liebl, Johanna

    2016-02-01

    Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy. PMID:26755662

  16. Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis

    PubMed Central

    Merk, Henriette; Zhang, Siwei; Lehr, Thorsten; Müller, Christoph; Ulrich, Melanie; Bibb, James A.; Adams, Ralf H.; Bracher, Franz; Zahler, Stefan; Vollmar, Angelika M.; Liebl, Johanna

    2016-01-01

    Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy. PMID:26755662

  17. Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis.

    PubMed

    Merk, Henriette; Zhang, Siwei; Lehr, Thorsten; Müller, Christoph; Ulrich, Melanie; Bibb, James A; Adams, Ralf H; Bracher, Franz; Zahler, Stefan; Vollmar, Angelika M; Liebl, Johanna

    2016-02-01

    Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy.

  18. Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion

    PubMed Central

    Alonso, Florian; Domingos-Pereira, Sonia; Le Gal, Loïc; Derré, Laurent; Meda, Paolo; Jichlinski, Patrice; Nardelli-Haefliger, Denise; Haefliger, Jacques-Antoine

    2016-01-01

    Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40−/−), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40−/− but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40−/− mice. As a result, Cx40−/− mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment. PMID:26883111

  19. Selective expression of constitutively active pro-apoptotic protein BikDD gene in primary mammary tumors inhibits tumor growth and reduces tumor initiating cells.

    PubMed

    Rahal, Omar M; Nie, Lei; Chan, Li-Chuan; Li, Chia-Wei; Hsu, Yi-Hsin; Hsu, Jennifer; Yu, Dihua; Hung, Mien-Chie

    2015-01-01

    standard toxicity assays or body weight changes. Taken together, our findings validated that selective expression of BikDD in the primary mammary tumors in immunocompetent hosts significantly reduced tumor burden and inhibited the residual tumor growth at off-therapy stage by eliminating TICs. Hence, the VISA-Claudin4-BikDD-mediated gene therapy is worthy of further investigation in breast cancer clinical trials. PMID:26885451

  20. Mice lacking NCF1 exhibit reduced growth of implanted melanoma and carcinoma tumors.

    PubMed

    Kelkka, Tiina; Pizzolla, Angela; Laurila, Juha Petteri; Friman, Tomas; Gustafsson, Renata; Källberg, Eva; Olsson, Olof; Leanderson, Tomas; Rubin, Kristofer; Salmi, Marko; Jalkanen, Sirpa; Holmdahl, Rikard

    2013-01-01

    The NADPH oxidase 2 (NOX2) complex is a professional producer of reactive oxygen species (ROS) and is mainly expressed in phagocytes. While the activity of the NOX2 complex is essential for immunity against pathogens and protection against autoimmunity, its role in the development of malignant tumors remains unclear. We compared wild type and Ncf1 (m1J) mutated mice, which lack functional NOX2 complex, in four different tumor models. Ncf1 (m1J) mutated mice developed significantly smaller tumors in two melanoma models in which B16 melanoma cells expressing a hematopoietic growth factor FLT3L or luciferase reporter were used. Ncf1 (m1J) mutated mice developed significantly fewer Lewis Lung Carcinoma (LLC) tumors, but the tumors that did develop, grew at a pace that was similar to the wild type mice. In the spontaneously arising prostate carcinoma model (TRAMP), tumor growth was not affected. The lack of ROS-mediated protection against tumor growth was associated with increased production of immunity-associated cytokines. A significant increase in Th2 associated cytokines was observed in the LLC model. Our present data show that ROS regulate rejection of the antigenic B16-luc and LLC tumors, whereas the data do not support a role for ROS in growth of intrinsically generated tumors. PMID:24358335

  1. Flaxseed oil enhances the effectiveness of trastuzumab in reducing the growth of HER2-overexpressing human breast tumors (BT-474).

    PubMed

    Mason, Julie K; Fu, Minghua; Chen, Jianmin; Thompson, Lilian U

    2015-01-01

    Flaxseed oil (FSO) reduces breast tumorigenesis and HER2 expression in animal models of luminal breast cancer. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). We aimed to determine the effect of 4% FSO alone and combined with TRAS on HER2-overexpressing tumor (BT-474) growth and to explore potential mechanisms with a specific focus on HER2, mitogen-activated protein kinase (MAPK) and Akt signaling and fatty acid profile. Athymic mice with established tumors were fed the basal diet (control) or 4% FSO diet, with or without TRAS (1 or 2.5 mg/kg) treatment for 4 weeks. Tumor growth, HER2 signaling biomarkers (mRNA and protein) and fatty acid profile were measured. Tumors treated with FSO alone showed no difference in tumor growth compared to control; however, compared to TRAS2.5 and other groups, FSO+TRAS2.5 caused significantly lower tumor growth and cell proliferation and higher apoptosis and the greatest lowering of signaling biomarker expressions (MAPK2, HER2 mRNA; pHER2 protein). Both TRAS and FSO had main effects of reducing the phosphorylated/total expression of Akt and MAPK protein expression. Dietary FSO altered the tumor fatty acid profile. In conclusion, 4% dietary FSO alone does not affect BT-474 tumor growth but enhances the tumor-reducing effect of TRAS (2.5 mg/kg). FSO×TRAS interactive effect may be modulated by their combined reductions of HER2 signaling through the Akt and MAPK pathways leading to reduced cell proliferation and increased apoptosis. FSO alters tumor fatty acid profile that likely contributes to effects on signaling pathways. This supports FSO as a complementary treatment for HER2+ breast cancer treated with TRAS.

  2. Dietary intake of a plant phospholipid/lipid conjugate reduces lung cancer growth and tumor angiogenesis

    PubMed Central

    Jensen-Taubman, Sandra; Rubinstein, Danielle; Viole, Gary; Stetler-Stevenson, William G.

    2014-01-01

    It is well recognized that early detection and cancer prevention are significant armaments in the ‘war against cancer’. Changes in lifestyle and diet have significant impact on the global incidence of cancer. For over 30 years, many investigators have studied the concept of chemoprevention. More recently, with the demonstration that antiangiogenic activity reduces tumor growth, the concept of angioprevention has emerged as a novel strategy in the deterrence of cancer development (carcinogenesis). In this study, we utilized a fast growing, highly aggressive murine Lewis lung cancer model to examine the in vivo antitumor effects of a novel, dietary supplement, known as plant phospholipid/lipid conjugate (pPLC). Our goal was to determine if pPLC possessed direct antitumor activity with relatively little toxicity that could be developed as a chemoprevention therapy. We used pPLC directly in this in vivo model due to the lack of aqueous solubility of this novel formulation, which precludes in vitro experimentation. pPLC contains known antioxidants, ferulic acid and lipoic acid, as well as soy sterols, formulated in a unique aqueous-insoluble matrix. The pPLC dietary supplement was shown to suppress in vivo growth of this tumor model by 30%. We also demonstrated a significant decrease in tumor angiogenesis accompanied by increased apoptosis and present preliminary evidence of enhanced expression of the hypoxia-related genes pentraxin-3 and metallothionein-3, by 24.9-fold and 10.9-fold, respectively, compared with vehicle control. These findings lead us to propose using this plant phosolipid/lipid conjugate as a dietary supplement that may be useful in cancer prevention. PMID:24510111

  3. Dietary intake of a plant phospholipid/lipid conjugate reduces lung cancer growth and tumor angiogenesis.

    PubMed

    Shuman Moss, Laurie A; Jensen-Taubman, Sandra; Rubinstein, Danielle; Viole, Gary; Stetler-Stevenson, William G

    2014-07-01

    It is well recognized that early detection and cancer prevention are significant armaments in the 'war against cancer'. Changes in lifestyle and diet have significant impact on the global incidence of cancer. For over 30 years, many investigators have studied the concept of chemoprevention. More recently, with the demonstration that antiangiogenic activity reduces tumor growth, the concept of angioprevention has emerged as a novel strategy in the deterrence of cancer development (carcinogenesis). In this study, we utilized a fast growing, highly aggressive murine Lewis lung cancer model to examine the in vivo antitumor effects of a novel, dietary supplement, known as plant phospholipid/lipid conjugate (pPLC). Our goal was to determine if pPLC possessed direct antitumor activity with relatively little toxicity that could be developed as a chemoprevention therapy. We used pPLC directly in this in vivo model due to the lack of aqueous solubility of this novel formulation, which precludes in vitro experimentation. pPLC contains known antioxidants, ferulic acid and lipoic acid, as well as soy sterols, formulated in a unique aqueous-insoluble matrix. The pPLC dietary supplement was shown to suppress in vivo growth of this tumor model by 30%. We also demonstrated a significant decrease in tumor angiogenesis accompanied by increased apoptosis and present preliminary evidence of enhanced expression of the hypoxia-related genes pentraxin-3 and metallothionein-3, by 24.9-fold and 10.9-fold, respectively, compared with vehicle control. These findings lead us to propose using this plant phosolipid/lipid conjugate as a dietary supplement that may be useful in cancer prevention. PMID:24510111

  4. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

    SciTech Connect

    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  5. Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs.

    PubMed

    Halvorsen, E C; Hamilton, M J; Young, A; Wadsworth, B J; LePard, N E; Lee, H N; Firmino, N; Collier, J L; Bennewith, K L

    2016-06-01

    Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.

  6. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    PubMed

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. PMID:21220492

  7. Flaxseed oil reduces the growth of human breast tumors (MCF-7) at high levels of circulating estrogen.

    PubMed

    Truan, Jennifer S; Chen, Jian-Min; Thompson, Lilian U

    2010-10-01

    Flaxseed (FS) has been shown to attenuate mammary tumorigenesis, possibly due to its high α-linolenic acid (ALA)-rich oil (FSO) content. This study determined the effect of FSO on the growth of estrogen receptor-positive human breast tumors (MCF-7) in ovariectomized athymic mice at high premenopausal-like estrogen (E2) levels. Mice with established MCF-7 tumors were fed basal diet (control) or basal diet supplemented with FSO (40 g/kg) for 8 wks. Compared with control, FSO reduced tumor size (33%, p<0.05) and tumor cell proliferation (38%, p<0.05) and increased apoptosis (110%, p<0.001). FSO also reduced human epidermal growth factor receptor-2 (79%, p<0.05) and epidermal growth factor receptor (57%, p=0.057) expression, which then may have led to a reduction in Akt (54%, p<0.05) and phosphorylation of mitogen-activated protein kinase (MAPK) to phosphorylated MAPK (pMAPK, 28%, p<0.05). Insulin-like growth factor-1 receptor, vascular endothelial growth factor receptor, MAPK and phosphorylated Akt were not affected. FSO increased (p<0.001) serum ALA, eicosapentaenoic acid and docosahexaenoic acid and, in vitro, ALA reduced MCF-7 cell proliferation (33%, p<0.001). Thus, FSO regressed estrogen receptor-positive human breast tumorigenesis at high E2 levels via downregulation of the growth factor mediated pathway, likely through its ALA content, and may explain the anti-tumorigenicity of FS.

  8. Small-molecule inhibition of PTPRZ reduces tumor growth in a rat model of glioblastoma

    PubMed Central

    Fujikawa, Akihiro; Nagahira, Asako; Sugawara, Hajime; Ishii, Kentaro; Imajo, Seiichi; Matsumoto, Masahito; Kuboyama, Kazuya; Suzuki, Ryoko; Tanga, Naomi; Noda, Masanori; Uchiyama, Susumu; Tomoo, Toshiyuki; Ogata, Atsuto; Masumura, Makoto; Noda, Masaharu

    2016-01-01

    Protein tyrosine phosphatase receptor-type Z (PTPRZ) is aberrantly over-expressed in glioblastoma and a causative factor for its malignancy. However, small molecules that selectively inhibit the catalytic activity of PTPRZ have not been discovered. We herein performed an in vitro screening of a chemical library, and identified SCB4380 as the first potent inhibitor for PTPRZ. The stoichiometric binding of SCB4380 to the catalytic pocket was demonstrated by biochemical and mass spectrometric analyses. We determined the crystal structure of the catalytic domain of PTPRZ, and the structural basis of the binding of SCB4380 elucidated by a molecular docking method was validated by site-directed mutagenesis studies. The intracellular delivery of SCB4380 by liposome carriers inhibited PTPRZ activity in C6 glioblastoma cells, and thereby suppressed their migration and proliferation in vitro and tumor growth in a rat allograft model. Therefore, selective inhibition of PTPRZ represents a promising approach for glioma therapy. PMID:26857455

  9. Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: Reduced tumor growth and increased animal endpoint survival in a small animal tumor model

    PubMed Central

    Yang, Wei; Ahmed, Muneeb; Tasawwar, Beenish; Levchenko, Tatynana; Sawant, Rupa R.; Torchilin, Vladimir; Goldberg, S. Nahum

    2012-01-01

    Background To investigate the effect of IV liposomal quercetin (a known down-regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model. Methods Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3–1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70°C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan-Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint. Results Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5±2.2 days for the control group, 16.6±2.9 days for tumors treated with RF alone, 15.5±2.1days for tumors treated with liposomal quercetin alone, and 22.0±3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3±20.4 days), followed by RF/doxorubicin (29.9±3.8 days). Conclusions IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post-ablation processes with multi-drug nanotherapies can increase overall ablation efficacy. PMID:22230341

  10. Nonlinear simulation of tumor growth.

    PubMed

    Cristini, Vittorio; Lowengrub, John; Nie, Qing

    2003-03-01

    We study solid tumor ( carcinoma) growth in the nonlinear regime using boundary-integral simulations. The tumor core is nonnecrotic and no inhibitor chemical species are present. A new formulation of the classical models [18,24,8,3] is developed and it is demonstrated that tumor evolution is described by a reduced set of two dimensionless parameters and is qualitatively unaffected by the number of spatial dimensions. One parameter describes the relative rate of mitosis to the relaxation mechanisms (cell mobility and cell-to-cell adhesion). The other describes the balance between apoptosis (programmed cell-death) and mitosis. Both parameters also include the effect of vascularization. Our analysis and nonlinear simulations reveal that the two new dimensionless groups uniquely subdivide tumor growth into three regimes associated with increasing degrees of vascularization: low (diffusion dominated, e.g., in vitro), moderate and high vascularization, that correspond to the regimes observed in vivo. We demonstrate that critical conditions exist for which the tumor evolves to nontrivial dormant states or grows self-similarly (i.e., shape invariant) in the first two regimes. This leads to the possibility of shape control and of controlling the release of tumor angiogenic factors by restricting the tumor volume-to-surface-area ratio. Away from these critical conditions, evolution may be unstable leading to invasive fingering into the external tissues and to topological transitions such as tumor breakup and reconnection. Interestingly we find that for highly vascularized tumors, while they grow unbounded, their shape always stays compact and invasive fingering does not occur. This is in agreement with recent experimental observations [30] of in vivo tumor growth, and suggests that the invasive growth of highly-vascularized tumors is associated to vascular and elastic anisotropies, which are not included in the model studied here.

  11. Inhibition of vimentin or B1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

    SciTech Connect

    Zhang, Xueping; Fournier, Marcia V; Ware, Joy L; Bissell, Mina J; Yacoub, Adly; Zehner, Zendra E

    2008-06-12

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin, or {alpha}6 and {beta}1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of {alpha}6 and {beta}1 integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and {beta}1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis. [Mol Cancer Ther 2009;8(3):499-508].

  12. Dual Inhibition of Epidermal Growth Factor Receptor and Insulin-like Growth Factor Receptor I Reduces Angiogenesis and Tumor Growth in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Galer, Chad E.; Corey, Christina L.; Wang, Zhuoying; Younes, Maher N.; Gomez-Rivera, Fernando; Jasser, Samar A.; Ludwig, Dale L.; El-Naggar, Adel K.; Weber, Randal S.; Myers, Jeffrey N.

    2010-01-01

    Purpose Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. The majority of the ~250,000 cases occurring annually in the United States are small, non-aggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and have increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve outcomes for patients with aggressive CSCC. Experimental Design We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-IGF-IR antibody, A12, alone or in combination with an anti-EGF-R antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC. Results Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of SCC cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) as well as increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92% respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = 0.044 and p < 0.001 respectively). Conclusions These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC. PMID:20848439

  13. Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition

    PubMed Central

    Zhang, Yi; Hoda, Md Nasrul; Zheng, Xuan; Li, Weiguo; Luo, Pengcheng; Maddipati, Krishna Rao; Seki, Tsugio; Ergul, Adviye

    2014-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE), Cyp4a-derived eicosanoid, is a lipid mediator that promotes tumor growth, as well as causing detrimental effects in cerebral circulation. We determined whether concurrent inhibition of cyclooxygenase-2 (COX-2) and 20-HETE affects colon tumor growth and ischemic stroke outcomes. The expression of Cyp4a and COXs and production of 20-HETE and PGE2 were determined in murine colon carcinoma (MC38) cells. We then examined the effects of combined treatment with rofecoxib, a potent COX-2 inhibitor, and HET0016, a potent Cyp4a inhibitor, on the growth and proliferation of MC38 cells. Subsequently, we tested the effects of HET0016 plus rofecoxib in MC38 tumor and ischemic stroke models. Cyp4a and COXs are highly expressed in MC38 cells. Respectively, HET0016 and rofecoxib inhibited 20-HETE and PGE2 formation in MC38 cells. Moreover, rofecoxib combined with HET0016 had greater inhibitory effects on the growth and proliferation of MC38 cells than did rofecoxib alone. Importantly, rofecoxib combined with HET0016 provided greater inhibition on tumor growth than did rofecoxib alone in MC38 tumor-bearing mice. Prolonged treatment with rofecoxib selectively induced circulating 20-HETE levels and caused cerebrovascular damage after ischemic stroke, whereas therapy with rofecoxib and HET0016 attenuated 20-HETE levels and reduced rofecoxib-induced cerebrovascular damage and stroke outcomes during anti-tumor therapy. Thus these results demonstrate that combination therapy with rofecoxib and HET0016 provides a new treatment of colon tumor, which can not only enhance the anti-tumor efficacy of rofecoxib, but also reduce rofecoxib-induced cerebrovascular damage and stroke outcomes. PMID:24990856

  14. Elimination of B-RAF in Oncogenic C-RAF-expressing Alveolar Epithelial Type II Cells Reduces MAPK Signal Intensity and Lung Tumor Growth*

    PubMed Central

    Zanucco, Emanuele; El-Nikhely, Nefertiti; Götz, Rudolf; Weidmann, Katharina; Pfeiffer, Verena; Savai, Rajkumar; Seeger, Werner; Ullrich, Axel; Rapp, Ulf R.

    2014-01-01

    Tumors are often greatly dependent on signaling cascades promoting cell growth or survival and may become hypersensitive to inactivation of key components within these signaling pathways. Ras and RAF mutations found in human cancer confer constitutive activity to these signaling molecules thereby converting them into an oncogenic state. RAF dimerization is required for normal Ras-dependent RAF activation and is required for the oncogenic potential of mutant RAFs. Here we describe a new mouse model for lung tumor development to investigate the role of B-RAF in oncogenic C-RAF-mediated adenoma initiation and growth. Conditional elimination of B-RAF in C-RAF BxB-expressing embryonic alveolar epithelial type II cells did not block adenoma formation. However, loss of B-RAF led to significantly reduced tumor growth. The diminished tumor growth upon B-RAF inactivation was due to reduced cell proliferation in absence of senescence and increased apoptosis. Furthermore, B-RAF elimination inhibited C-RAF BxB-mediated activation of the mitogenic cascade. In line with these data, mutation of Ser-621 in C-RAF BxB abrogated in vitro the dimerization with B-RAF and blocked the ability to activate the MAPK cascade. Taken together these data indicate that B-RAF is an important factor in oncogenic C-RAF-mediated tumorigenesis. PMID:25096573

  15. New Blocking Antibodies against Novel AGR2-C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice

    PubMed Central

    Arumugam, Thiruvengadam; Deng, Defeng; Bover, Laura; Wang, Huamin; Logsdon, Craig D.; Ramachandran, Vijaya

    2015-01-01

    Anterior gradient 2 (AGR2) promotes cancer growth, metastasis and resistance to therapy via unknown mechanisms. We investigated the effects of extracellular AGR2 signaling through the orphan GPI-linked receptor C4.4A in pancreatic ductal adenocarcinoma (PDAC). Proliferation, migration and invasion and apoptosis were measured using colorimetric, Boyden chamber, and fluorescence-activated cell sorting analyses. We developed blocking monoclonal antibodies against AGR2 and C4.4A and tested their effects, along with siRNAs, on cancer cell functions and on orthotopic tumors in nude mice. Extracellular AGR2 stimulated proliferation, migration, invasion and chemoresistance of PDAC cell lines. AGR2 interacted with C4.4A in cell lysates and mixtures of recombinant proteins. Knockdown of C4.4A reduced migration and resistance to gemcitabine. PDAC tissues, but not adjacent healthy pancreatic tissues, expressed high levels of AGR2 and C4.4A. AGR2 signaling through C4.4A required laminins 1 or 5 and integrin β1. Administration of antibodies against AGR2 and C4.4A reduced growth and metastasis and caused regression of aggressive xenograft tumors leading to increased survival of mice. These data support a model in which AGR2 binds and signals via C4.4A in an autocrine loop and promotes the growth of pancreas tumors in mice. Blocking monoclonal antibodies against AGR2 and C4.4A may have therapeutic potential against PDAC. PMID:25646014

  16. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth

    PubMed Central

    Huang, Jianfeng; Li, Lena; Lian, Jihong; Schauer, Silvia; Vesely, Paul W.; Kratky, Dagmar; Hoefler, Gerald; Lehner, Richard

    2016-01-01

    Summary The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh–/– tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh–/– mice. Mechanistically, reduced tumor growth in Ces3/Tgh–/– mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth. PMID:27050512

  17. Spontaneous Preterm Delivery, Particularly with Reduced Fetal Growth, is Associated with DNA Hypomethylation of Tumor Related Genes

    PubMed Central

    Chen, Xinhua; Bai, Guang; Scholl, Theresa O

    2016-01-01

    Background Preterm delivery and sub-optimal fetal growth are associated with each other and affect both mother and infant. Our aim was to determine (i) whether there are detectable differences in DNA methylation between early and late gestation and (ii) whether changes in DNA methylation from entry are associated with spontaneous preterm delivery with and without reduced fetal growth. Methods We conducted a case-control study nested within a large prospective cohort. Gene specific methylation was measured by Methyl-Profiler PCR Array in a Human Breast Cancer Signature Panel of 24 genes from maternal peripheral leukocytes genomic DNA at entry and 3rd trimester (sampled at 16 and 30 weeks of gestation, respectively). Clonal bisulfite DNA sequencing was performed to confirm the changes in selected genes (CYP1B1, GADD45A and CXCL12). Multivariable analysis was used for data analysis. Results There was significantly decrease in DNA methylation in 15 of 24 genes during the 3rd trimester in cases of spontaneous preterm delivery (n=23) as compared to the controls (n=19) (p<0.05–p<0.01 for each gene). Similar results were observed by bisulfite sequencing for 3 genes. The change in DNA methylation between late and early gestation was significantly different in cases (overall decrease in methylation was −4.0 ± 1.5%) compared to the controls (overall increase in methylation was 12.6 ± 2.19%, p<0.0001). A graded pattern of DNA methylation was observed in 15 genes. Cases who delivered preterm with reduced fetal growth had the lowest level of methylation, cases delivering preterm without reduced fetal growth were next and term controls were highest in methylation (p for trend <0.05 to p<0.01 for each gene). Cases of preterm delivery also had significantly lower dietary choline intake. Conclusions These data suggest that epigenetic modification is associated with an increased risk of spontaneous preterm delivery, spontaneous preterm delivery with reduced fetal growth in

  18. Growth as a solid tumor or reduced glucose concentrations in culture reversibly induce CD44-mediated hyaluronan recognition by Chinese hamster ovary cells.

    PubMed Central

    Zheng, Z; Cummings, R D; Pummill, P E; Kincade, P W

    1997-01-01

    The density, molecular isoform, and posttranslational modifications of CD44 can markedly influence growth and metastatic behavior of tumors. Many CD44 functions, including some involving tumors, have been attributed to its ability to recognize hyaluronan (HA). However, only certain CD44-bearing cells bind soluble or immobilized HA. We now show that CD44 made by wild-type Chinese hamster ovary (CHO-K1) cells and a ligand-binding subclone differ with respect to N-linked glycosylation. While both bear CD44 with highly branched, complex-type glycoforms, CD44 expressed by the wild type was more extensively sialylated. CHO-K1 cells which failed to recognize HA when grown in culture gained this ability when grown as a solid tumor and reverted to a non-HA-binding state when returned to culture. The ability of CHO-K1 cells to recognize HA was also reversibly induced when glucose concentrations in the medium were reduced. Glucose restriction influenced CD44-mediated HA binding by many but not all, of a series of murine tumors. Glucose concentrations and glycosylation inhibitors only partially influenced CD44 receptor function on resting murine B lymphocytes. These observations suggest that glucose levels or other local environmental conditions may markedly influence glycosylation pathways used by some tumor cells, resulting in dramatic alteration of CD44-mediated functions. PMID:9276740

  19. Myoglobin tames tumor growth and spread.

    PubMed

    Flögel, Ulrich; Dang, Chi V

    2009-04-01

    Tumor growth is accompanied by tissue hypoxia, but does this reduced oxygen availability promote further tumor expansion, resulting in a vicious cycle? In this issue of the JCI, Galluzzo et al. report that increasing oxygen tension in tumor cells by ectopically expressing the oxygen-binding hemoprotein myoglobin indeed affects tumorigenesis (see the related article beginning on page 865). Tumors derived from cells transfected with myoglobin grew more slowly, were less hypoxic, and were less metastatic. These results will spur further mechanistic inquiry into the role of hypoxia in tumor expansion. PMID:19348046

  20. Myoglobin tames tumor growth and spread.

    PubMed

    Flögel, Ulrich; Dang, Chi V

    2009-04-01

    Tumor growth is accompanied by tissue hypoxia, but does this reduced oxygen availability promote further tumor expansion, resulting in a vicious cycle? In this issue of the JCI, Galluzzo et al. report that increasing oxygen tension in tumor cells by ectopically expressing the oxygen-binding hemoprotein myoglobin indeed affects tumorigenesis (see the related article beginning on page 865). Tumors derived from cells transfected with myoglobin grew more slowly, were less hypoxic, and were less metastatic. These results will spur further mechanistic inquiry into the role of hypoxia in tumor expansion.

  1. Actin-resistant DNAse I Expression From Oncolytic Adenovirus Enadenotucirev Enhances Its Intratumoral Spread and Reduces Tumor Growth.

    PubMed

    Tedcastle, Alison; Illingworth, Sam; Brown, Alice; Seymour, Leonard W; Fisher, Kerry D

    2016-04-01

    Spread of oncolytic viruses through tumor tissue is essential to effective virotherapy. Interstitial matrix is thought to be a significant barrier to virus particle convection between "islands" of tumor cells. One way to address this is to encode matrix-degrading enzymes within oncolytic viruses, for secretion from infected cells. To test the hypothesis that extracellular DNA provides an important barrier, we assessed the ability of DNase to promote virus spread. Nonreplicating Ad5 vectors expressing actin-resistant DNase (aDNAse I), proteinase K (PK), hyaluronidase (rhPH20), and chondroitinase ABC (CABC) were injected into established DLD human colorectal adenocarcinoma xenografts, transcomplemented with a replicating Ad5 virus. Each enzyme improved oncolysis by the replicating adenovirus, with no evidence of tumor cells being shed into the bloodstream. aDNAse I and rhPH20 hyaluronidase were then cloned into conditionally-replicating group B adenovirus, Enadenotucirev (EnAd). EnAd encoding each enzyme showed significantly better antitumor efficacy than the parental virus, with the aDNAse I-expressing virus showing improved spread. Both DNase and hyaluronidase activity was still measurable 32 days postinfection. This is the first time that extracellular DNA has been implicated as a barrier for interstitial virus spread, and suggests that oncolytic viruses expressing aDNAse I may be promising candidates for clinical translation. PMID:26708004

  2. Actin-resistant DNAse I Expression From Oncolytic Adenovirus Enadenotucirev Enhances Its Intratumoral Spread and Reduces Tumor Growth.

    PubMed

    Tedcastle, Alison; Illingworth, Sam; Brown, Alice; Seymour, Leonard W; Fisher, Kerry D

    2016-04-01

    Spread of oncolytic viruses through tumor tissue is essential to effective virotherapy. Interstitial matrix is thought to be a significant barrier to virus particle convection between "islands" of tumor cells. One way to address this is to encode matrix-degrading enzymes within oncolytic viruses, for secretion from infected cells. To test the hypothesis that extracellular DNA provides an important barrier, we assessed the ability of DNase to promote virus spread. Nonreplicating Ad5 vectors expressing actin-resistant DNase (aDNAse I), proteinase K (PK), hyaluronidase (rhPH20), and chondroitinase ABC (CABC) were injected into established DLD human colorectal adenocarcinoma xenografts, transcomplemented with a replicating Ad5 virus. Each enzyme improved oncolysis by the replicating adenovirus, with no evidence of tumor cells being shed into the bloodstream. aDNAse I and rhPH20 hyaluronidase were then cloned into conditionally-replicating group B adenovirus, Enadenotucirev (EnAd). EnAd encoding each enzyme showed significantly better antitumor efficacy than the parental virus, with the aDNAse I-expressing virus showing improved spread. Both DNase and hyaluronidase activity was still measurable 32 days postinfection. This is the first time that extracellular DNA has been implicated as a barrier for interstitial virus spread, and suggests that oncolytic viruses expressing aDNAse I may be promising candidates for clinical translation.

  3. Reduced 64Cu Uptake and Tumor Growth Inhibition by Knockdown of Human Copper Transporter 1 in Xenograft Mouse Model of Prostate Cancer

    PubMed Central

    Cai, Huawei; Wu, Jiu-sheng; Muzik, Otto; Hsieh, Jer-Tsong; Lee, Robert J.; Peng, Fangyu

    2015-01-01

    Copper is an element required for cell proliferation and angiogenesis. Human prostate cancer xenografts with increased 64Cu radioactivity were visualized previously by PET using 64CuCl2 as a radiotracer (64CuCl2 PET). This study aimed to determine whether the increased tumor 64Cu radioactivity was due to increased cellular uptake of 64Cu mediated by human copper transporter 1 (hCtr1) or simply due to nonspecific binding of ionic 64CuCl2 to tumor tissue. In addition, the functional role of hCtr1 in proliferation of prostate cancer cells and tumor growth was also assessed. Methods A lentiviral vector encoding short-hairpin RNA specific for hCtr1 (Lenti-hCtr1-shRNA) was constructed for RNA interference–mediated knockdown of hCtr1 expression in prostate cancer cells. The degree of hCtr1 knockdown was determined by Western blot, and the effect of hCtr1 knockdown on copper uptake and proliferation were examined in vitro by cellular 64Cu uptake and cell proliferation assays. The effects of hCtr1 knockdown on tumor uptake of 64Cu were determined by PET quantification and tissue radioactivity assay. The effects of hCtr1 knockdown on tumor growth were assessed by PET/CT and tumor size measurement with a caliper. Results RNA interference–mediated knockdown of hCtr1 was associated with the reduced cellular uptake of 64Cu and the suppression of prostate cancer cell proliferation in vitro. At 24 h after intravenous injection of the tracer 64CuCl2, the 64Cu uptake by the tumors with knockdown of hCtr1 (4.02 ± 0.31 percentage injected dose per gram [%ID/g] in Lenti-hCtr1-shRNA-PC-3 and 2.30 ± 0.59 %ID/g in Lenti-hCtr1-shRNA-DU-145) was significantly lower than the 64Cu uptake by the control tumors without knockdown of hCtr1 (7.21 ± 1.48 %ID/g in Lenti-SCR-shRNA-PC-3 and 5.57 ± 1.20 % ID/g in Lenti-SCR-shRNA-DU-145, P < 0.001) by PET quantification. Moreover, the volumes of prostate cancer xenograft tumors with knockdown of hCtr1 (179 ± 111 mm3 for Lenti-hCtr1-shRNA-PC-3

  4. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice

    PubMed Central

    Xia, Yujing; He, Lei; Chen, Kan; Li, Jingjing; Li, Sainan; Liu, Tong; Zheng, Yuanyuan; Wang, Jianrong; Lu, Wenxia; Zhou, Yuqing; Yin, Qin; Abudumijiti, Huerxidan; Chen, Rongxia; Zhang, Rong; Zhou, Li; Zhou, Zheng; Zhu, Rong; Yang, Jing; Wang, Chengfen; Zhang, Huawei; Zhou, Yingqun; Xu, Ling; Guo, Chuanyong

    2015-01-01

    Cancer cells exhibit an altered metabolic phenotype known as the aerobic glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell glycolysis. Aerobic glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression. PMID:25938543

  5. Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth

    PubMed Central

    Cheray, Mathilde; Pacaud, Romain; Nadaradjane, Arulraj; Oliver, Lisa; Vallette, François M; Cartron, Pierre-François

    2016-01-01

    DNA methylation is a fundamental feature of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantage. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. By focusing on interactions existing between DNMT3A and DNMT3A-binding protein (D3A-BP), our work identifies the DNMT3A/ISGF3γ interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response to the conventional chemotherapeutic treatment of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the disruption of DNMT3A/ISGF3γ interactions increases the efficiency of chemotherapeutic treatment on established tumors in mice. Thus, our data opens a promising and innovative alternative to the development of specific DNMT inhibitors. PMID:27698935

  6. Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth

    PubMed Central

    Cheray, Mathilde; Pacaud, Romain; Nadaradjane, Arulraj; Oliver, Lisa; Vallette, François M; Cartron, Pierre-François

    2016-01-01

    DNA methylation is a fundamental feature of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantage. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. By focusing on interactions existing between DNMT3A and DNMT3A-binding protein (D3A-BP), our work identifies the DNMT3A/ISGF3γ interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response to the conventional chemotherapeutic treatment of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the disruption of DNMT3A/ISGF3γ interactions increases the efficiency of chemotherapeutic treatment on established tumors in mice. Thus, our data opens a promising and innovative alternative to the development of specific DNMT inhibitors.

  7. Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

    PubMed Central

    Gremonprez, Félix; Descamps, Benedicte; Izmer, Andrei; Vanhove, Christian; Vanhaecke, Frank; De Wever, Olivier; Ceelen, Wim

    2015-01-01

    Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible. PMID:26375674

  8. Role of mast cells in tumor growth.

    PubMed

    Conti, Pio; Castellani, Maria L; Kempuraj, Durasamy; Salini, Vincenzo; Vecchiet, Jacopo; Tetè, Stefano; Mastrangelo, Filiberto; Perrella, Alessandro; De Lutiis, Maria Anna; Tagen, Michael; Theoharides, Theoharis C

    2007-01-01

    The growth of malignant tumors is determined in large part by the proliferative capacity of the tumor cells. Clinical observations and animal experiments have established that tumor cells elicit immune responses. Histopathologic studies show that many tumors are surrounded by mononuclear cell and mast cell infiltrates. Mast cells are ubiquitous in the body and are critical for allergic reactions. Increasing evidence indicates that mast cells secrete proinflammatory cytokines and are involved in neuro-inflammatory processes and cancer. Mast cells accumulate in the stroma surrounding certain tumors, especially mammary adenocarcinoma, and the molecules they secrete can benefit the tumor. However, mast cells can also increase at the site of tumor growth and participate in tumor rejection. Mast cells may be recruited by tumor-derived chemoattractants and selectively secrete molecules such as growth factors, histamine, heparin, VEGF, and IL-8, as well as proteases that permit the formation of new blood vessels and metastases. Tumor mast cell intersections play regulatory and modulatory roles affecting various aspects of tumor growth. Discovery of these new roles of mast cells further complicates the understanding of tumor growth. This review focuses on the strategic importance of mast cells to the progression of tumors, and proposes a revised immune effector mechanism of mast cell involvement in tumor growth. PMID:18000287

  9. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    PubMed Central

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

    2009-01-01

    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 subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET 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 co-localization 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. PMID:19179545

  10. Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model

    PubMed Central

    Selvi, Ruthrotha B.; Swaminathan, Amrutha; Chatterjee, Snehajyoti; Shanmugam, Muthu K.; Li, Feng; Ramakrishnan, Gowsica B.; Siveen, Kodappully Sivaraman; Chinnathambi, Arunachalam; Zayed, M. Emam; Alharbi, Sulaiman Ali; Basha, Jeelan; Bhat, Akshay; Vasudevan, Madavan; Dharmarajan, Arunasalam; Sethi, Gautam; Kundu, Tapas K.

    2015-01-01

    Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up-regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing. PMID:26517526

  11. Image based modeling of tumor growth.

    PubMed

    Meghdadi, N; Soltani, M; Niroomand-Oscuii, H; Ghalichi, F

    2016-09-01

    Tumors are a main cause of morbidity and mortality worldwide. Despite the efforts of the clinical and research communities, little has been achieved in the past decades in terms of improving the treatment of aggressive tumors. Understanding the underlying mechanism of tumor growth and evaluating the effects of different therapies are valuable steps in predicting the survival time and improving the patients' quality of life. Several studies have been devoted to tumor growth modeling at different levels to improve the clinical outcome by predicting the results of specific treatments. Recent studies have proposed patient-specific models using clinical data usually obtained from clinical images and evaluating the effects of various therapies. The aim of this review is to highlight the imaging role in tumor growth modeling and provide a worthwhile reference for biomedical and mathematical researchers with respect to tumor modeling using the clinical data to develop personalized models of tumor growth and evaluating the effect of different therapies.

  12. Image based modeling of tumor growth.

    PubMed

    Meghdadi, N; Soltani, M; Niroomand-Oscuii, H; Ghalichi, F

    2016-09-01

    Tumors are a main cause of morbidity and mortality worldwide. Despite the efforts of the clinical and research communities, little has been achieved in the past decades in terms of improving the treatment of aggressive tumors. Understanding the underlying mechanism of tumor growth and evaluating the effects of different therapies are valuable steps in predicting the survival time and improving the patients' quality of life. Several studies have been devoted to tumor growth modeling at different levels to improve the clinical outcome by predicting the results of specific treatments. Recent studies have proposed patient-specific models using clinical data usually obtained from clinical images and evaluating the effects of various therapies. The aim of this review is to highlight the imaging role in tumor growth modeling and provide a worthwhile reference for biomedical and mathematical researchers with respect to tumor modeling using the clinical data to develop personalized models of tumor growth and evaluating the effect of different therapies. PMID:27596102

  13. 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.

  14. Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition

    PubMed Central

    Järvinen, Tero A. H.; Prince, Stuart

    2015-01-01

    Decorin (DCN) is the best characterized member of the extracellular small leucine-rich proteoglycan family present in connective tissues, typically in association with or “decorating” collagen fibrils. It has substantial interest to clinical medicine owing to its antifibrotic, anti-inflammatory, and anticancer effects. Studies on DCN knockout mice have established that a lack of DCN is permissive for tumor development and it is regarded as a tumor suppressor gene. A reduced expression or a total disappearance of DCN has been reported to take place in various forms of human cancers during tumor progression. Furthermore, when used as a therapeutic molecule, DCN has been shown to inhibit tumor progression and metastases in experimental cancer models. DCN affects the biology of various types of cancer by targeting a number of crucial signaling molecules involved in cell growth, survival, metastasis, and angiogenesis. The active sites for the neutralization of different growth factors all reside in different parts of the DCN molecule. An emerging concept that multiple proteases, especially those produced by inflammatory cells, are capable of cleaving DCN suggests that native DCN could be inactivated in a number of pathological inflammatory conditions. In this paper, we review the role of DCN in cancer. PMID:26697491

  15. Cancer Progression and Tumor Growth Kinetics

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Kalpathy-Cramer, Jayashree; Wilkerson, Julia; Sprinkhuizen, Sara; Song, Yi-Qiao; Bates, Susan; Rosen, Bruce; Fojo, Tito

    2013-03-01

    We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed. Work supported by the National Science Foundation and the National Institutes of Health

  16. The Universal Dynamics of Tumor Growth

    PubMed Central

    Brú, Antonio; Albertos, Sonia; Luis Subiza, José; García-Asenjo, José López; Brú, Isabel

    2003-01-01

    Scaling techniques were used to analyze the fractal nature of colonies of 15 cell lines growing in vitro as well as of 16 types of tumor developing in vivo. All cell colonies were found to exhibit exactly the same growth dynamics—which correspond to the molecular beam epitaxy (MBE) universality class. MBE dynamics are characterized by 1), a linear growth rate, 2), the constraint of cell proliferation to the colony/tumor border, and 3), surface diffusion of cells at the growing edge. These characteristics were experimentally verified in the studied colonies. That these should show MBE dynamics is in strong contrast with the currently established concept of tumor growth: the kinetics of this type of proliferation rules out exponential or Gompertzian growth. Rather, a clear linear growth regime is followed. The importance of new cell movements—cell diffusion at the tumor border—lies in the fact that tumor growth must be conceived as a competition for space between the tumor and the host, and not for nutrients or other factors. Strong experimental evidence is presented for 16 types of tumor, the growth of which cell surface diffusion may be the main mechanism responsible in vivo. These results explain most of the clinical and biological features of colonies and tumors, offer new theoretical frameworks, and challenge the wisdom of some current clinical strategies. PMID:14581197

  17. A multiphase model for three-dimensional tumor growth

    PubMed Central

    Sciumè, G; Shelton, S; Gray, WG; Miller, CT; Hussain, F; Ferrari, M; Decuzzi, P; Schrefler, BA

    2014-01-01

    Several mathematical formulations have analyzed the time-dependent behaviour 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 (TCAT). A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) 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 (MTS) 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 behaviour: initially, the rapidly growing tumor cells 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 tumor cells 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 tumor and healthy cells to the ECM, and the less favourable transport of nutrients. In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced

  18. Quercetin Reduces Ehrlich Tumor-Induced Cancer Pain in Mice

    PubMed Central

    Calixto-Campos, Cassia; Corrêa, Mab P.; Carvalho, Thacyana T.; Zarpelon, Ana C.; Hohmann, Miriam S. N.; Rossaneis, Ana C.; Coelho-Silva, Leticia; Pavanelli, Wander R.; Pinge-Filho, Phileno; Crespigio, Jefferson; Bernardy, Catia C. F.; Casagrande, Rubia; Verri, Waldiceu A.

    2015-01-01

    Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation. PMID:26351625

  19. Inhibition of platelet activation prevents the P-selectin and integrin-dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo.

    PubMed

    Mezouar, Soraya; Darbousset, Roxane; Dignat-George, Françoise; Panicot-Dubois, Laurence; Dubois, Christophe

    2015-01-15

    Venous thromboembolism constitutes one of the main causes of death during the progression of a cancer. We previously demonstrated that tissue factor (TF)-bearing cancer cell-derived microparticles accumulate at the site of injury in mice developing a pancreatic cancer. The presence of these microparticles at the site of thrombosis correlates with the size of the platelet-rich thrombus. The objective of this study was to determine the involvement of TF expressed by cancer cell-derived microparticles on thrombosis associated with cancer. We observed that pancreatic cancer cell derived microparticles expressed TF, its inhibitor tissue factor pathway inhibitor (TFPI) as well as the integrins αvβ1 and αvβ3. In mice bearing a tumor under-expressing TF, a significant decrease in circulating TF activity associated with an increase bleeding time and a 100-fold diminished fibrin generation and platelet accumulation at the site of injury were observed. This was mainly due to the interaction of circulating cancer cell-derived microparticles expressing TFPI with activated platelets and fibrinogen. In an ectopic model of cancer, treatment of mice with Clopidogrel, an anti-platelet drug, decreased the size of the tumors and restored hemostasis by preventing the accumulation of cancer cell-derived microparticles at the site of thrombosis. In a syngeneic orthotopic model of pancreatic cancer Clopidogrel also significantly inhibited the development of metastases. Together, these results indicate that an anti-platelet strategy may efficiently treat thrombosis associated with cancer and reduce the progression of pancreatic cancer in mice.

  20. 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

  1. Bioavailable copper modulates oxidative phosphorylation and growth of tumors.

    PubMed

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

    2013-11-26

    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.

  2. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment

    PubMed Central

    Hatipoglu, Gökçe; Hock, Stefan W; Weiss, Ruth; Fan, Zheng; Sehm, Tina; Ghoochani, Ali; Buchfelder, Michael; Savaskan, Nicolai E; Eyüpoglu, Ilker Y

    2015-01-01

    Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on

  3. ROLE OF CHEMOKINES IN TUMOR GROWTH

    PubMed Central

    Raman, Dayanidhi; Baugher, Paige J.; Thu, Yee Mon; Richmond, Ann

    2007-01-01

    Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed. PMID:17629396

  4. Mathematical Modeling of Branching Morphogenesis and Vascular Tumor Growth

    NASA Astrophysics Data System (ADS)

    Yan, Huaming

    Feedback regulation of cell lineages is known to play an important role in tissue size control, but the effect in tissue morphogenesis has yet to be explored. We first use a non-spatial model to show that a combination of positive and negative feedback on stem and/or progenitor cell self-renewal leads to bistable or bi-modal growth behaviors and ultrasensitivity to external growth cues. Next, a spatiotemporal model is used to demonstrate spatial patterns such as local budding and branching arise in this setting, and are not consequences of Turing-type instabilities. We next extend the model to a three-dimensional hybrid discrete-continuum model of tumor growth to study the effects of angiogenesis, tumor progression and cancer therapies. We account for the crosstalk between the vasculature and cancer stem cells (CSCs), and CSC transdifferentiation into vascular endothelial cells (gECs), as observed experimentally. The vasculature stabilizes tumor invasiveness but considerably enhances growth. A gEC network structure forms spontaneously within the hypoxic core, consistent with experimental findings. The model is then used to study cancer therapeutics. We demonstrate that traditional anti-angiogenic therapies decelerate tumor growth, but make the tumor highly invasive. Chemotherapies help to reduce tumor sizes, but cannot control the invasion. Anti-CSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness. However, gECs inherit mutations present in CSCs and are resistant to traditional therapies. We show that anti-gEC treatments block the support on CSCs by gECs, and reduce both tumor size and invasiveness. Our study suggests that therapies targeting the vasculature, CSCs and gECs, when combined, are highly synergistic and are capable of controlling both tumor size and shape.

  5. Ontogenetic growth of multicellular tumor spheroids

    NASA Astrophysics Data System (ADS)

    Condat, C. A.; Menchón, S. A.

    2006-11-01

    In ontogenetic growth models, the basal metabolic rate is usually assumed to depend on the individual mass following a power law. Here it is shown that, in the case of multicellular tumor spheroids, the emergence of a necrotic core invalidates this assumption. The implications of this result for spheroid growth are discussed, and a procedure to determine the growth parameters using macroscopic measurements is proposed.

  6. Autocrine growth factors and solid tumor malignancy.

    PubMed Central

    Walsh, J. H.; Karnes, W. E.; Cuttitta, F.; Walker, A.

    1991-01-01

    The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy. Images PMID:1926844

  7. Blood porphyrin luminescence and tumor growth correlation

    NASA Astrophysics Data System (ADS)

    Courrol, Lilia Coronato; Silva, Flávia Rodrigues de Oliveira; Bellini, Maria Helena; Mansano, Ronaldo Domingues; Schor, Nestor; Vieira, Nilson Dias, Jr.

    2007-02-01

    Fluorescence technique appears very important for the diagnosis of cancer. Fluorescence detection has advantages over other light-based investigation methods: high sensitivity, high speed, and safety. Renal cell carcinoma (RCC) accounts for approximately 3% of new cancer incidence and mortality in the United States. Unfortunately many RCC masses remain asymptomatic and nonpalpable until they are advanced. Diagnosis and localization of early carcinoma play an important role in the prevention and curative treatment of RCC. Certain drugs or chemicals such as porphyrin derivatives accumulate substantially more in tumors than normal tissues. The autofluorescence of blood porphyrin of healthy and tumor induced male SCID mice was analyzed using fluorescence and excitation spectroscopy. A significant contrast between normal and tumor blood could be established. Blood porphyrin fluorophore showed enhanced fluorescence band (around 630 nm) in function of the tumor growth. This indicates that either the autofluorescence intensity of the blood fluorescence may provide a good parameter for the "first approximation" characterization of the tumor stage.

  8. Effects of anatomical constraints on tumor growth

    NASA Astrophysics Data System (ADS)

    Capogrosso Sansone, B.; Delsanto, P. P.; Magnano, M.; Scalerandi, M.

    2001-08-01

    Competition for available nutrients and the presence of anatomical barriers are major determinants of tumor growth in vivo. We extend a model recently proposed to simulate the growth of neoplasms in real tissues to include geometrical constraints mimicking pressure effects on the tumor surface induced by the presence of rigid or semirigid structures. Different tissues have different diffusivities for nutrients and cells. Despite the simplicity of the approach, based on a few inherently local mechanisms, the numerical results agree qualitatively with clinical data (computed tomography scans of neoplasms) for the larynx and the oral cavity.

  9. 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

  10. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.

    PubMed

    El Ghazal, Roland; Yin, Xin; Johns, Scott C; Swanson, Lee; Macal, Monica; Ghosh, Pradipta; Zuniga, Elina I; Fuster, Mark M

    2016-05-01

    In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  11. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.

    PubMed

    El Ghazal, Roland; Yin, Xin; Johns, Scott C; Swanson, Lee; Macal, Monica; Ghosh, Pradipta; Zuniga, Elina I; Fuster, Mark M

    2016-05-01

    In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer. PMID:27237321

  12. A tumor growth model with deformable ECM

    PubMed Central

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

    2015-01-01

    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. PMID:25427284

  13. Key roles of necroptotic factors in promoting tumor growth

    PubMed Central

    Liu, Xinjian; Zhou, Min; Mei, Ling; Ruan, Jiaying; Hu, Qian; Peng, Jing; Su, Hang; Liao, Hong; Liu, Shanling; Liu, WeiPing; Wang, He; Huang, Qian; Li, Fang; Li, Chuan-Yuan

    2016-01-01

    Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID:26959742

  14. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

    PubMed Central

    Weissmann, Marina; Arvatz, Gil; Horowitz, Netanel; Feld, Sari; Naroditsky, Inna; Zhang, Yi; Ng, Mary; Hammond, Edward; Nevo, Eviatar; Vlodavsky, Israel; Ilan, Neta

    2016-01-01

    Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanase-neutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment. PMID:26729870

  15. Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice

    PubMed Central

    He, Chengwei; Qu, Xiying; Wan, Jianbo; Rong, Rong; Huang, Lili; Cai, Chun; Zhou, Keyuan; Gu, Yan; Qian, Steven Y.; Kang, Jing X.

    2012-01-01

    Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n−6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n−6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n−6 AA and increased D6D activity can lead to enhanced n−6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention. PMID:23112819

  16. Stochastic Modelling of Gompertzian Tumor Growth

    NASA Astrophysics Data System (ADS)

    O'Rourke, S. F. C.; Behera, A.

    2009-08-01

    We study the effect of correlated noise in the Gompertzian tumor growth model for non-zero correlation time. The steady state probability distributions and average population of tumor cells are analyzed within the Fokker-Planck formalism to investigate the importance of additive and multiplicative noise. We find that the correlation strength and correlation time have opposite effects on the steady state probability distributions. It is observed that the non-bistable Gompertzian model, driven by correlated noise exhibits a stochastic resonance and phase transition. This behaviour of the Gompertz model is unaffected with the change of correlation time and occurs as a result of multiplicative noise.

  17. Stochastic model for tumor growth with immunization

    NASA Astrophysics Data System (ADS)

    Bose, Thomas; Trimper, Steffen

    2009-05-01

    We analyze a stochastic model for tumor cell growth with both multiplicative and additive colored noises as well as nonzero cross correlations in between. Whereas the death rate within the logistic model is altered by a deterministic term characterizing immunization, the birth rate is assumed to be stochastically changed due to biological motivated growth processes leading to a multiplicative internal noise. Moreover, the system is subjected to an external additive noise which mimics the influence of the environment of the tumor. The stationary probability distribution Ps is derived depending on the finite correlation time, the immunization rate, and the strength of the cross correlation. Ps offers a maximum which becomes more pronounced for increasing immunization rate. The mean-first-passage time is also calculated in order to find out under which conditions the tumor can suffer extinction. Its characteristics are again controlled by the degree of immunization and the strength of the cross correlation. The behavior observed can be interpreted in terms of a biological model of tumor evolution.

  18. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

    PubMed

    Wang, Zhihui; Liu, Jin-Qing; Liu, Zhenzhen; Shen, Rulong; Zhang, Guoqiang; Xu, Jianping; Basu, Sujit; Feng, Youmei; Bai, Xue-Feng

    2013-03-01

    IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

  19. A comparison and catalog of intrinsic tumor growth models.

    PubMed

    Sarapata, E A; de Pillis, L G

    2014-08-01

    Determining the mathematical dynamics and associated parameter values that should be used to accurately reflect tumor growth continues to be of interest to mathematical modelers, experimentalists and practitioners. However, while there are several competing canonical tumor growth models that are often implemented, how to determine which of the models should be used for which tumor types remains an open question. In this work, we determine the best fit growth dynamics and associated parameter ranges for ten different tumor types by fitting growth functions to at least five sets of published experimental growth data per type of tumor. These time-series tumor growth data are used to determine which of the five most common tumor growth models (exponential, power law, logistic, Gompertz, or von Bertalanffy) provides the best fit for each type of tumor.

  20. Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

    PubMed Central

    Zhao, Zhizheng; Fan, Huiting; Higgins, Tim; Qi, Jia; Haines, Diana; Trivett, Anna; Oppenheim, Joost J.; Wei, Hou; Li, Jie; Lin, Hongsheng; Howard, O.M. Zack

    2014-01-01

    Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and antiinflammatory drugs provide first line treatment for cancer pain, but both are limited by side effects. Fufang Kushen injection (FKI) is GMP produced, traditional Chinese medicine used alone or with chemotherapy to reduce cancer-associated pain. FKI limited mouse sarcoma growth both in vivo and in vitro, in part, by reducing the phosphorylation of ERK and AKT kinases and BAD. FKI inhibited TRPV1 mediated capsaicin-induced ERK phosphorylation and reduced tumor-induced proinflammatory cytokine production. Thus, FKI limited cancer pain both directly by blocking TRPV1 signaling and indirectly by reducing tumor growth. PMID:25242356

  1. Mathematical Modeling of Interleukin-35 Promoting Tumor Growth and Angiogenesis

    PubMed Central

    Liao, Kang-Ling; Bai, Xue-Feng; Friedman, Avner

    2014-01-01

    Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8 T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased. PMID:25356878

  2. Devazepide, a nonpeptide antagonist of CCK receptors, induces apoptosis and inhibits Ewing tumor growth.

    PubMed

    Carrillo, Jaime; Agra, Noelia; Fernández, Noemí; Pestaña, Angel; Alonso, Javier

    2009-08-01

    The Ewing family of tumors is a group of highly malignant tumors that mainly arise in bone and most often affect children and young adults in the first two decades of life. Despite the use of multimodal therapy, the long-term disease-free survival rate of patients with Ewing tumors is still disappointingly low, making the discovery of innovative therapeutic strategies all the more necessary. We have recently shown that cholecystokinin (CCK), a neuroendocrine peptide, involved in many biological functions, including cell growth and proliferation, is a relevant target of the EWS/FLI1 oncoprotein characteristic of Ewing tumors. CCK silencing inhibits cell proliferation and tumor growth in vivo, suggesting that CCK acts as an autocrine growth factor for Ewing cells. Here, we analyzed the impact of two CCK receptor antagonists, devazepide (a CCK1-R antagonist) and L365 260 (a CCK2-R antagonist), on the growth of Ewing tumor cells. Devazepide (10 micromol/l) inhibited cell growth of four different Ewing tumor cells in vitro (range 85-88%), whereas the effect of the CCK2-R antagonist on cell growth was negligible. In a mouse tumor xenograft model, devazepide reduced tumor growth by 40%. Flow cytometry experiments showed that devazepide, but not L365 260, induced apoptosis of Ewing tumor cells. In summary, devazepide induces cell death of Ewing tumor cells, suggesting that it could represent a new therapeutic approach in the management of Ewing's tumor patients.

  3. Insulin-responsiveness of tumor growth.

    PubMed

    Chantelau, Ernst

    2009-05-01

    In October 2008, the 2nd International Insulin & Cancer Workshop convened roughly 30 researchers from eight countries in Düsseldorf/Germany. At this meeting, which was industry-independent like the preceding one in 2007, the following issues were discussed a) association between certain cancers and endogenous insulin production in humans, b) growth-promoting effects of insulin in animal experiments, c) mitogenic and anti-apoptotic activity of pharmaceutic insulin and insulin analogues in in vitro experiments, d) potential mechanisms of insulin action on cell growth, mediated by IGF-1 receptor and insulin receptor signaling, and e) IGF-1 receptor targeting for inhibition of tumor growth. It was concluded that further research is necessary to elucidate the clinical effects of these observations, and their potential for human neoplastic disease and treatment.

  4. 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. PMID:27197160

  5. Investigating Mechanisms of Alkalinization for Reducing Primary Breast Tumor Invasion

    PubMed Central

    Robey, Ian F.; Nesbit, Lance A.

    2013-01-01

    The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (P < 0.01). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (P ≤ 0.003). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion. PMID:23936808

  6. Autocrine growth factors for human tumor clonogenic cells.

    PubMed

    Hamburger, A W; White, C P

    1985-11-01

    A human epithelial-derived cell line, SW-13, releases a soluble substance that functions as an autocrine growth factor. SW-13 cells, derived from a human adenocarcinoma of the adrenal cortex, form a few small colonies when suspended in soft agar at low densities. The number of colonies increased significantly when either viable SW-13 cells or serum-free medium conditioned by SW-13 cells (CM) was added to agar underlayers. CM increased colony formation in a dose-dependent fashion. Clonal growth at low cell densities was dependent on the presence of both horse serum and SW-13 CM. Neither activity alone was capable of sustaining growth. Even when cells were plated at high densities CM could not substitute for serum, but could reduce the threshold serum concentration. The results suggest that autocrine and serum-derived factors act in concert to maintain clonal growth of epithelial tumor cells in soft agar.

  7. Fes tyrosine kinase expression in the tumor niche correlates with enhanced tumor growth, angiogenesis, circulating tumor cells, metastasis, and infiltrating macrophages.

    PubMed

    Zhang, Shengnan; Chitu, Violeta; Stanley, E Richard; Elliott, Bruce E; Greer, Peter A

    2011-02-15

    Fes is a protein tyrosine kinase with cell autonomous oncogenic activities that are well established in cell culture and animal models, but its involvement in human cancer has been unclear. Abundant expression of Fes in vascular endothelial cells and myeloid cell lineages prompted us to explore roles for Fes in the tumor microenvironment. In an orthotopic mouse model of breast cancer, we found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis, and circulating tumor cells. The tumor microenvironment in Fes-deficient mice also showed reduced vascularity and fewer macrophages. In co-culture with tumor cells, Fes-deficient macrophages also poorly promoted tumor cell invasive behavior. Taken together, our observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, in part by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages.

  8. Cellular Potts Modeling of Tumor Growth, Tumor Invasion, and Tumor Evolution

    PubMed Central

    Szabó, András; Merks, Roeland M. H.

    2013-01-01

    Despite a growing wealth of available molecular data, the growth of tumors, invasion of tumors into healthy tissue, and response of tumors to therapies are still poorly understood. Although genetic mutations are in general the first step in the development of a cancer, for the mutated cell to persist in a tissue, it must compete against the other, healthy or diseased cells, for example by becoming more motile, adhesive, or multiplying faster. Thus, the cellular phenotype determines the success of a cancer cell in competition with its neighbors, irrespective of the genetic mutations or physiological alterations that gave rise to the altered phenotype. What phenotypes can make a cell “successful” in an environment of healthy and cancerous cells, and how? A widely used tool for getting more insight into that question is cell-based modeling. Cell-based models constitute a class of computational, agent-based models that mimic biophysical and molecular interactions between cells. One of the most widely used cell-based modeling formalisms is the cellular Potts model (CPM), a lattice-based, multi particle cell-based modeling approach. The CPM has become a popular and accessible method for modeling mechanisms of multicellular processes including cell sorting, gastrulation, or angiogenesis. The CPM accounts for biophysical cellular properties, including cell proliferation, cell motility, and cell adhesion, which play a key role in cancer. Multiscale models are constructed by extending the agents with intracellular processes including metabolism, growth, and signaling. Here we review the use of the CPM for modeling tumor growth, tumor invasion, and tumor progression. We argue that the accessibility and flexibility of the CPM, and its accurate, yet coarse-grained and computationally efficient representation of cell and tissue biophysics, make the CPM the method of choice for modeling cellular processes in tumor development. PMID:23596570

  9. Host Cxcr2-dependent regulation of mammary tumor growth and metastasis

    PubMed Central

    Sharma, Bhawna; Nannuru, Kalyan C.; Varney, Michelle L.

    2016-01-01

    Host-derived angiogenic and inflammatory tumor supportive microenvironment regulates progression and metastasis, but the molecular mechanism(s) underlying host-tumor interactions remains unclear. Tumor expression of CXCR2 and its ligands have been shown to regulate angiogenesis, invasion, tumor growth, and metastasis. In this report, we hypothesized that host-derived Cxcr2-dependent signaling plays an important role in breast cancer growth and metastasis. Two mammary tumor cell lines Cl66 and 4T1 cells were orthotopically implanted into the mammary fat pad of wild-type and Cxcr2−/− female BALB/c mice. Tumor growth and spontaneous lung metastasis were monitored. Immunohistochemical analyses of the tumor tissues were performed to analyze proliferation, angiogenesis, apoptosis and immune cell infiltration. Our results demonstrated that knock-down of host Cxcr2 decreases tumor growth and metastasis by reducing angiogenesis, proliferation and enhancing apoptosis. Host Cxcr2 plays an important role in governing the pro-inflammatory response in mammary tumors as evaluated by decreased Gr1+ tumor-associated granulocytes, F4/80+ tumor associated macrophages, and CD11b+Gr1+ myeloid derived suppressor cells in Cxcr2−/− mice as compared to control wild-type mice. Together, these results demonstrate that host Cxcr2-dependent signaling regulates mammary tumor growth and metastasis by promoting angiogenesis and pro-inflammatory responses. PMID:25511644

  10. Macrophage Migration Inhibitory Factor promotes tumor growth and metastasis by inducing Myeloid Derived Suppressor Cells in the tumor microenvironment

    PubMed Central

    Simpson, Kendra D.; Templeton, Dennis J.; Cross, Janet V.

    2012-01-01

    The Macrophage Migration Inhibitory Factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show here that, in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion, and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response, and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches. PMID:23125418

  11. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  12. Inhibition of tumor growth by elimination of granulocytes

    PubMed Central

    1995-01-01

    As observed for many types of cancers, heritable variants of ultraviolet light-induced tumors often grow more aggressively than the parental tumors. The aggressive growth of some variants is due to the loss of a T cell-recognized tumor-specific antigen; however, other variants retain such antigens. We have analyzed an antigen retention variant and found that the variant tumor cells grow at the same rate as the parental tumor cells in vitro, but grew more rapidly than the parental cells in the T cell-deficient host. The growth of the variant cells was stimulated in vitro by factors released from tumor-induced leukocytes and by several defined growth factors. In addition, the variant cancer cells actually attracted more leukocytes in vitro than the parental cells. Furthermore, elimination of granulocytes in vivo in nude mice by a specific antigranulocyte antibody inhibited the growth of the variant cancer, indicating that this tumor requires granulocytes for rapid growth. PMID:7807024

  13. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  14. Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth

    PubMed Central

    Sano, Michael B.; Arena, Christopher B.; Bittleman, Katelyn R.; DeWitt, Matthew R.; Cho, Hyung J.; Szot, Christopher S.; Saur, Dieter; Cissell, James M.; Robertson, John; Lee, Yong W.; Davalos, Rafael V.

    2015-01-01

    Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models. PMID:26459930

  15. Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth

    NASA Astrophysics Data System (ADS)

    Sano, Michael B.; Arena, Christopher B.; Bittleman, Katelyn R.; Dewitt, Matthew R.; Cho, Hyung J.; Szot, Christopher S.; Saur, Dieter; Cissell, James M.; Robertson, John; Lee, Yong W.; Davalos, Rafael V.

    2015-10-01

    Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models.

  16. Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors.

    PubMed

    Voutouri, Chrysovalantis; Mpekris, Fotios; 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.

  17. A new ODE tumor growth modeling based on tumor population dynamics

    SciTech Connect

    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.

  18. 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

  19. P-selectin-mediated platelet adhesion promotes tumor growth.

    PubMed

    Qi, Cuiling; Wei, Bo; Zhou, Weijie; Yang, Yang; Li, Bin; Guo, Simei; Li, Jialin; Ye, Jie; Li, Jiangchao; Zhang, Qianqian; Lan, Tian; He, Xiaodong; Cao, Liu; Zhou, Jia; Geng, Jianguo; Wang, Lijing

    2015-03-30

    Blood platelets foster carcinogenesis. We found that platelets are accumulated in human tumors. P-selectin deficiency and soluble P-selectin abolish platelet deposition within tumors, decreasing secretion of vascular endothelial growth factor and angiogenesis, thereby suppressing tumor growth. Binding of the P-selectin cytoplasmic tail to talin1 triggers the talin1 N-terminal head to interact with the β3 cytoplasmic tail. This activates αIIbβ3 and recruits platelets into tumors. Platelet infiltration into solid tumors occurs through a P-selectin-dependent mechanism.

  20. Inhibition of rate of tumor growth by creatine and cyclocreatine.

    PubMed Central

    Miller, E E; Evans, A E; Cohn, M

    1993-01-01

    Growth rate inhibition of subcutaneously implanted tumors results from feeding rats and athymic nude mice diets containing 1% cyclocreatine or 1%, 2%, 5%, or 10% creatine. The tumors studied included rat mammary tumors (Ac33tc in Lewis female rats and 13762A in Fischer 344 female rats), rat sarcoma MCI in Lewis male rats, and tumors resulting from the injection of two human neuroblastoma cell lines, IMR-5 and CHP-134, in athymic nude mice. Inhibition was observed regardless of the time experimental diets were administered, either at the time of tumor implantation or after the appearance of palpable tumors. For mammary tumor Ac33tc, the growth inhibition during 24 days after the implantation was approximately 50% for both 1% cyclocreatine and 1% creatine, and inhibition increased as creatine was increased from 2% to 10% of the diet. For the other rat mammary tumor (13762A), there was approximately 35% inhibition by both 1% cyclocreatine and 2% creatine. In the case of the MCI sarcoma, the inhibitory effect appeared more pronounced at earlier periods of growth, ranging from 26% to 41% for 1% cyclocreatine and from 30% to 53% for 1% creatine; there was no significant difference in growth rate between the tumors in the rats fed 1% and 5% creatine. The growth rate of tumors in athymic nude mice, produced by implantation of the human neuroblastoma IMR-5 cell line, appeared somewhat more effectively inhibited by 1% cyclocreatine than by 1% creatine, and 5% creatine feeding was most effective. For the CHP-134 cell line, 33% inhibition was observed for the 1% cyclocreatine diet and 71% for the 5% creatine diet. In several experiments, a delay in appearance of tumors was observed in animals on the experimental diets. In occasional experiments, neither additive inhibited tumor growth rate for the rat tumors or the athymic mouse tumors. Images Fig. 3 PMID:8475072

  1. Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models.

    PubMed

    Eichten, Alexandra; Adler, Alexander P; Cooper, Blerta; Griffith, Jennifer; Wei, Yi; Yancopoulos, George D; Lin, Hsin Chieh; Thurston, Gavin

    2013-04-01

    Vascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult. These difficulties arise in part because the functional effects of VEGF inhibition on tumor vessels are still unclear. We therefore assessed rapid molecular, morphologic and functional vascular responses following treatment with aflibercept (also known as VEGF Trap or ziv-aflibercept in the United States) in preclinical tumor models with a range of responses to anti-VEGF therapy, including Colo205 human colorectal carcinoma (highly sensitive), C6 rat glioblastoma (moderately sensitive), and HT1080 human fibrosarcoma (resistant), and correlated these changes to long-term tumor growth inhibition. We found that an overall decrease in tumor vessel perfusion, assessed by dynamic contrast-enhanced ultrasound (DCE-US), and increases in tumor hypoxia correlated well with long-term tumor growth inhibition, whereas changes in vascular gene expression and microvessel density did not. Our findings support previous clinical studies showing that decreased tumor perfusion after anti-VEGF therapy (measured by DCE-US) correlated with response. Thus, measuring tumor perfusion changes shortly after treatment with VEGF inhibitors, or possibly other anti-angiogenic therapies, may be useful to predict treatment efficacy. PMID:23238831

  2. Tumor growth suppression by the combination of nanobubbles and ultrasound.

    PubMed

    Suzuki, Ryo; Oda, Yusuke; Omata, Daiki; Nishiie, Norihito; Koshima, Risa; Shiono, Yasuyuki; Sawaguchi, Yoshikazu; Unga, Johan; Naoi, Tomoyuki; Negishi, Yoichi; Kawakami, Shigeru; Hashida, Mitsuru; Maruyama, Kazuo

    2016-03-01

    We previously developed novel liposomal nanobubbles (Bubble liposomes [BL]) that oscillate and collapse in an ultrasound field, generating heat and shock waves. We aimed to investigate the feasibility of cancer therapy using the combination of BL and ultrasound. In addition, we investigated the anti-tumor mechanism of this cancer therapy. Colon-26 cells were inoculated into the flank of BALB/c mice to induce tumors. After 8 days, BL or saline was intratumorally injected, followed by transdermal ultrasound exposure of tumor tissue (1 MHz, 0-4 W/cm2 , 2 min). The anti-tumor effects were evaluated by histology (necrosis) and tumor growth. In vivo cell depletion assays were performed to identify the immune cells responsible for anti-tumor effects. Tumor temperatures were significantly higher when treated with BL + ultrasound than ultrasound alone. Intratumoral BL caused extensive tissue necrosis at 3-4 W/cm2 of ultrasound exposure. In addition, BL + ultrasound significantly suppressed tumor growth at 2-4 W/cm2 . In vivo depletion of CD8+ T cells (not NK or CD4+ T cells) completely blocked the effect of BL + ultrasound on tumor growth. These data suggest that CD8+ T cells play a critical role in tumor growth suppression. Finally, we concluded that BL + ultrasound, which can prime the anti-tumor cellular immune system, may be an effective hyperthermia strategy for cancer treatment.

  3. Roles of pleiotrophin in tumor growth and angiogenesis.

    PubMed

    Papadimitriou, Evangelia; Mikelis, Constantinos; Lampropoulou, Evgenia; Koutsioumpa, Marina; Theochari, Katerina; Tsirmoula, Sotiria; Theodoropoulou, Christina; Lamprou, Margarita; Sfaelou, Evanthia; Vourtsis, Dionyssios; Boudouris, Panagiotis

    2009-12-01

    Pleiotrophin (PTN) is a heparin-binding growth factor with diverse biological activities, the most studied of these being those related to the nervous system, tumor growth and angiogenesis. Although interest in the involvement of PTN in tumor growth is increasing, many questions remain unanswered, particularly concerning the receptors and the signaling pathways involved. In this review, we briefly introduce PTN, and summarize data on its involvement in tumor growth and angiogenesis, and on what is known to date concerning the receptors and pathways involved.

  4. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  5. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth.

    PubMed

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  6. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    SciTech Connect

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-03-28

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  7. Pharmacological Inhibition of Microsomal Prostaglandin E Synthase-1 Suppresses Epidermal Growth Factor Receptor-Mediated Tumor Growth and Angiogenesis

    PubMed Central

    Bocci, Elena; Coletta, Isabella; Polenzani, Lorenzo; Mangano, Giorgina; Alisi, Maria Alessandra; Cazzolla, Nicola; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2012-01-01

    Background Blockade of Prostaglandin (PG) E2 production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE2 promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. Methodology/Principal Findings Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1β) increased mPGES-1 expression, PGE2 production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE2 production, both in quiescent and in cells stimulated by IL-1β. AF3485 abolished IL-1β-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. Conclusion Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE2 mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth. PMID:22815767

  8. 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.

  9. Vietnam's campaign to reduce population growth.

    PubMed

    Haub, C

    1999-10-01

    This paper reports campaigns to reduce the population growth in Vietnam. In July, red banners flew above the broad boulevard in Hanoi proclaiming World Population Day. This widespread public attention to population issues is not surprising, given the country's sharp reduction in fertility and widespread citizen support for smaller families. Since 1961, Vietnam has been trying to formulate a policy to reduce the population rate growth. The policy was a reaction to the results of the 1960 Census of the Democratic Republic of Vietnam and reflected long-standing concerns over food shortages, as well as a desire to improve women's health and welfare. After the reunification in 1975, the policy was extended to the entire country. Since then, Vietnam's growth rate has been declining, suggesting that the national campaign for smaller families is succeeding in changing deeply held attitudes and perceptions, in addition to current practices. While the fertility decline in Vietnam may not be the world's fastest, the success of the national population policy has forever altered the country's prospect for population growth.

  10. Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils

    PubMed Central

    Zhu, Ha; Xu, Junfang; Zheng, Yuanyuan; Cao, Xuetao

    2016-01-01

    Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs) play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth. PMID:27446967

  11. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.

    PubMed

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  12. VAMP-Associated Protein B (VAPB) Promotes Breast Tumor Growth by Modulation of Akt Activity

    PubMed Central

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer. PMID:23049696

  13. The Effect of Electroacupuncture on Osteosarcoma Tumor Growth and Metastasis: Analysis of Different Treatment Regimens

    PubMed Central

    Smeester, Branden A.; O'Brien, Elaine E.; Ericson, Marna E.; Triemstra, Jennifer L.; Beitz, Alvin J.

    2013-01-01

    Osteosarcoma is the most common malignant bone tumor found in children and adolescents and is associated with many complications including cancer pain and metastasis. While cancer patients often seek complementary and alternative medicine (CAM) approaches to treat cancer pain and fatigue or the side effects of chemotherapy and treatment, there is little known about the effect of acupuncture treatment on tumor growth and metastasis. Here we evaluate the effects of six different electroacupuncture (EA) regimens on osteosarcoma tumor growth and metastasis in both male and female mice. The most significant positive effects were observed when EA was applied to the ST-36 acupoint twice weekly (EA-2X/3) beginning at postimplantation day 3 (PID 3). Twice weekly treatment produced robust reductions in tumor growth. Conversely, when EA was applied twice weekly (EA-2X/7), starting at PID 7, there was a significant increase in tumor growth. We further demonstrate that EA-2X/3 treatment elicits significant reductions in tumor lymphatics, vasculature, and innervation. Lastly, EA-2X/3 treatment produced a marked reduction in pulmonary metastasis, thus providing evidence for EA's potential antimetastatic capabilities. Collectively, EA-2X/3 treatment was found to reduce both bone tumor growth and lung metastasis, which may be mediated in part through reductions in tumor-associated vasculature, lymphatics, and innervation. PMID:24228059

  14. Antiangiogenic and proapoptotic activities of allyl isothiocyanate inhibit ascites tumor growth in vivo.

    PubMed

    Kumar, Akhilesh; D'Souza, Saritha S; Tickoo, Sanjay; Salimath, Bharathi P; Singh, H B

    2009-03-01

    The authors investigate the antiangiogenic and proapoptotic effects of mustard essential oil containing allyl isothiocyanate (AITC) and explore its mechanism of action on Ehrlich ascites tumor (EAT) cells. Swiss albino mice transplanted with EAT cells were used to study the effect of AITC. AITC was effective at a concentration of 10 mum as demonstrated by the inhibition of proliferation of EAT cells when compared with the normal HEK293 cells. It significantly reduced ascites secretion and tumor cell proliferation by about 80% and inhibited vascular endothelial growth factor expression in tumor-bearing mice in vivo. It also reduced vessel sprouting and exhibited potent antiangiogenic activity in the chorioallantoic membrane and cornea of the rat. AITC arrested the growth of EAT cells by inducing apoptosis and effectively arrested cell cycle progression at the G1 phase. The results clearly suggest that AITC inhibits tumor growth by both antiangiogenic and proapoptotic mechanisms.

  15. Pediatric brain tumor treatment: growth consequences and their management.

    PubMed

    Mostoufi-Moab, Sogol; Grimberg, Adda

    2010-09-01

    Tumors of the central nervous system, the most common solid tumors of childhood, are a major source of cancer-related morbidity and mortality in children. Survival rates have improved significantly following treatment for childhood brain tumors, with this growing cohort of survivors at high risk of adverse medical and late effects. Endocrine morbidities are the most prominent disorder among the spectrum of longterm conditions, with growth hormone deficiency the most common endocrinopathy noted, either from tumor location or after cranial irradiation and treatment effects on the hypothalamic/pituitary unit. Deficiency of other anterior pituitary hormones can contribute to negative effects on growth, body image and composition, sexual function, skeletal health, and quality of life. Pediatric and adult endocrinologists often provide medical care to this increasing population. Therefore, a thorough understanding of the epidemiology and pathophysiology of growth failure as a consequence of childhood brain tumor, both during and after treatment, is necessary and the main focus of this review.

  16. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma.

    PubMed

    Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yanfei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

    2014-07-30

    X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.

  17. Motif mimetic of epsin perturbs tumor growth and metastasis

    PubMed Central

    Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Liu, Xiaolei; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jiali; Brophy, Megan L.; Yu, Lili; Song, Kai; Silasi-Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hoogeun; Mehta-D’Souza, Padmaja; Towner, Rheal; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, R. Sathish; Chen, Hong

    2015-01-01

    Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID:26571402

  18. Tumor growth inhibition through targeting liposomally bound curcumin to tumor vasculature.

    PubMed

    Mondal, Goutam; Barui, Sugata; Saha, Soumen; Chaudhuri, Arabinda

    2013-12-28

    Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~500 μg/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures.

  19. Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

    PubMed Central

    Ranjan, Alok; Srivastava, Sanjay K.

    2016-01-01

    Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6–7 μM after 24 h of treatment. Significant autophagy was induced by penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with penfluridol and chloroquine as compared to penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since penfluridol is already in clinic, positive findings from our study will accelerate its clinical development. PMID:27189859

  20. 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.

  1. A Mathematical Model Coupling Tumor Growth and Angiogenesis

    PubMed Central

    Gomez, Hector

    2016-01-01

    We present a mathematical model for vascular tumor growth. We use phase fields to model cellular growth and reaction-diffusion equations for the dynamics of angiogenic factors and nutrients. The model naturally predicts the shift from avascular to vascular growth at realistic scales. Our computations indicate that the negative regulation of the Delta-like ligand 4 signaling pathway slows down tumor growth by producing a larger density of non-functional capillaries. Our results show good quantitative agreement with experiments. PMID:26891163

  2. pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth

    PubMed Central

    Zhao, Ying; Zhang, Yinlong; Su, Shishuai; Wang, Jing; Wu, Meiyu; Shi, Quanwei; Anderson, Gregory J.; Thomsen, Johannes; Zhao, Ruifang; Ji, Tianjiao; Wang, Jie

    2015-01-01

    Occluding tumor blood supply by delivering the extracellular domain of coagulation-inducing protein tissue factor (truncated tissue factor, tTF) to tumor vasculature has enormous potential to eliminate solid tumors. Yet few of the delivery technologies are moved into clinical practice due to their non-specific tissue biodistribution and rapid clearance by the reticuloendothelial system. Here we introduced a novel tTF delivery method by generating a fusion protein (tTF-pHLIP) consisting of tTF fused with a peptide with a low pH-induced transmembrane structure (pHLIP). This protein targets the acidic tumor vascular endothelium and effectively induces local blood coagulation. tTF-pHLIP, wherein pHLIP is cleverly designed to mimic the natural tissue factor transmembrane domain, triggered thrombogenic activity of the tTF by locating it to the endothelial cell surface, as demonstrated by coagulation assays and confocal microscopy. Systemic administration of tTF-pHLIP into tumor-bearing mice selectively induced thrombotic occlusion of tumor vessels, reducing tumor perfusion and impairing tumor growth without overt side effects. Our work introduces a promising strategy for using tTF as an anti-cancer drug, which has great potential value for clinical applications. PMID:26143637

  3. 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.

  4. Growth-hormone-releasing factor immunoreactivity in human endocrine tumors.

    PubMed Central

    Bostwick, D. G.; Quan, R.; Hoffman, A. R.; Webber, R. J.; Chang, J. K.; Bensch, K. G.

    1984-01-01

    Seventy-three human tumors and adjacent nonneoplastic tissues were analyzed immunohistochemically for the presence of growth-hormone-releasing factor (GRF). Four of 9 pancreatic endocrine tumors, 2 of 3 appendiceal carcinoids, and 1 of 5 cecal carcinoids were immunoreactive for GRF. One of the GRF-containing pancreatic tumors was associated with acromegaly. Histologically, the growth patterns of these tumors were variable, and the distribution of immunoreactive cells was patchy and irregular. There were no normal cells that contained GRF. These results indicate that GRF production by human tumors is more common than previously thought, although clinical acromegaly may not be apparent in patients who harbor such neoplasms. Images Figure 1 PMID:6093542

  5. Physical determinants of vascular network remodeling during tumor growth.

    PubMed

    Welter, M; Rieger, H

    2010-10-01

    The process in which a growing tumor transforms a hierarchically organized arterio-venous blood vessel network into a tumor specific vasculature is analyzed with a theoretical model. The physical determinants of this remodeling involve the morphological and hydrodynamic properties of the initial network, generation of new vessels (sprouting angiogenesis), vessel dilation (circumferential growth), vessel regression, tumor cell proliferation and death, and the interdependence of these processes via spatio-temporal changes of blood flow parameters, oxygen/nutrient supply and growth factor concentration fields. The emerging tumor vasculature is non-hierarchical, compartmentalized into well-characterized zones, displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size, and transports drug injections efficiently. Implications for current theoretical views on tumor-induced angiogenesis are discussed.

  6. 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. PMID:25665006

  7. Near-criticality underlies the behavior of early tumor growth

    NASA Astrophysics Data System (ADS)

    Remy, Guillaume; Cluzel, Philippe

    2016-04-01

    The controlling factors that underlie the growth of tumors have often been hard to identify because of the presence in this system of a large number of intracellular biochemical parameters. Here, we propose a simplifying framework to identify the key physical parameters that govern the early growth of tumors. We model growth by means of branching processes where cells of different types can divide and differentiate. First, using this process that has only one controlling parameter, we study a one cell type model and compute the probability for tumor survival and the time of tumor extinction. Second, we show that when cell death and cell division are perfectly balanced, stochastic effects dominate the growth dynamics and the system exhibits a near-critical behavior that resembles a second-order phase transition. We show, in this near-critical regime, that the time interval before tumor extinction is power-law distributed. Finally, we apply this branching formalism to infer, from experimental growth data, the number of different cell types present in the observed tumor.

  8. STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation.

    PubMed

    Takashima, Ken; Takeda, Yohei; Oshiumi, Hiroyuki; Shime, Hiroaki; Okabe, Masaru; Ikawa, Masahito; Matsumoto, Misako; Seya, Tsukasa

    2016-09-30

    An interferon-inducing DNA sensor STING participates in tumor rejection in mouse models. Here we examined what mechanisms contribute to STING-dependent growth retardation of B16 melanoma sublines by NK cells in vivo. The studies were designed using WT and STING KO black mice, and B16D8 (an NK-sensitive melanoma line having STING) and STING KO B16D8 sublines established for this study. The results from tumor-implant studies suggested that STING in host immune cells and tumor cells induced distinct profiles of chemokines including CXCL10, CCL5 and IL-33, and both participated in NK cell infiltration and activation in B16D8 tumor. Spontaneous activation of STING occurs in host-immune and tumor cells of this NK-sensitive tumor, thereby B16D8 tumor growth being suppressed in this model. Our data show that STING induces tumor cytotoxicity by NK cells through tumor and host immune cell network to contribute to innate surveillance and suppression of tumors in vivo. PMID:27608599

  9. Pretreatment photosensitizer dosimetry reduces variation in tumor response

    SciTech Connect

    Zhou Xiaodong; Pogue, Brian W. . E-mail: Brian.W.Pogue@Dartmouth.edu; Chen Bin; Demidenko, Eugene; Joshi, Rohan; Hoopes, Jack; Hasan, Tayyaba

    2006-03-15

    Purpose: To compensate for photosensitizer uptake variation in photodynamic therapy (PDT), via control of delivered light dose through photodynamic dose calculation based on online dosimetry of photosensitizer in tissue before treatment. Methods and Materials: Photosensitizer verteporfin was quantified via multiple fluorescence microprobe measurements immediately before treatment. To compensate individual PDT treatments, photodynamic doses were calculated on an individual animal basis, by matching the light delivered to provide an equal photosensitizer dose multiplied by light dose. This was completed for the lower quartile, median, and upper quartile of the photosensitizer distribution. PDT-induced tumor responses were evaluated by the tumor regrowth assay. Results: Verteporfin uptake varied considerably among tumors and within a tumor. The coefficient of variation in the surviving fraction was found significantly decreased in groups compensated to the lower quartile (CL-PDT), the median (CM-PDT), and the upper quartile (CU-PDT) of photosensitizer distribution. The CL-PDT group was significantly less effective compared with NC-PDT (Noncompensated PDT), CM-PDT, and CU-PDT treatments. No significant difference in effectiveness was observed between NC-PDT, CM-PDT, and CU-PDT treatment groups. Conclusions: This research suggests that accurate quantification of tissue photosensitizer levels and subsequent adjustment of light dose will allow for reduced subject variation and improved treatment consistency.

  10. Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

    PubMed Central

    Magrini, Elena; Villa, Alessandra; Angiolini, Francesca; Doni, Andrea; Mazzarol, Giovanni; Rudini, Noemi; Maddaluno, Luigi; Komuta, Mina; Topal, Baki; Prenen, Hans; Schachner, Melitta; Confalonieri, Stefano; Dejana, Elisabetta; Bianchi, Fabrizio; Mazzone, Massimiliano; Cavallaro, Ugo

    2014-01-01

    While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6–mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies. PMID:25157817

  11. Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization.

    PubMed

    Magrini, Elena; Villa, Alessandra; Angiolini, Francesca; Doni, Andrea; Mazzarol, Giovanni; Rudini, Noemi; Maddaluno, Luigi; Komuta, Mina; Topal, Baki; Prenen, Hans; Schachner, Melitta; Confalonieri, Stefano; Dejana, Elisabetta; Bianchi, Fabrizio; Mazzone, Massimiliano; Cavallaro, Ugo

    2014-10-01

    While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6-mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies. PMID:25157817

  12. Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model.

    PubMed

    Yoshida, Fumiyo; Yamamoto, Tetsuya; Nakai, Kei; Kumada, Hiroaki; Shibata, Yasushi; Tsuruta, Wataro; Endo, Kiyoshi; Tsurubuchi, Takao; Matsumura, Akira

    2008-05-18

    We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced. PMID:18272285

  13. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models

    PubMed Central

    Funahashi, Yasuhiro; Okamoto, Kiyoshi; Adachi, Yusuke; Semba, Taro; Uesugi, Mai; Ozawa, Yoichi; Tohyama, Osamu; Uehara, Taisuke; Kimura, Takayuki; Watanabe, Hideki; Asano, Makoto; Kawano, Satoshi; Tizon, Xavier; McCracken, Paul J; Matsui, Junji; Aoshima, Ken; Nomoto, Kenichi; Oda, Yoshiya

    2014-01-01

    Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell–pericyte interactions, and in the epithelial–mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits. PMID:25060424

  14. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as "first order", through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  15. Tissue perfusion inhomogeneity during early tumor growth in rats.

    PubMed

    Endrich, B; Reinhold, H S; Gross, J F; Intaglietta, M

    1979-02-01

    Tissue perfusion in BA 1112 sarcomas of WAG inbred Rijswijk rats was determined from in vivo measurements of capillary density, length, and erythrocyte velocity in modified Algire chamber preparations. Studies were done with the use of television techniques in situ during a period of 26 days, both in control chambers and after implantation of a 0.1-mm3 piece of tumor tissue. Perfusion in control areas void of tumor tissue. Perfusion in control areas void of tumor was approximately 8-10 ml/minute/100 g of tissue. Flow in active tumor growth regions on the outward side of the tumor edge was through undifferentiated channels and had characteristics of flow through a porous medium. Despite enhanced arterial supply, the stabilized tumor microcirculation at the inward side of the growing tumor retained its perfusion rate constant (15-18 ml/min/100 g). Perfusion in central portions of the tumor was about 2-4 ml/minute/100 g during 12 days, whereas the tumor doubled in diameter. Our findings support the concept of temporal and functional blood flow inhomogeneity in the microcirculation of spreading tumors. PMID:283271

  16. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.

    PubMed

    Jardim-Perassi, Bruna Victorasso; Arbab, Ali S; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R S; Iskander, A S M; Shankar, Adarsh; Ali, Meser M; de Campos Zuccari, Debora Aparecida Pires

    2014-01-01

    As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell

  17. Influence of lithium on mammary tumor growth in vivo.

    PubMed

    Ziche, M; Maiorana, A; Oka, T; Gullino, P M

    1980-05-01

    The possibility that lithium ions stimulate growth of mammary tumors in vivo has been suggested by their mitogenic action in vitro on normal and neoplastic mammary epithelium [8] and their clinical use as stimulators of neutrophil production in tumor-bearing patients treated with cytotoxic drugs [14,15]. Three experiments were performed to assess this possibility. Buffalo/N female rats received a single injection of N-nitrosomethylurea (NMU) at a dose known to produce mammary carcinomas in about 50% of animals under standard conditions. Under lithium treatment, the incidence of tumors did not increase significantly. Sprague-Dawley female rats treated with a single dose of 7,12-dimethylbenz[alpha] anthracene (DMBA), but showing no mammary tumors after 4 months, received lithium in their drinking water for 3 additional months. The number of late-appearing tumors was not increased by lithium treatment. Buffalo/N females with NMU-induced tumors were castrated, and the subsequent changes in tumor volume were compared in lithium-treated and control animals. The regression-regrowth curves were not altered by lithium treatment. These results are in contrast to the growth stimulatory capacity of lithium on mammary epithelium observed in vitro [8] and indicate it is very unlikely that lithium ions have an undesirable growth stimulatory action on primary mammary carcinomas in vivo.

  18. Effect of treatment with baicalein on the intracerebral tumor growth and survival of orthotopic glioma models.

    PubMed

    Wang, Fu-Rong; Jiang, Yong-Sheng

    2015-08-01

    Baicalein, a widely used Chinese herbal medicine, has been proved as a promising chemopreventive compound for many cancers. The aim of this work was to assess the anti-tumor effect of baicalein in the orthotopic glioma models. It was found that treatment of mice with U87 gliomas with baicalein (20 and 40 mg/kg/day, i.p.) significantly inhibited the intracerebral tumor growth and prolonged the survival. Furthermore, treatment with baicalein suppressed cell proliferation, promoted apoptosis, and arrested cell cycle in U87 gliomas. In addition, treatment with baicalein reduced tumor permeability, attenuated edema of tumors and brains, and improved tight junctions in gliomas. Finally, treatment with baicalein reduced the expression of HIF-1α, VEGF, and VEGFR2 in U87 gliomas. In addition, treatment with baicalein also markedly suppressed tumor growth and prolonged the survival of rats with 9L gliomas. In conclusion, baicalein has an obvious anti-tumor activity in the orthotopic glioma models. Our results suggested that treatment with baicalein might be an effective therapy for recurrent malignant brain cancers through suppressing tumor growth and alleviating edema.

  19. Inhibition of tumor angiogenesis and growth by nanoparticle-mediated p53 gene therapy in mice.

    PubMed

    Prabha, S; Sharma, B; Labhasetwar, V

    2012-08-01

    Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53 gene-loaded NPs (p53NPs). We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this was accomplished was disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

  20. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma

    PubMed Central

    Lv, Yang-Fan; Yan, Guang-Ning; Meng, Gang; Zhang, Xi; Guo, Qiao-Nan

    2015-01-01

    The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3. PMID:26265454

  1. DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis

    PubMed Central

    Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

    2016-01-01

    Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer. PMID:26967562

  2. Silencing Met receptor tyrosine kinase signaling decreased oral tumor growth and increased survival of nude mice

    PubMed Central

    Tao, X.; Hill, K.S.; Gaziova, I.; Sastry, S.K.; Qui, S.; Szaniszlo, P.; Fennewald, S.; Resto, V.A.; Elferink, L.A.

    2013-01-01

    SUMMARY Objectives The hepatocyte growth factor receptor (Met) is frequently overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC), correlating positively with high-grade tumors and shortened patient survival. As such, Met may represent an important therapeutic target. The purpose of this study was to explore the role of Met signaling for HNSCC growth and locoregional dissemination. Materials and methods Using a lentiviral system for RNA interference, we knocked down Met in established HNSCC cell lines that express high levels of the endogenous receptor. The effect of Met silencing on in vitro proliferation, cell survival and migration was examined using western analysis, immunohisto-chemistry and live cell imaging. In vivo tumor growth, dissemination and mouse survival was assessed using an orthotopic tongue mouse model for HNSCC. Results We show that Met knockdown (1) impaired activation of downstream MAPK signaling; (2) reduced cell viability and anchorage independent growth; (3) abrogated HGF-induced cell motility on laminin; (4) reduced In vivo tumor growth by increased cell apoptosis; (5) caused reduced incidence of tumor dissemination to regional lymph nodes and (6) increased the survival of nude mice with orthotopic xenografts. Conclusion Met signaling is important for HNSCC growth and locoregional dissemination In vivo and that targeting Met may be an important strategy for therapy. PMID:24268630

  3. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis. PMID:26452220

  4. Growth hormone and risk for cardiac tumors in Carney complex.

    PubMed

    Bandettini, W Patricia; Karageorgiadis, Alexander S; Sinaii, Ninet; Rosing, Douglas R; Sachdev, Vandana; Schernthaner-Reiter, Marie Helene; Gourgari, Evgenia; Papadakis, Georgios Z; Keil, Meg F; Lyssikatos, Charalampos; Carney, J Aidan; Arai, Andrew E; Lodish, Maya; Stratakis, Constantine A

    2016-09-01

    Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.

  5. Growth hormone and risk for cardiac tumors in Carney complex.

    PubMed

    Bandettini, W Patricia; Karageorgiadis, Alexander S; Sinaii, Ninet; Rosing, Douglas R; Sachdev, Vandana; Schernthaner-Reiter, Marie Helene; Gourgari, Evgenia; Papadakis, Georgios Z; Keil, Meg F; Lyssikatos, Charalampos; Carney, J Aidan; Arai, Andrew E; Lodish, Maya; Stratakis, Constantine A

    2016-09-01

    Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor. PMID:27535175

  6. Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.

    PubMed

    Sun, Meng; Lou, Wei; Chun, Jae Yeon; Cho, Daniel S; Nadiminty, Nagalakshmi; Evans, Christopher P; Chen, Jun; Yue, Jiao; Zhou, Qinghua; Gao, Allen C

    2010-03-01

    Prostate cancer is a frequently occurring disease and is the second leading cause of cancer-related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer, and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis, and short patient survival. In the present study, the authors performed a cell-based rapid screen of the Prestwick Chemical Library consisting of 1120 Food and Drug Administration-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anticancer agents for prostate cancer. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. The authors found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits growth of human prostate cancer cells and in vivo tumor formation. Administration of sanguinarine, beginning 3 days after ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume. In addition, sanguinarine sensitized paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of prostate cancer overexpressing survivin. PMID:21318089

  7. 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

  8. The Role of Oxygen in Avascular Tumor Growth.

    PubMed

    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

  9. The Role of Oxygen in Avascular Tumor Growth.

    PubMed

    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.

  10. Semiautomatic growth analysis of multicellular tumor spheroids.

    PubMed

    Rodday, Bjoern; Hirschhaeuser, Franziska; Walenta, Stefan; Mueller-Klieser, Wolfgang

    2011-10-01

    Multicellular tumor spheroids (MCTS) are routinely employed as three-dimensional in vitro models to study tumor biology. Cultivation of MCTS in spinner flasks provides better growing conditions, especially with regard to the availability of nutrients and oxygen, when compared with microtiter plates. The main endpoint of drug response experiments is spheroid size. It is common practice to analyze spheroid size manually with a microscope and an ocular micrometer. This requires removal of some spheroids from the flask, which entails major limitations such as loss of MCTS and the risk of contamination. With this new approach, the authors present an efficient and highly reproducible method to analyze the size of complete MCTS populations in culture containers with transparent, flat bottoms. MCTS sediments are digitally scanned and spheroid volumes are calculated by computerized image analysis. The equipment includes regular office hardware (personal computer, flatbed scanner) and software (Adobe Photoshop, Microsoft Excel, ImageJ). The accuracy and precision of the method were tested using industrial precision steel beads with known diameter. In summary, in comparison with other methods, this approach provides benefits in terms of semiautomation, noninvasiveness, and low costs.

  11. Molecular Cochaperones: Tumor Growth and Cancer Treatment

    PubMed Central

    Calderwood, Stuart K.

    2013-01-01

    Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents. PMID:24278769

  12. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

    PubMed Central

    Shrestha, Sanjeeb; Noh, Jae Myoung; Kim, Shin-Yeong; Ham, Hwa-Yong; Kim, Yeon-Ja; Yun, Young-Jin; Kim, Min-Ju; Kwon, Min-Soo; Song, Dong-Keun; Hong, Chang-Won

    2016-01-01

    ABSTRACT Tumor microenvironments polarize neutrophils to protumoral phenotypes. Here, we demonstrate that the angiotensin converting enzyme inhibitors (ACEis) and angiotensin II type 1 receptor (AGTR1) antagonist attenuate tumor growth via polarization of neutrophils toward an antitumoral phenotype. The ACEis or AGTR1 antagonist enhanced hypersegmentation of human neutrophils and increased neutrophil cytotoxicity against tumor cells. This neutrophil hypersegmentation was dependent on the mTOR pathway. In a murine tumor model, ACEis and AGTR1 antagonist attenuated tumor growth and enhanced neutrophil hypersegmentation. ACEis inhibited tumor-induced polarization of neutrophils to a protumoral phenotype. Neutrophil depletion reduced the antitumor effect of ACEi. Together, these data suggest that the modulation of Ang II pathway attenuates tumor growth via polarization of neutrophils to an antitumoral phenotype. PMID:26942086

  13. Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth

    PubMed Central

    Muders, Michael H.; Vohra, Pawan K.; Dutta, Shamit K; Wang, Enfeng; Ikeda, Yasuhiro; Wang, Ling; Udugamasooriya, D. Gomika; Memic, Adnan; Rupashinghe, Chamila N.; Baretton, Gustavo B.; Aust, Daniela E.; Langer, Silke; Datta, Kaustubh; Simons, Michael; Spaller, Mark R.; Mukhopadhyay, Debabrata

    2009-01-01

    Translational Relevance The five year survival rate in patients with ductal adenocarcinoma of the pancreas is less than 4%. Accordingly, new targets for the treatment of this deadly disease are urgently needed. In this study, we show that targeting GAIP interacting protein C-terminal (GIPC, also known as Synectin) and its PDZ-domain reduces pancreatic cancer growth significantly in vitro and in vivo. Additionally, the blockage of GIPC/Synectin was accompanied by a reduction of IGF-1R protein levels. In summary, the use of a GIPC-PDZ domain inhibitor may be a viable option in the treatment of pancreatic adenocarcinoma in future. Purpose Various studies have demonstrated the importance of GAIP interacting protein, C-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth promoting receptors like IGF-1R and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to demonstrate the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-1 receptor as one of its associated receptors was tested. Experimental Design In vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with shRNA against GIPC/Synectin. Additionally, a GIPC-PDZ-targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Results Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing

  14. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes.

    PubMed

    Nishikawa, Makiya; Hyoudou, Kenji; Kobayashi, Yuki; Umeyama, Yukari; Takakura, Yoshinobu; Hashida, Mitsuru

    2005-12-01

    To develop effective anti-metastatic therapy, targeted or sustained delivery of catalase was examined in mice. We found that mouse lung with metastatic colonies of adenocarcinoma colon26 cells exhibited reduced catalase activity. The interaction of the tumor cells with macrophages or hepatocytes generated detectable amounts of ROS, and increased the activity of matrix metalloproteinases. Hepatocyte-targeted delivery of catalase was successfully achieved by galactosylation, which was highly effective in inhibiting the hepatic metastasis of colon26 cells. PEGylation, which increased the retention of catalase in the circulation, effectively inhibited the pulmonary metastasis of the cells. To examine which processes in tumor metastasis are inhibited by catalase derivatives, the tissue distribution and proliferation of tumor cells in mice was quantitatively analyzed using firefly luciferase-expressing tumor cells. An injection of PEG-catalase just before the inoculation of melanoma B16-BL6/Luc cells significantly reduced the number of the tumor cells in the lung at 24 h. Daily dosing of PEG-catalase greatly inhibited the proliferation of the tumor cells, and increased the survival rate of the tumor-bearing mice. These results indicate that targeted or sustained delivery of catalase to sites where tumor cells metastasize is a promising approach for inhibiting metastatic tumor growth. PMID:16256238

  15. Multiscale models for the growth of avascular tumors

    NASA Astrophysics Data System (ADS)

    Martins, M. L.; Ferreira, S. C.; Vilela, M. J.

    2007-06-01

    In the past 30 years we have witnessed an extraordinary progress on the research in the molecular biology of cancer, but its medical treatment, widely based on empirically established protocols, still has many limitations. One of the reasons for that is the limited quantitative understanding of the dynamics of tumor growth and drug response in the organism. In this review we shall discuss in general terms the use of mathematical modeling and computer simulations related to cancer growth and its applications to improve tumor therapy. Particular emphasis is devoted to multiscale models which permit integration of the rapidly expanding knowledge concerning the molecular basis of cancer and the complex, nonlinear interactions among tumor cells and their microenvironment that will determine the neoplastic growth at the tissue level.

  16. The Influence of Liver Resection on Intrahepatic Tumor Growth.

    PubMed

    Brandt, Hannes H; Nißler, Valérie; Croner, Roland S

    2016-01-01

    The high incidence of tumor recurrence after resection of metastatic liver lesions remains an unsolved problem. Small tumor cell deposits, which are not detectable by routine clinical imaging, may be stimulated by hepatic regeneration factors after liver resection. It is not entirely clear, however, which factors are crucial for tumor recurrence. The presented mouse model may be useful to explore the mechanisms that play a role in the development of recurrent malignant lesions after liver resection. The model combines the easy-to-perform and reproducible techniques of defined amounts of liver tissue removal and tumor induction (by injection) in mice. The animals were treated with either a single laparotomy, a 30% liver resection, or a 70% liver resection. All animals subsequently received a tumor cell injection into the remaining liver tissue. After two weeks of observation, the livers and tumors were evaluated for size and weight and examined by immunohistochemistry. After a 70% liver resection, the tumor volume and weight were significantly increased compared to a laparotomy alone (p <0.05). In addition, immunohistochemistry (Ki67) showed an increased tumor proliferation rate in the resection group (p <0.05). These findings demonstrate the influence of hepatic regeneration mechanisms on intrahepatic tumor growth. Combined with methods like histological workup or RNA analysis, the described mouse model could serve as foundation for a close examination of different factors involved in tumor growth and metastatic disease recurrence within the liver. A considerable number of variables like the length of postoperative observation, the cell line used for injection or the timing of injection and liver resection offer multiple angles when exploring a specific question in the context of post-hepatectomy metastases. The limitations of this procedure are the authorization to perform the procedure on animals, access to an appropriate animal testing facility and acquisition

  17. Effect of tumor microenvironmental factors on tumor growth dynamics modeled by correlated colored noises with colored cross-correlation

    NASA Astrophysics Data System (ADS)

    Idris, Ibrahim Mu'awiyya; Abu Bakar, Mohd Rizam

    2016-07-01

    The effect of non-immunogenic tumor microenvironmental factors on tumor growth dynamics modeled by correlated additive and multiplicative colored noises is investigated. Using the Novikov theorem, Fox approach and Ansatz of Hanggi, an approximate Fokker-Planck equation for the system is obtained and analytic expression for the steady state distribution Pst(x) is derived. Based on the numerical results, we find that fluctuations of microenvironmental factors within the tumor site with parameter θ have a diffusive effect on the tumor growth dynamics, and the tumor response to the microenvironmental factors with parameter α inhibits growth at weak correlation time τ. Moreover, at increasing correlation time τ the inhibitive effect of tumor response α is suppressed and instead a systematic growth promotion is noticed. The result also reveals that the strength of the correlation time τ has a strong influence on the growth effects exerted by the non-immunogenic component of tumor microenvironment on tumor growth.

  18. Histone Methylase MLL1 plays critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo

    PubMed Central

    Ansari, Khairul I.; Kasiri, Sahba; Mandal, Subhrangsu S.

    2012-01-01

    Mixed lineage leukemias (MLL) are human histone H3 lysine-4 specific methyl transferases that play critical roles in gene expression, epigenetics, and cancer. Herein, we demonstrated that antisense-mediated knockdown of MLL1 induced cell cycle arrest and apoptosis in cultured cells. Intriguingly, application of MLL1-antisense specifically knocked down MLL1 in vivo and suppressed the growth of xenografted cervical tumor implanted in nude mouse. MLL1-knockdown downregulated various growth and angiogenic factors such as HIF1α, VEGF and CD31 in tumor tissue affecting tumor growth. MLL1 is overexpressed along the line of vascular network and localized adjacent to endothelial cell layer expressing CD31, indicating potential roles of MLL1 in vasculogenesis. MLL1 is also overexpressed in the hypoxic regions along with HIF1α. Overall, our studies demonstrated that MLL1 is a key player in hypoxia signaling, vasculogenesis, and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy. PMID:22926525

  19. Reduced expression of CD109 in tumor-associated endothelial cells promotes tumor progression by paracrine interleukin-8 in hepatocellular carcinoma

    PubMed Central

    Zhang, Yuan-Yuan; Ao, Jian-Yang; Cai, Hao; Ma, De-Ning; Wang, Cheng-Hao; Qin, Cheng-Dong; Gao, Dong-Mei; Tang, Zhao-You

    2016-01-01

    Tumor-associated endothelial cells (TEC) directly facilitate tumor progression, but little is known about the mechanisms. We investigated the function of CD109 in TEC and its clinical significance in hepatocellular carcinoma (HCC). The correlation between CD109 expressed on tumor vessels and the prognosis after surgical resection of HCC was studied. The effect of human umbilical vein endothelial cells (HUVEC) with different CD109 expression on hepatoma cell proliferation, migration, and invasion was compared in co-culture assay. Associated key factors were screened by human cytokine antibody array and validated thereafter. HUVEC with different CD109 expression were co-implanted with HCCLM3 or HepG2 cells in nude mice to investigate the effect of CD109 expression on tumor growth and metastasis. Reduced expression of CD109 on tumor vessels was associated with large tumor size, microvascular invasion, and advanced tumor stage. CD109 was an independent risk factor for disease-free survival (P = 0.001) after curative resection of HCC. CD109 knockdown in HUVEC promoted hepatoma cell proliferation, migration, and invasion. Interleukin-8 (IL-8) was a key tumor-promoting factor secreted from CD109 knockdown HUVEC. CD109 knockdown upregulated IL-8 expression through activation of TGF-β/Akt/NF-κB pathway in HUVEC. Co-implantation with CD109 knockdown HUVEC accelerated tumor growth and metastasis in mice models. In conclusion, CD109 expression on tumor vessels is a potential prognostic marker for HCC, and its reduced expression on TEC promoted tumor progression by paracrine IL-8. PMID:27121053

  20. Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth

    PubMed Central

    Adamo, Hanibal; Thysell, Elin; Jernberg, Emma; Stattin, Pär; Widmark, Anders; Wikström, Pernilla; Bergh, Anders

    2016-01-01

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer. PMID:27280718

  1. Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

    PubMed

    Yan, Ping; Gong, Hui; Zhai, Xiaoyan; Feng, Yi; Wu, Jun; He, Sheng; Guo, Jian; Wang, Xiaoxia; Guo, Rui; Xie, Jun; Li, Ren-Ke

    2016-04-01

    Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator. PMID:26835537

  2. Short communication: genital tumor growth factor-β1 levels in HIV-infected Indian women are associated with reduced levels of innate antimicrobial products and increased HIV shedding.

    PubMed

    Thakar, Madhuri; Patil, Rahul; Shukre, Subodh; Bichare, Shubhangi; Kadam, Poonam; Khopkar, Priyanka; Ghate, Manisha; Paranjape, Ramesh

    2014-07-01

    Tumor growth factor (TGF)-β1 is a cytokine with potent immunoinhibitory functions and is known to be secreted by vaginal epithelial cells. The present study was designed to determine the association of cervicovaginal levels of TGF- β1 with various innate immune secretions such as cytokines and antimicrobial polypeptides [Trappin-2/Elafin and secretory leukocyte protease inhibitor (SLPI)] and cervical HIV shedding in HIV-infected Indian women. TGF- β1, antimicrobial polypeptides, and cytokine levels were estimated in the cervicovaginal lavages (CVLs) of 36 age-matched HIV-infected and 31 HIV-uninfected asymptomatic Indian women using an ELISA and Bio-Plex Assay, respectively. The nonparametric Mann-Whitney test and Spearman's test were used to compare the levels from both the groups and to determine the association of the TGF-β1 levels with cervical viral shedding and antimicrobial peptides. The levels of Trappin-2/Elafin and SLPI were similar in the CVLs of HIV-infected and HIV-uninfected women, but were significantly associated with a low cervical viral load (r=-0.501, p=0.005 for Trappin-2/Elafin and r=-0.488, p=0.007 for SLPI). Eleven (30.5%) of the 36 HIV-infected women showed 5- to 30-fold higher levels of TGF-β1 as compared to the levels in uninfected women. The TGF-β1 levels were significantly associated with higher cervical viral load (r=0.425, p=0.03) and with lower levels of Trappin-2/Elafin (r=-0.407, p=0.03) and SLPI (r=-0.405, p=0.04). The findings indicate a possible interdependent mechanism driving the identified higher TGF-β1 and lower antimicrobial peptide (Trappin-2/Elafin and SLPI) levels at the genital mucosa surface in HIV-infected women. We postulate that a combination of increased TGF-β1 secretion and altered levels of Trappin-2/Elafin and SLPI contributes to increased HIV shedding. The observation warrants further studies to identify the underlying mechanisms linking increased mucosal TGF-β1 levels and genital HIV shedding

  3. 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

  4. 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.

  5. Pediatric Brain Tumor Treatment: Growth Consequences and their Management

    PubMed Central

    Mostoufi-Moab, Sogol; Grimberg, Adda

    2014-01-01

    Tumors of the central nervous system, the most common solid tumors of childhood, are a major source of cancer-related morbidity and mortality in children. Survival rates have improved significantly following treatment for childhood brain tumors, with this growing cohort of survivors at high risk of adverse medical and late effects. Endocrine morbidities are the most prominent disorder among the spectrum of long-term conditions, with growth hormone deficiency the most common endocrinopathy noted, either from tumor location or after cranial irradiation and treatment effects on the hypothalamic/pituitary unit. Deficiency of other anterior pituitary hormones can contribute to negative effects on growth, body image and composition, sexual function, skeletal health, and quality of life. Pediatric and adult endocrinologists often provide medical care to this increasing population. Therefore, a thorough understanding of the epidemiology and pathophysiology of growth failure as a consequence of childhood brain tumor, both during and after treatment, is necessary and the main focus of this review. PMID:21037539

  6. Phase transitions in tumor growth: II prostate cancer cell lines

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, A.; De Miguel, M. P.; Izquierdo-Kulich, E.; Royuela-García, M.; Tejera, E.; Nieto-Villar, J. M.

    2015-05-01

    We propose a mechanism for prostate cancer cell lines growth, LNCaP and PC3 based on a Gompertz dynamics. This growth exhibits a multifractal behavior and a "second order" phase transition. Finally, it was found that the cellular line PC3 exhibits a higher value of entropy production rate compared to LNCaP, which is indicative of the robustness of PC3, over to LNCaP and may be a quantitative index of metastatic potential tumors.

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

    PubMed Central

    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

    2014-01-01

    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. Interleukin-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. Here, 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 IFNγ production by CD8+ T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor-antigen-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 (Treg) 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. PMID:25429071

  8. Development, Selection, and Validation of Tumor Growth Models

    NASA Astrophysics Data System (ADS)

    Shahmoradi, Amir; Lima, Ernesto; Oden, J. Tinsley

    In recent years, a multitude of different mathematical approaches have been taken to develop multiscale models of solid tumor growth. Prime successful examples include the lattice-based, agent-based (off-lattice), and phase-field approaches, or a hybrid of these models applied to multiple scales of tumor, from subcellular to tissue level. Of overriding importance is the predictive power of these models, particularly in the presence of uncertainties. This presentation describes our attempt at developing lattice-based, agent-based and phase-field models of tumor growth and assessing their predictive power through new adaptive algorithms for model selection and model validation embodied in the Occam Plausibility Algorithm (OPAL), that brings together model calibration, determination of sensitivities of outputs to parameter variances, and calculation of model plausibilities for model selection. Institute for Computational Engineering and Sciences.

  9. Joint fitting reveals hidden interactions in tumor growth.

    PubMed

    Barberis, L; Pasquale, M A; Condat, C A

    2015-01-21

    Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Crucial to the system evolution are the interactions between these populations. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses alone, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination.

  10. Impact of macrophages on tumor growth characteristics in a murine ocular tumor model.

    PubMed

    Stei, Marta M; Loeffler, Karin U; Kurts, Christian; Hoeller, Tobias; Pfarrer, Christiane; Holz, Frank G; Herwig-Carl, Martina C

    2016-10-01

    Tumor associated macrophages (TAM), mean vascular density (MVD), PAS positive extravascular matrix patterns, and advanced patients' age are associated with a poor prognosis in uveal melanoma. These correlations may be influenced by M2 macrophages and their cytokine expression pattern. Thus, the effect of TAM and their characteristic cytokines on histologic tumor growth characteristics were studied under the influence of age. Ninety five CX3CR1(+/GFP) mice (young 8-12weeks, old 10-12months) received an intravitreal injection of 1 × 10(5) HCmel12 melanoma cells. Subgroups were either systemically macrophage-depleted by Clodronate liposomes (n = 23) or received melanoma cells, which were pre-incubated with the supernatant of M1- or M2-polarized macrophages (n = 26). Eyes were processed histologically/immunohistochemically (n = 75), or for flow cytometry (n = 20) to analyze tumor size, mean vascular density (MVD), extravascular matrix patterns, extracellular matrix (ECM) and the presence/polarization of TAM. Prognostically significant extravascular matrix patterns (parallels with cross-linkings, loops, networks) were found more frequently in tumors of untreated old compared to tumors of untreated young mice (p = 0.024); as well as in tumors of untreated mice compared to tumors of macrophage-depleted mice (p = 0.014). Independent from age, M2-conditioned tumors showed more TAM (p = 0.001), increased collagen IV levels (p = 0.024) and a higher MVD (p = 0.02) than M1-conditioned tumors. Flow cytometry revealed a larger proportion of M2-macrophages in old than in young mice. The results indicate that TAM and their cytokines appear to be responsible for a more aggressive tumor phenotype. Tumor favoring and pro-angiogenic effects can be directly attributed to a M2-dominated tumor microenvironment rather than to age-dependent factors alone. However, an aged immunoprofile with an increased number of M2-macrophages may provide a tumor-favoring basis

  11. 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)

  12. Building Context with Tumor Growth Modeling Projects in Differential Equations

    ERIC Educational Resources Information Center

    Beier, Julie C.; Gevertz, Jana L.; Howard, Keith E.

    2015-01-01

    The use of modeling projects serves to integrate, reinforce, and extend student knowledge. Here we present two projects related to tumor growth appropriate for a first course in differential equations. They illustrate the use of problem-based learning to reinforce and extend course content via a writing or research experience. Here we discuss…

  13. Enhancement or inhibition of tumor growth by interferon: dependence on treatment protocol.

    PubMed

    Murasko, D M; Fresa, K; Mark, R

    1983-12-15

    MSC cells are tumor cells originally induced in BALB/c mice by Moloney sarcoma virus. In these studies we demonstrated that, although these tumor cells are sensitive in vitro both to lysis by NK or NK-like cells and to the growth-inhibitory effect of murine L-cell interferon (IFN), the growth of the tumor in vivo could be either inhibited or enhanced by IFN. The outcome of in vivo IFN treatment was dependent on the timing and route of IFN administration relative to tumor challenge. IFN given systematically at the same time as tumor challenge resulted in enhancement of primary tumor formation, rate of tumor growth and subsequent progressive tumor growth. In contrast, IFN administered at the site of tumor inoculation on days 1-3 after tumor challenge inhibited tumor formation and growth. Histopathology of tissue sections obtained from the site of tumor challenge confirmed these results. Similar studies performed in mice given 450 rads of X-irradiation showed that IFN could still inhibit tumor growth when administered at the site of tumor inoculation on days 1-3 after tumor challenge. IFN administered simultaneously with tumor challenge, however, did not enhance tumor growth in irradiated mice. These results are consistent with the interpretation that 1) inhibition of MSC-induced tumor growth by IFN has a radioresistant component and 2) the enhancement of MSC-induced tumor formation by IFN is dependent on interaction with a radiosensitive population of cells, possibly lymphoid cells. PMID:6360916

  14. Reduced Glucocorticoid Receptor Expression Predicts Bladder Tumor Recurrence and Progression

    PubMed Central

    Ishiguro, Hitoshi; Kawahara, Takashi; Zheng, Yichun; Netto, George J.; Miyamoto, Hiroshi

    2015-01-01

    Objectives To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. Methods We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. Results Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P = .026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P < .001) and 61 (73%) of 84 non–muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P < .001) were moderately to strongly immunoreactive for GR. Kaplan-Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P = .025), progression of MI tumors (P = .082), and cancer-specific survival of MI tumors (P = .067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P = .034). Conclusions GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. PMID:25015855

  15. Ketone body utilization drives tumor growth and metastasis

    PubMed Central

    Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.

    2012-01-01

    We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID:23082722

  16. Ketone body utilization drives tumor growth and metastasis.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-01

    We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two-compartment tumor metabolism." Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID:23082722

  17. 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. PMID:27196773

  18. Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth.

    PubMed

    Ma, Xiaojun; Aoki, Tomohiro; Tsuruyama, Tatsuaki; Narumiya, Shuh

    2015-07-15

    Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

  19. Bioassay and Attributes of a Growth Factor Associated with Crown Gall Tumors 1

    PubMed Central

    Lippincott, Barbara B.; Lippincott, James A.

    1970-01-01

    An improved bioassay is described for a factor that promotes tumor growth which was first obtained from extracts of pinto bean leaves with crown gall tumors. Sixteen primary pinto bean leaves per sample are inoculated with sufficient Agrobacterium tumefaciens to initiate about 5 to 10 tumors per leaf and treated with tumor growth factor at day 3 after inoculation. The diameters of 30 to 48 round tumors (no more than 3 randomly selected per leaf) are measured per test sample at day 6. Mean tumor diameter increased linearly with the logarithm of the concentration of tumor growth factor applied. The tumor growth factor was separated by column chromatography from an ultraviolet light-absorbing compound previously reported to be associated with fractions having maximal tumor growth factor activity. Partly purified tumor growth factor showed no activity in a cytokinin bioassay or an auxin bioassay, and negligible activity in gibberellin bioassays. Representatives of these three classes of growth factors did not promote tumor growth. Extracts from crown gall tumors on primary pinto bean leaves, primary castor bean leaves, Bryophyllum leaves, carrot root slices, and tobacco stems showed tumor growth factor activity, whereas extracts from healthy control tissues did not. Extracts from actively growing parts of healthy pinto beans, Bryophyllum, and tobacco, however, showed tumor growth factor activity. Tumor growth factor is proposed to be a normal plant growth factor associated with rapidly growing tissues. Its synthesis may be activated in nongrowing tissues by infection with Agrobacterium sp. PMID:16657534

  20. Bioassay and attributes of a growth factor associated with crown gall tumors.

    PubMed

    Lippincott, B B; Lippincott, J A

    1970-11-01

    An improved bioassay is described for a factor that promotes tumor growth which was first obtained from extracts of pinto bean leaves with crown gall tumors. Sixteen primary pinto bean leaves per sample are inoculated with sufficient Agrobacterium tumefaciens to initiate about 5 to 10 tumors per leaf and treated with tumor growth factor at day 3 after inoculation. The diameters of 30 to 48 round tumors (no more than 3 randomly selected per leaf) are measured per test sample at day 6. Mean tumor diameter increased linearly with the logarithm of the concentration of tumor growth factor applied. The tumor growth factor was separated by column chromatography from an ultraviolet light-absorbing compound previously reported to be associated with fractions having maximal tumor growth factor activity. Partly purified tumor growth factor showed no activity in a cytokinin bioassay or an auxin bioassay, and negligible activity in gibberellin bioassays. Representatives of these three classes of growth factors did not promote tumor growth. Extracts from crown gall tumors on primary pinto bean leaves, primary castor bean leaves, Bryophyllum leaves, carrot root slices, and tobacco stems showed tumor growth factor activity, whereas extracts from healthy control tissues did not. Extracts from actively growing parts of healthy pinto beans, Bryophyllum, and tobacco, however, showed tumor growth factor activity. Tumor growth factor is proposed to be a normal plant growth factor associated with rapidly growing tissues. Its synthesis may be activated in nongrowing tissues by infection with Agrobacterium sp. PMID:16657534

  1. Arsenic trioxide disrupts glioma stem cells via promoting PML degradation to inhibit tumor growth

    PubMed Central

    Zhou, Wenchao; Cheng, Lin; Shi, Yu; Ke, Susan Q.; Huang, Zhi; Fang, Xiaoguang; Chu, Cheng-wei; Xie, Qi; Bian, Xiu-wu; Rich, Jeremy N.; Bao, Shideng

    2015-01-01

    Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As2O3) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As2O3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As2O3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As2O3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As2O3 treatment preferentially inhibited cell growth of GSCs but not matched non-stem tumor cells (NSTCs). Furthermore, As2O3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As2O3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs. PMID:26510911

  2. Arsenic trioxide disrupts glioma stem cells via promoting PML degradation to inhibit tumor growth.

    PubMed

    Zhou, Wenchao; Cheng, Lin; Shi, Yu; Ke, Susan Q; Huang, Zhi; Fang, Xiaoguang; Chu, Cheng-wei; Xie, Qi; Bian, Xiu-wu; Rich, Jeremy N; Bao, Shideng

    2015-11-10

    Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As2O3) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As2O3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As2O3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As2O3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As2O3 treatment preferentially inhibited cell growth of GSCs but not matched non-stem tumor cells (NSTCs). Furthermore, As2O3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As2O3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs. PMID:26510911

  3. Endothelial cell tumor growth is Ape/ref-1 dependent.

    PubMed

    Biswas, Ayan; Khanna, Savita; Roy, Sashwati; Pan, Xueliang; Sen, Chandan K; Gordillo, Gayle M

    2015-09-01

    Tumor-forming endothelial cells have highly elevated levels of Nox-4 that release H2O2 into the nucleus, which is generally not compatible with cell survival. We sought to identify compensatory mechanisms that enable tumor-forming endothelial cells to survive and proliferate under these conditions. Ape-1/ref-1 (Apex-1) is a multifunctional protein that promotes DNA binding of redox-sensitive transcription factors, such as AP-1, and repairs oxidative DNA damage. A validated mouse endothelial cell (EOMA) tumor model was used to demonstrate that Nox-4-derived H2O2 causes DNA oxidation that induces Apex-1 expression. Apex-1 functions as a chaperone to keep transcription factors in a reduced state. In EOMA cells Apex-1 enables AP-1 binding to the monocyte chemoattractant protein-1 (mcp-1) promoter and expression of that protein is required for endothelial cell tumor formation. Intraperitoneal injection of the small molecule inhibitor E3330, which specifically targets Apex-1 redox-sensitive functions, resulted in a 50% decrease in tumor volume compared with mice injected with vehicle control (n = 6 per group), indicating that endothelial cell tumor proliferation is dependent on Apex-1 expression. These are the first reported results to establish Nox-4 induction of Apex-1 as a mechanism promoting endothelial cell tumor formation.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis.

    PubMed

    Lehuédé, Camille; Dupuy, Fanny; Rabinovitch, Rebecca; Jones, Russell G; Siegel, Peter M

    2016-09-15

    Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. ©2016 AACR. PMID:27587539

  6. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis.

    PubMed

    Lehuédé, Camille; Dupuy, Fanny; Rabinovitch, Rebecca; Jones, Russell G; Siegel, Peter M

    2016-09-15

    Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. ©2016 AACR.

  7. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling.

    PubMed

    Pasula, Satish; Cai, Xiaofeng; Dong, Yunzhou; Messa, Mirko; McManus, John; Chang, Baojun; Liu, Xiaolei; Zhu, Hua; Mansat, Robert Silasi; Yoon, Seon-Joo; Hahn, Scott; Keeling, Jacob; Saunders, Debra; Ko, Genevieve; Knight, John; Newton, Gail; Luscinskas, Francis; Sun, Xiaohong; Towner, Rheal; Lupu, Florea; Xia, Lijun; Cremona, Ottavio; De Camilli, Pietro; Min, Wang; Chen, Hong

    2012-12-01

    Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, however, loss of epsins 1 and 2 resulted in disorganized vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promoted binding of epsin to ubiquitinated VEGFR2. Loss of epsins 1 and 2 specifically impaired endocytosis and degradation of VEGFR2, which resulted in excessive VEGF signaling that compromised tumor vascular function by exacerbating nonproductive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Promotion of excessive VEGF signaling within tumors via a block of epsin 1 and 2 function may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies.

  8. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    PubMed Central

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+ Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL. PMID:26137413

  9. Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

    PubMed Central

    Fernández-Rodríguez, Rubén; Rodríguez-Baena, Francisco Javier; Martino-Echarri, Estefanía; Peris-Torres, Carlos; del Carmen Plaza-Calonge, María; Rodríguez-Manzaneque, Juan Carlos

    2016-01-01

    The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1. PMID:27120788

  10. Escherichia coli growth under modeled reduced gravity

    NASA Technical Reports Server (NTRS)

    Baker, Paul W.; Meyer, Michelle L.; Leff, Laura G.

    2004-01-01

    Bacteria exhibit varying responses to modeled reduced gravity that can be simulated by clino-rotation. When Escherichia coli was subjected to different rotation speeds during clino-rotation, significant differences between modeled reduced gravity and normal gravity controls were observed only at higher speeds (30-50 rpm). There was no apparent affect of removing samples on the results obtained. When E. coli was grown in minimal medium (at 40 rpm), cell size was not affected by modeled reduced gravity and there were few differences in cell numbers. However, in higher nutrient conditions (i.e., dilute nutrient broth), total cell numbers were higher and cells were smaller under reduced gravity compared to normal gravity controls. Overall, the responses to modeled reduced gravity varied with nutrient conditions; larger surface to volume ratios may help compensate for the zone of nutrient depletion around the cells under modeled reduced gravity.

  11. Liver-Tumor Hybrid Organoids for Modeling Tumor Growth and Drug Response In Vitro

    PubMed Central

    Skardal, Aleksander; Devarasetty, Mahesh; Rodman, Christopher; Atala, Anthony; Soker, Shay

    2015-01-01

    Current in vitro models for tumor growth and metastasis are poor facsimiles of in vivo cancer physiology and thus, are not optimal for anti-cancer drug development. Three dimensional (3D) tissue organoid systems, which utilize human cells in a tailored microenvironment, have the potential to recapitulate in vivo conditions and address the drawbacks of current tissue culture dish 2D models. In this study, we created liver-based cell organoids in a rotating wall vessel bioreactor. The organoids were further inoculated with colon carcinoma cells in order to create liver-tumor organoids for in vitro modeling of liver metastasis. Immunofluorescent staining revealed notable phenotypic differences between tumor cells in 2D and inside the organoids. In 2D they displayed an epithelial phenotype, and only after transition to the organoids did the cells present with a mesenchymal phenotype. The cell surface marker expression results suggested that WNT pathway might be involved in the phenotypic changes observed between cells in 2D and organoid conditions, and may lead to changes in cell proliferation. Manipulating the WNT pathway with an agonist and antagonist showed significant changes in sensitivity to the anti-proliferative drug 5-fluoruracil. Collectively, the results show the potential of in vitro 3D liver-tumor organoids to serve as a model for metastasis growth and for testing the response of tumor cells to current and newly discovered drugs. PMID:25777294

  12. 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

  13. 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

  14. The role of the microenvironment in tumor growth and invasion

    PubMed Central

    Kim, Yangjin; Stolarska, Magdalena A.; Othmer, Hans G.

    2011-01-01

    Mathematical modeling and computational analysis are essential for understanding the dynamics of the complex gene networks that control normal development and homeostasis, and can help to understand how circumvention of that control leads to abnormal outcomes such as cancer. Our objectives here are to discuss the different mechanisms by which the local biochemical and mechanical microenvironment, which is comprised of various signaling molecules, cell types and the extracellular matrix (ECM), affects the progression of potentially-cancerous cells, and to present new results on two aspects of these effects. We first deal with the major processes involved in the progression from a normal cell to a cancerous cell at a level accessible to a general scientific readership, and we then outline a number of mathematical and computational issues that arise in cancer modeling. In Section 2 we present results from a model that deals with the effects of the mechanical properties of the environment on tumor growth, and in Section 3 we report results from a model of the signaling pathways and the tumor microenvironment (TME), and how their interactions affect the development of breast cancer. The results emphasize anew the complexities of the interactions within the TME and their effect on tumor growth, and show that tumor progression is not solely determined by the presence of a clone of mutated immortal cells, but rather that it can be ‘community-controlled’. It Takes a Village – Hilary Clinton PMID:21736894

  15. MT95-4, a fully humanized antibody raised against aminopeptidase N, reduces tumor progression in a mouse model

    PubMed Central

    Akita, Shin; Hattori, Noboru; Masuda, Takeshi; Horimasu, Yasushi; Nakashima, Taku; Iwamoto, Hiroshi; Fujitaka, Kazunori; Miyake, Masayuki; Kohno, Nobuoki

    2015-01-01

    Aminopeptidase N (APN/CD13) is involved in tumor cell invasion and tumor angiogenesis and is considered a promising therapeutic target in the treatment of cancer. To develop a novel monoclonal antibody-based cancer therapy targeting APN/CD13, we established a fully humanized anti-APN/CD13 monoclonal antibody, MT95-4. In vitro, MT95-4 inhibited APN/CD13 enzymatic activity on the tumor cell surface and blocked tumor cell invasion. B16 mouse melanoma cells stably expressing human APN/CD13 were also established and were inoculated s.c. or injected i.v. into nude mice. We found that expression of human APN/CD13 in murine melanoma cells increased the size of subcutaneous tumors, extent of lung metastasis and degree of angiogenesis in the subcutaneous tumors; these tumor-promoting and angiogenesis-promoting characteristics were reduced by the i.p. administration of MT95-4. To further verify the specificity of MT95-4 for neutralization of APN/CD13 activity, MT95-4 was administered into NOD/SCID mice inoculated s.c. with H1299 or PC14 cells, which exhibit high expression of APN/CD13, or with A549 cells, which exhibit weak expression of APN/CD13. MT95-4 reduced tumor growth and angiogenesis in mice bearing H1299-derived and PC14-derived tumors, but not in mice bearing A549-derived tumors. These results suggested that the antitumor and anti-angiogenic effects of MT95-4 were dependent on APN/CD13 expression in tumor cells. Given that MT95-4 is the first fully humanized monoclonal antibody against APN/CD13, MT95-4 should be recognized as a promising candidate for monoclonal antibody therapy against tumors expressing APN/CD13. PMID:25950387

  16. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo

    SciTech Connect

    Chian, Song; Thapa, Ruby; Chi, Zhexu; Wang, Xiu Jun; Tang, Xiuwen

    2014-05-16

    Highlights: • Luteolin inhibits the Nrf2 pathway in mouse liver and in xenografted tumors. • Luteolin markedly inhibits the growth of xenograft tumors. • Luteolin enhances the anti-cancer effect of cisplatin in mice in vivo. • Luteolin could serve as an adjuvant in the chemotherapy of NSCLC. - Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2{sup −/−} mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.

  17. c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations

    PubMed Central

    Otte, Anna; Rauprich, Finn; von der Ohe, Juliane; Yang, Yuanyuan; Kommoss, Friedrich; Feuerhake, Friedrich; Hillemanns, Peter; Hass, Ralf

    2015-01-01

    A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth. PMID:26436697

  18. Depletion of Ascorbic Acid Restricts Angiogenesis and Retards Tumor Growth in a Mouse Model

    PubMed Central

    Telang, Sucheta; Clem, Amy L; Eaton, John W; Chesney, Jason

    2007-01-01

    Abstract Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo-/-) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer. PMID:17325743

  19. The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment

    PubMed Central

    Dalmasso, Guillaume; Cougnoux, Antony; Delmas, Julien; Darfeuille-Michaud, Arlette; Bonnet, Richard

    2014-01-01

    The gut microbiota is suspected to promote colorectal cancer (CRC). Escherichia coli are more frequently found in CCR biopsies than in healthy mucosa; furthermore, the majority of mucosa-associated E. coli isolated from CCR harbors the pks genomic island (pks+ E. coli) that is responsible for the synthesis of colibactin, a genotoxic compound. We have recently reported that transient contact of a few malignant cells with colibactin-producing E. coli increases tumor growth in a xenograft mouse model. Growth is sustained by cellular senescence that is accompanied by the production of growth factors. We demonstrated that cellular senescence is a consequence of the pks+ E. coli-induced alteration of p53 SUMOylation, an essential post-translational modification in eukaryotic cells. The underlying mechanisms for this process involve the induction of miR-20a-5p expression, which targets SENP1, a key protein in the regulation of the SUMOylation process. These results are consistent with the expression of SENP1, miR-20a-5p and growth factors that are observed in a CRC mouse model and in human CCR biopsies colonized by pks+ E. coli. Overall, the data reveal a new paradigm for carcinogenesis in which pks+ E. coli infection induces cellular senescence characterized by the production of growth factors that promote the proliferation of uninfected cells and, subsequently, tumor growth. PMID:25483338

  20. Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors

    PubMed Central

    Zhang, Ying; Ertl, Hildegund C.J.

    2016-01-01

    The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice. PMID:26943036

  1. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells.

    PubMed

    Hoffmann, Sebastian; Rockenstein, Andreas; Ramaswamy, Anette; Celik, Ilhan; Wunderlich, Anette; Lingelbach, Susanne; Hofbauer, Lorenz C; Zielke, Andreas

    2007-01-29

    The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer

  2. 3D Multi-Cell Simulation of Tumor Growth and Angiogenesis

    PubMed Central

    Shirinifard, Abbas; Gens, J. Scott; Zaitlen, Benjamin L.; Popławski, Nikodem J.; Swat, Maciej; Glazier, James A.

    2009-01-01

    We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors. PMID:19834621

  3. In-vivo visualization of melanoma tumor microvessels and blood flow velocity changes accompanying tumor growth

    NASA Astrophysics Data System (ADS)

    Ishida, Hiroki; Hachiga, Tadashi; Andoh, Tsugunobu; Akiguchi, Shunsuke

    2012-11-01

    We demonstrate that using micro multipoint laser Doppler velocimetry (μ-MLDV) for noninvasive in-vivo imaging of blood vessels is useful for diagnosing malignant melanomas by comparison with visual diagnosis by dermoscopy. The blood flow velocity in microvessels varied during growth of melanomas transplanted in mouse ears. Mouse ears were observed by μ-MLDV up to 16 days after transplantation. The blood flow velocity in the tumor increased with increasing time and reached maximum of 4.5 mm/s at 9 days, which is more than twice that prior to transplantation. After 12 days, when the lesion had grown to an area of 6.6 mm2, we observed the formation of new blood vessels in the tumor. Finally, when the lesion had an area of 18 mm2 after 16 days, the flow velocity in the tumor decreased to approximately 3.2 mm/s.

  4. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model

    NASA Astrophysics Data System (ADS)

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-11-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress

  5. Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4

    PubMed Central

    Brigatte, Patrícia; Faiad, Odair Jorge; Ferreira Nocelli, Roberta Cornélio; Landgraf, Richardt G.; Palma, Mario Sergio; Cury, Yara; Curi, Rui; Sampaio, Sandra Coccuzzo

    2016-01-01

    We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs. PMID:27190493

  6. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study.

    PubMed

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors.

  7. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study

    PubMed Central

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G.; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors. PMID:26670463

  8. Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis.

    PubMed

    Bachelier, Richard; Confavreux, Cyrille B; Peyruchaud, Olivier; Croset, Martine; Goehrig, Delphine; van der Pluijm, Gabri; Clézardin, Philippe

    2014-09-15

    The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest. PMID:24615579

  9. Lowering bone mineral affinity of bisphosphonates as a therapeutic strategy to optimize skeletal tumor growth inhibition in vivo.

    PubMed

    Fournier, Pierrick G J; Daubiné, Florence; Lundy, Mark W; Rogers, Michael J; Ebetino, Frank H; Clézardin, Philippe

    2008-11-01

    Bisphosphonates bind avidly to bone mineral and are potent inhibitors of osteoclast-mediated bone destruction. They also exhibit antitumor activity in vitro. Here, we used a mouse model of human breast cancer bone metastasis to examine the effects of risedronate and NE-10790, a phosphonocarboxylate analogue of the bisphosphonate risedronate, on osteolysis and tumor growth. Osteolysis was measured by radiography and histomorphometry. Tumor burden was measured by fluorescence imaging and histomorphometry. NE-10790 had a 70-fold lower bone mineral affinity compared with risedronate. It was 7-fold and 8,800-fold less potent than risedronate at reducing, respectively, breast cancer cell viability in vitro and bone loss in ovariectomized animals. We next showed that risedronate given at a low dosage in animals bearing human B02-GFP breast tumors reduced osteolysis by inhibiting bone resorption, whereas therapy with higher doses also inhibited skeletal tumor burden. Conversely, therapy with NE-10790 substantially reduced skeletal tumor growth at a dosage that did not inhibit osteolysis, a higher dosage being able to also reduce bone destruction. The in vivo antitumor activity of NE-10790 was restricted to bone because it did not inhibit the growth of subcutaneous B02-GFP tumor xenografts nor the formation of B16-F10 melanoma lung metastases. Moreover, NE-10790, in combination with risedronate, reduced both osteolysis and skeletal tumor burden, whereas NE-10790 or risedronate alone only decreased either tumor burden or osteolysis, respectively. In conclusion, our study shows that decreasing the bone mineral affinity of bisphosphonates is an effective therapeutic strategy to inhibit skeletal tumor growth in vivo.

  10. An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis.

    PubMed

    Guo, Wenli; Zhang, Shuping; Chen, Yue; Zhang, Daoqiang; Yuan, Lin; Cong, Haibo; Liu, Sijin

    2015-09-01

    Epidemiological and experimental studies have suggested that deregulated hepcidin-ferroportin (FPN) signaling is associated with the increased risk of cancers. However, the effects of deregulated hepcidin-FPN signaling on tumor behaviors such as metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2 cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop tumors was also demonstrated in lungs of Hamp1(-/-) mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hamp1(-/-) mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulating tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded tumor growth and metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and vimentin. Additionally, there was also a reduction of lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the hepcidin-FPN signaling in modulating tumor growth and metastasis, providing new evidence to understand the contribution of this signaling in cancers.

  11. Close interactions between mesenchymal stem cells and neuroblastoma cell lines lead to tumor growth inhibition.

    PubMed

    Bianchi, Giovanna; Morandi, Fabio; Cilli, Michele; Daga, Antonio; Bocelli-Tyndall, Chiara; Gambini, Claudio; Pistoia, Vito; Raffaghello, Lizzia

    2012-01-01

    Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment.

  12. Close Interactions between Mesenchymal Stem Cells and Neuroblastoma Cell Lines Lead to Tumor Growth Inhibition

    PubMed Central

    Bianchi, Giovanna; Morandi, Fabio; Cilli, Michele; Daga, Antonio; Bocelli-Tyndall, Chiara; Gambini, Claudio

    2012-01-01

    Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment. PMID:23119082

  13. 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.

  14. Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress.

    PubMed

    Chen, Y; Zhang, Z; Yang, K; Du, J; Xu, Y; Liu, S

    2015-07-01

    Although previous studies suggest that myeloid zinc-finger 1 (MZF-1) is a multifaceted transcription factor that may function as either an oncogene or a tumor suppressor, the molecular bases determining its different traits remain elusive. Increasing evidence suggests that disorders in iron metabolism affect tumorigenesis and tumor behaviors, and that excess tumor iron stimulates tumor progression through various mechanisms such as enhancing DNA replication and energy metabolism. Ferroportin (FPN) is the only known iron exporter in mammalian cells, and it determines global iron egress out of cells. FPN reduction leads to decreased iron efflux and increased intracellular iron that consequentially aggravates the oncogenic effects of iron. MZF-1 was recently identified as a transcription factor that regulates FPN expression. Thus far, however, the molecular mechanisms underlying the MZF-1-FPN signaling in cancers are largely unknown. Here, we found a significant reduction of FPN levels in prostate tumors relative to adjacent tissues, and demonstrated a crucial role of FPN in tumor growth through controlling tumor iron concentration. Inhibition of MZF-1 expression led to reduced FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, increase of MZF-1 expression restrained tumor cell growth by promoting FPN-driven iron egress. Importantly, we demonstrated that AP4 and c-Myb jointly modulated MZF-1 transcription, and that miR-492 was also directly involved in regulating MZF-1 concentration through binding to the 3' untranslated regions of its mRNA. These results correlate with reduced AP4 and c-Myb expression and elevated miR-492 expression found in prostate tumors as compared with adjacent tissues that resulted in diminished MZF-1 and FPN. Moreover, we demonstrated that alterations of AP4, c-Myb and miR-492 levels significantly affected tumor cell growth. Targeting

  15. AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo

    PubMed Central

    Faubert, Brandon; Boily, Gino; Izreig, Said; Griss, Takla; Samborska, Bozena; Dong, Zhifeng; Dupuy, Fanny; Chambers, Christopher; Fuerth, Benjamin J.; Viollet, Benoit; Mamer, Orval A.; Avizonis, Daina; DeBerardinis, Ralph J.; Siegel, Peter M.; Jones, Russell G.

    2012-01-01

    Summary AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells, and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and non-transformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development, and its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation. PMID:23274086

  16. Triparanol suppresses human tumor growth in vitro and in vivo

    SciTech Connect

    Bi, Xinyu; Han, Xingpeng; Zhang, Fang; He, Miao; Zhang, Yi; Zhi, Xiu-Yi; Zhao, Hong

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  17. Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma.

    PubMed

    Huynh, H; Ngo, V C; Choo, S P; Poon, D; Koong, H N; Thng, C H; Toh, H C; Zheng, L; Ong, L C; Jin, Y; Song, I C; Chang, A P C; Ong, H S; Chung, A Y F; Chow, P K H; Soo, K C

    2009-09-01

    Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.

  18. Mitochondrial dysfunction in breast cancer cells prevents tumor growth

    PubMed Central

    Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lamb, Rebecca; Hulit, James; Howell, Anthony; Gandara, Ricardo; Sartini, Marina; Rubin, Emanuel; Lisanti, Michael P.; Sotgia, Federica

    2013-01-01

    Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients, especially by targeting cancer stem cells. Metformin exerts its protective effects by functioning as a weak “mitochondrial poison,” as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism (OXPHOS). Thus, mitochondrial metabolism must play an essential role in promoting tumor growth. To determine the functional role of “mitochondrial health” in breast cancer pathogenesis, here we used mitochondrial uncoupling proteins (UCPs) to genetically induce mitochondrial dysfunction in either human breast cancer cells (MDA-MB-231) or cancer-associated fibroblasts (hTERT-BJ1 cells). Our results directly show that all three UCP family members (UCP-1/2/3) induce autophagy and mitochondrial dysfunction in human breast cancer cells, which results in significant reductions in tumor growth. Conversely, induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect. More specifically, overexpression of UCP-1 in stromal fibroblasts increases β-oxidation, ketone body production and the release of ATP-rich vesicles, which “fuels” tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells. Hence, the effects of mitochondrial dysfunction are truly compartment-specific. Thus, we conclude that the beneficial anticancer effects of mitochondrial inhibitors (such as metformin) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment. Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions. PMID:23257779

  19. A Walnut-Enriched Diet Reduces the Growth of LNCaP Human Prostate Cancer Xenografts in Nude Mice

    PubMed Central

    Tan, Dun-Xian; Manchester, Lucien C.; Korkmaz, Ahmet; Fuentes-Broto, Lorena; Hardman, W. Elaine; Rosales-Corral, Sergio A.; Qi, Wenbo

    2013-01-01

    It was investigated whether a standard mouse diet (AIN-76A) supplemented with walnuts reduced the establishment and growth of LNCaP human prostate cancer cells in nude (nu/nu) mice. The walnut-enriched diet reduced the number of tumors and the growth of the LNCaP xenografts; 3 of 16 (18.7%) of the walnut-fed mice developed tumors; conversely, 14 of 32 mice (44.0%) of the control diet-fed animals developed tumors. Similarly, the xenografts in the walnut-fed animals grew more slowly than those in the control diet mice. The final average tumor size in the walnut-diet animals was roughly one-fourth the average size of the prostate tumors in the mice that ate the control diet. PMID:23758186

  20. Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition.

    PubMed

    Maity, Gargi; De, Archana; Das, Amlan; Banerjee, Snigdha; Sarkar, Sandipto; Banerjee, Sushanta K

    2015-07-01

    Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis. PMID:25867761

  1. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  2. 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.

  3. Copper transporter 2 regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo.

    PubMed

    Blair, Brian G; Larson, Christopher A; Adams, Preston L; Abada, Paolo B; Pesce, Catherine E; Safaei, Roohangiz; Howell, Stephen B

    2011-01-01

    Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using a short hairpin RNA interference. Robust expression of CTR2 was observed in parental tumors grown in vivo, whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells, and decreased the vascular density, but it did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cis-diamminedichloroplatinum(II) [cisplatin (cDDP)] by 9.1-fold and greatly increased its therapeutic efficacy. Because altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake 2.5-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by platelet-derived growth factor coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1 and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc42. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP.

  4. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.

    PubMed Central

    Connolly, D T; Heuvelman, D M; Nelson, R; Olander, J V; Eppley, B L; Delfino, J J; Siegel, N R; Leimgruber, R M; Feder, J

    1989-01-01

    Vascular permeability factor (VPF) is an Mr 40-kD protein that has been purified from the conditioned medium of guinea pig line 10 tumor cells grown in vitro, and increases fluid permeability from blood vessels when injected intradermally. Addition of VPF to cultures of vascular endothelial cells in vitro unexpectedly stimulated cellular proliferation. VPF promoted the growth of new blood vessels when administered into healing rabbit bone grafts or rat corneas. The identity of the growth factor activity with VPF was established in four ways: (a) the molecular weight of the activity in preparative SDS-PAGE was the same as VPF (Mr approximately 40 kD); (b) multiple isoforms (pI greater than or equal to 8) for both VPF and the growth-promoting activity were observed; (c) a single, unique NH2-terminal amino acid sequence was obtained; (d) both growth factor and permeability-enhancing activities were immunoadsorbed using antipeptide IgG that recognized the amino terminus of VPF. Furthermore, 125I-VPF was shown to bind specifically and with high affinity to endothelial cells in vitro and could be chemically cross-linked to a high-molecular weight cell surface receptor, thus demonstrating a mechanism whereby VPF can interact directly with endothelial cells. Unlike other endothelial cell growth factors, VPF did not stimulate [3H]thymidine incorporation or promote growth of other cell types including mouse 3T3 fibroblasts or bovine smooth muscle cells. VPF, therefore, appears to be unique in its ability to specifically promote increased vascular permeability, endothelial cell growth, and angio-genesis. Images PMID:2478587

  5. Porous biodegradable EW62 medical implants resist tumor cell growth.

    PubMed

    Hakimi, O; Ventura, Y; Goldman, J; Vago, R; Aghion, E

    2016-04-01

    Magnesium alloys have been widely investigated for biodegradable medical applications. However, the shielding of harmful cells (eg. bacteria or tumorous cells) from immune surveillance may be compounded by the increased porosity of biodegradable materials. We previously demonstrated the improved corrosion resistance and mechanical properties of a novel EW62 (Mg-6%Nd-2%Y-0.5%Zr)) magnesium alloy by rapid solidification followed by extrusion (RS) compared to its conventional counterpart (CC). The present in vitro study evaluated the influence of rapid solidification on cytotoxicity to murine osteosarcoma cells. We found that CC and RS corrosion extracts significantly reduced cell viability over a 24-h exposure period. Cell density was reduced over 48 h following direct contact on both CC and RS surfaces, but was further reduced on the CC surface. The direct presence of cells accelerated corrosion for both materials. The corroded RS material exhibited superior mechanical properties relative to the CC material. The data show that the improved corrosion resistance of the rapidly solidified EW62 alloy (RS) resulted in a relatively reduced cytotoxic effect on tumorous cells. Hence, the tested alloy in the form of a rapidly solidified substance may introduce a good balance between its biodegradation characteristics and cytotoxic effect towards cancerous and normal cells. PMID:26838879

  6. 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

  7. Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.

    PubMed

    Hover, Laura D; Young, Christian D; Bhola, Neil E; Wilson, Andrew J; Khabele, Dineo; Hong, Charles C; Moses, Harold L; Owens, Philip

    2015-11-01

    The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.

  8. VCC-1, a novel chemokine, promotes tumor growth

    SciTech Connect

    Weinstein, Edward J.; Head, Richard; Griggs, David W.; Sun Duo; Evans, Robert J.; Swearingen, Michelle L.; Westlin, Marisa M.; Mazzarella, Richard . E-mail: richard.a.mazzarella@pfizer.com

    2006-11-10

    We have identified a novel human gene by transcriptional microarray analysis, which is co-regulated in tumors and angiogenesis model systems with VEGF expression. Isolation of cDNA clones containing the full-length VCC-1 transcript from both human and mouse shows a 119 amino acid protein with a 22 amino acid cleavable signal sequence in both species. Comparison of the protein product of this gene with hidden Markov models of all known proteins shows weak but significant homology with two known chemokines, SCYA17 and SCYA16. Northern analysis of human tissues detects a 1 kb band in lung and skeletal muscle. Murine VCC-1 expression can also be detected in lung as well as thyroid, submaxillary gland, epididymis, and uterus tissues by slot blot analysis. By quantitative real time RT-PCR 71% of breast tumors showed 3- to 24-fold up-regulation of VCC-1. In situ hybridization of breast carcinomas showed strong expression of the gene in both normal and transformed mammary gland ductal epithelial cells. In vitro, human microvascular endothelial cells grown on fibronectin increase VCC-1 expression by almost 100-fold. In addition, in the mouse angioma endothelial cell line PY4.1 the gene was over-expressed by 28-fold 6 h after induction of tube formation while quiescent and proliferating cells showed no change. VCC-1 expression is also increased by VEGF and FGF treatment, about 6- and 5-fold, respectively. Finally, 100% of mice injected with NIH3T3 cells over-expressing VCC-1 develop rapidly progressing tumors within 21 days while no growth is seen in any control mice injected with NIH3T3 cells containing the vector alone. These results strongly suggest that VCC-1 plays a role in angiogenesis and possibly in the development of tumors in some tissue types.

  9. Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration.

    PubMed

    Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M; Ricciardo, Belinda; Nelson, Delia J

    2013-01-01

    Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.

  10. In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin.

    PubMed

    Nie, Guangjun; Chen, Guohua; Sheftel, Alex D; Pantopoulos, Kostas; Ponka, Prem

    2006-10-01

    Mitochondrial ferritin (MtFt) is a mitochondrial iron-storage protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular iron homeostasis in mammalian cells. Using tumor xenografts, we examined the effects of MtFt overexpression on tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted tumor growth in nude mice. Mitochondrial iron deposition in MtFt-expressing tumors was directly observed by transmission electron microscopy. A cytosolic iron starvation phenotype in MtFt-expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins, and concomitantly both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to decreases in total cellular heme content and heme oxygenase-1 levels. In addition, elevated MtFt in tumors was also associated with a decrease in total aconitase activity and lower frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partially deficient heme and iron-sulfur cluster synthesis. It is likely that deprivation of iron in the cytosol is the cause for the significant inhibition of xenograft tumor growth.

  11. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo.

    PubMed

    Guan, Siao-Syun; Chang, Jungshan; Cheng, Chun-Chia; Luo, Tsai-Yueh; Ho, Ai-Sheng; Wang, Chia-Chi; Wu, Cheng-Tien; Liu, Shing-Hwa

    2014-07-15

    Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo. PMID:24947902

  12. A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors.

    PubMed

    Asa, Sylvia L; Digiovanni, Rebecca; Jiang, Jing; Ward, Megan L; Loesch, Kimberly; Yamada, Shozo; Sano, Toshiaki; Yoshimoto, Katsuhiko; Frank, Stuart J; Ezzat, Shereen

    2007-08-01

    Pituitary tumors are a diverse group of neoplasms that are classified based on clinical manifestations, hormone excess, and histomorphologic features. Those that cause growth hormone (GH) excess and acromegaly are subdivided into morphologic variants that have not yet been shown to have pathogenetic significance or predictive value for therapy and outcome. Here, we identify a selective somatic histidine-to-leucine substitution in codon 49 of the extracellular domain of the GH receptor (GHR) in a morphologic subtype of human GH-producing pituitary tumors that is characterized by the presence of cytoskeletal aggresomes. This GHR mutation significantly impairs glycosylation-mediated receptor processing, maturation, ligand binding, and signaling. Pharmacologic GH antagonism recapitulates the morphologic phenotype of pituitary tumors from which this mutation was identified, inducing the formation of cytoskeletal keratin aggresomes. This novel GHR mutation provides evidence for impaired hormone autofeedback in the pathogenesis of these pituitary tumors. It explains the lack of responsiveness to somatostatin analogue therapy of this tumor type, in contrast to the exquisite sensitivity of tumors that lack aggresomes, and has therapeutic implications for the safety of GH antagonism as a therapeutic modality in acromegaly. PMID:17671221

  13. Role in Tumor Growth of a Glycogen Debranching Enzyme Lost in Glycogen Storage Disease

    PubMed Central

    Guin, Sunny; Pollard, Courtney; Ru, Yuanbin; Ritterson Lew, Carolyn; Duex, Jason E.; Dancik, Garrett; Owens, Charles; Spencer, Andrea; Knight, Scott; Holemon, Heather; Gupta, Sounak; Hansel, Donna; Hellerstein, Marc; Lorkiewicz, Pawel; Lane, Andrew N.; Fan, Teresa W.-M.

    2014-01-01

    Background Bladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances. Methods Here we used a genome-wide functional short-hairpin RNA (shRNA) screen to identify suppressors of in vivo bladder tumor xenograft growth (n = 50) using bladder cancer UMUC3 cells. Next-generation sequencing was used to identify the most frequently occurring shRNAs in tumors. Genes so identified were studied in 561 patients with bladder cancer for their association with stratification of clinical outcome by Kaplan-Meier analysis. The best prognostic marker was studied to determine its mechanism in tumor suppression using anchorage-dependent and -independent growth, xenograft (n = 20), and metabolomic assays. Statistical significance was determined using two-sided Student t test and repeated-measures statistical analysis. Results We identified the glycogen debranching enzyme AGL as a prognostic indicator of patient survival (P = .04) and as a novel regulator of bladder cancer anchorage-dependent (P < .001), anchorage-independent (mean ± standard deviation, 180 ± 23.1 colonies vs 20±9.5 in control, P < .001), and xenograft growth (P < .001). Rescue experiments using catalytically dead AGL variants revealed that this effect is independent of AGL enzymatic functions. We demonstrated that reduced AGL enhances tumor growth by increasing glycine synthesis through increased expression of serine hydroxymethyltransferase 2. Conclusions Using an in vivo RNA interference screen, we discovered that AGL, a glycogen debranching enzyme, has a biologically and statistically significant role in suppressing human cancer growth. PMID:24700805

  14. A soluble form of GAS1 inhibits tumor growth and angiogenesis in a triple negative breast cancer model.

    PubMed

    Jiménez, Adriana; López-Ornelas, Adolfo; Estudillo, Enrique; González-Mariscal, Lorenza; González, Rosa O; Segovia, José

    2014-10-01

    We previously demonstrated the capacity of GAS1 (Growth Arrest Specific 1) to inhibit the growth of gliomas by blocking the GDNF-RET signaling pathway. Here, we show that a soluble form of GAS1 (tGAS1), decreases the number of viable MDA MB 231 human breast cancer cells, acting in both autocrine and paracrine manners when secreted from producing cells. Moreover, tGAS1 inhibits the growth of tumors implanted in female nu/nu mice through a RET-independent mechanism which involves interfering with the Artemin (ARTN)-GFRα3-(GDNF Family Receptor alpha 3) mediated intracellular signaling and the activation of ERK. In addition, we observed that the presence of tGAS1 reduces the vascularization of implanted tumors, by preventing the migration of endothelial cells. The present results support a potential adjuvant role for tGAS1 in the treatment of breast cancer, by detaining tumor growth and inhibiting angiogenesis.

  15. Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions

    PubMed Central

    Seidenfaden, Ralph; Krauter, Andrea; Schertzinger, Frank; Gerardy-Schahn, Rita; Hildebrandt, Herbert

    2003-01-01

    Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), promotes neural plasticity and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression profiles were initiated by enzymatic removal of PSA and by ectopic expression of NCAM or PSA-NCAM. Removal of PSA from the cell surface led to reduced proliferation and activated extracellular signal-regulated kinase (ERK), inducing enhanced survival and neuronal differentiation of neuroblastoma cells. Blocking with an NCAM-specific peptide prevented these effects. Combinatorial transinteraction studies with cells and membranes with different PSA and NCAM phenotypes revealed that heterophilic NCAM binding mimics the cellular responses to PSA removal. In conclusion, our data demonstrate that PSA masks heterophilic NCAM signals, having a direct impact on tumor cell growth. This provides a mechanism for how PSA may promote the genesis and progression of highly aggressive PSA-NCAM-positive tumors. PMID:12897159

  16. Silencing of Doublecortin-Like (DCL) Results in Decreased Mitochondrial Activity and Delayed Neuroblastoma Tumor Growth

    PubMed Central

    Verissimo, Carla S.; Elands, Rachel; Cheng, Sou; Saaltink, Dirk-Jan; ter Horst, Judith P.; Alme, Maria N.; Pont, Chantal; van de Water, Bob; Håvik, Bjarte; Fitzsimons, Carlos P.; Vreugdenhil, Erno

    2013-01-01

    Doublecortin-like (DCL) is a microtubule-binding protein crucial for neuroblastoma (NB) cell proliferation. We have investigated whether the anti-proliferative effect of DCL knockdown is linked to reduced mitochondrial activity. We found a delay in tumor development after DCL knockdown in vivo in doxycycline-inducible NB tumor xenografts. To understand the mechanisms underlying this tumor growth retardation we performed a series of in vitro experiments in NB cell lines. DCL colocalizes with mitochondria, interacts with the mitochondrial outer membrane protein OMP25/ SYNJ2BP and DCL knockdown results in decreased expression of genes involved in oxidative phosphorylation. Moreover, DCL knockdown decreases cytochrome c oxidase activity and ATP synthesis. We identified the C-terminal Serine/Proline-rich domain and the second microtubule-binding area as crucial DCL domains for the regulation of cytochrome c oxidase activity and ATP synthesis. Furthermore, DCL knockdown causes a significant reduction in the proliferation rate of NB cells under an energetic challenge induced by low glucose availability. Together with our previous studies, our results corroborate DCL as a key player in NB tumor growth in which DCL controls not only mitotic spindle formation and the stabilization of the microtubule cytoskeleton, but also regulates mitochondrial activity and energy availability, which makes DCL a promising molecular target for NB therapy. PMID:24086625

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

    SciTech Connect

    Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

    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, a 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.

  18. Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

    PubMed Central

    Casalà, Carla; Briansó, Ferran; Castrejón, Nerea; Rodríguez, Eva; Suñol, Mariona; Carcaboso, Angel M.; Lavarino, Cinzia; Mora, Jaume; de Torres, Carmen

    2016-01-01

    The calcium–sensing receptor is a G protein-coupled receptor that exerts cell-type specific functions in numerous tissues and some cancers. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. We have now assessed cinacalcet, an allosteric activator of the CaSR approved for clinical use, as targeted therapy for this developmental tumor using neuroblastoma cell lines and patient-derived xenografts (PDX) with different MYCN and TP53 status. In vitro, acute exposure to cinacalcet induced endoplasmic reticulum stress coupled to apoptosis via ATF4-CHOP-TRB3 in CaSR-positive, MYCN-amplified cells. Both phenotypes were partially abrogated by phospholipase C inhibitor U73122. Prolonged in vitro treatment also promoted dose- and time-dependent apoptosis in CaSR-positive, MYCN-amplified cells and, irrespective of MYCN status, differentiation in surviving cells. Cinacalcet significantly inhibited tumor growth in MYCN-amplified xenografts and reduced that of MYCN-non amplified PDX. Morphology assessment showed fibrosis in MYCN-amplified xenografts exposed to the drug. Microarrays analyses revealed up-regulation of cancer-testis antigens (CTAs) in cinacalcet-treated MYCN-amplified tumors. These were predominantly CTAs encoded by genes mapping on chromosome X, which are the most immunogenic. Other modulated genes upon prolonged exposure to cinacalcet were involved in differentiation, cell cycle exit, microenvironment remodeling and calcium signaling pathways. CTAs were up-regulated in PDX and in vitro models as well. Moreover, progressive increase of CaSR expression upon cinacalcet treatment was seen both in vitro and in vivo. In summary, cinacalcet reduces neuroblastoma tumor growth and up-regulates CTAs. This effect represents a therapeutic opportunity and provides surrogate circulating markers of neuroblastoma response to this treatment. PMID:26893368

  19. 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

  20. Luteolin and its inhibitory effect on tumor growth in systemic malignancies

    SciTech Connect

    Kapoor, Shailendra

    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-inducing 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.

  1. FEM-based simulation of tumor growth in medical image

    NASA Astrophysics Data System (ADS)

    Luo, Shuqian; Nie, Ying

    2004-05-01

    Brain model has found wide applications in areas including surgical-path planning, image-guided surgery systems, and virtual medical environments. In comparison with the modeling of normal brain anatomy, the modeling of anatomical abnormalities appears to be rather weak. Particularly, there are considerable differences between abnormal brain images and normal brain images, due to the growth of brain tumor. In order to find the correspondence between abnormal brain images and normal ones, it is necessary to make an estimation or simulation of the brain deformation. In this paper, a deformable model of brain tissue with both geometric and physical nonlinear properties based on finite element method is presented. It is assumed that the brain tissue are nonlinearly elastic solids obeying the equations of an incompressible nonlinearly elastics neo-Hookean model. we incorporate the physical inhomogeneous of brain tissue into our FEM model. The non-linearity of the model needs to solve the deformation of the model using an iteration method. The Updated Lagrange for iteration is used. To assure the convergence of iteration, we adopt the fixed arc length method. This model has advantages over those linear models in its more real tissue properties and its capability of simulating more serious brain deformation. The inclusion of second order displacement items into the balance and geometry functions allows for the estimation of more serious brain deformation. We referenced the model presented by Stelios K so as to ascertain the initial position of tumor as well as our tumor model definition. Furthermore, we expend it from 2-D to 3-D and simplify the calculation process.

  2. Carbon Monoxide Expedites Metabolic Exhaustion to Inhibit Tumor Growth

    PubMed Central

    Wegiel, Barbara; Gallo, David; Csizmadia, Eva; Harris, Clair; Belcher, John; Vercellotti, Gregory M.; Penacho, Nuno; Seth, Pankaj; Sukhatme, Vikas; Ahmed, Asif; Pandolfi, Pier Paolo; Helczynski, Leszek; Bjartell, Anders; Persson, Jenny Liao; Otterbein, Leo E

    2013-01-01

    One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. PMID:24121491

  3. A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization During Tumor Growth and Metastasis

    PubMed Central

    Dong, Dezheng; Stapleton, Christopher; Luo, Biquan; Xiong, Shigang; Ye, Wei; Zhang, Yi; Jhaveri, Niyati; Zhu, Genyuan; Ye, Risheng; Liu, Zhi; Bruhn, Kevin W.; Craft, Noah; Groshen, Susan; Hofman, Florence M.; Lee, Amy S.

    2011-01-01

    GRP78/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we demonstrated that Grp78 heterozygosity not only impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis, the Grp78+/− mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this report, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models where wild-type, syngeneic mammary tumor cells were injected into the host, we showed that Grp78+/− mice suppressed tumor growth and angiogenesis during the early but not late phase of tumor growth. Growth of metastatic lesions of wild-type, syngeneic melanoma cells in the Grp78+/− mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and demonstrated severe reduction of tumor angiogenesis and metastatic growth with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells demonstrated that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression and metastasis. PMID:21467168

  4. Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model

    SciTech Connect

    Yin, Shu-Cheng; Guo, Wei; Tao, Ze-Zhang

    2013-09-13

    Highlights: •We identified that PPP inhibits IGF-1R/Akt pathway in NPC cells. •PPP dose-dependently inhibits NPC cell proliferation in vitro. •PPP suppresses tumor growth of NPC in nude mice. •PPP have little effect on microtubule assembly. -- Abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor with tyrosine kinase activity and plays important roles in cell transformation, tumor growth, tumor invasion, and metastasis. Picropodophyllin (PPP) is a selective IGF-1R inhibitor and shows promising antitumor effects for several human cancers. However, its antitumor effects in nasopharyngeal carcinoma (NPC) remain unclear. The purpose of this study is to investigate the antitumor activity of PPP in NPC using in vitro cell culture and in vivo animal model. We found that PPP dose-dependently decreased the IGF-induced phosphorylation and activity of IGF-1R and consequently reduced the phosphorylation of Akt, one downstream target of IGF-1R. In addition, PPP inhibited NPC cell proliferation in vitro. The half maximal inhibitory concentration (IC50) of PPP for NPC cell line CNE-2 was ⩽1 μM at 24 h after treatment and ⩽0.5 μM at 48 h after treatment, respectively. Moreover, administration of PPP by intraperitoneal injection significantly suppressed the tumor growth of xenografted NPC in nude mice. Taken together, these results suggest targeting IGF-1R by PPP may represent a new strategy for treatment of NPCs with positive IGF-1R expression.

  5. Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes.

    PubMed

    Wei, Yao; Li, Mingzhen; Cui, Shufang; Wang, Dong; Zhang, Chen-Yu; Zen, Ke; Li, Limin

    2016-01-01

    Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7) with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release. PMID:27322220

  6. Kinetics of tumor growth and regression in IgG multiple myeloma

    PubMed Central

    Sullivan, Peter W.; Salmon, Sydney E.

    1972-01-01

    Studies of immunoglobulin synthesis, total body tumor cell number, and tumor kinetics were carried out in a series of patients with IgG multiple myeloma. The changes in tumor size associated with tumor growth or with regression were underestimated when the concentration of serum M-component was used as the sole index of tumor mass. Calculation of the total body M-component synthetic rate (corrected for concentration-dependent changes in IgG metabolism) and tumor cell number gave a more accurate and predictable estimate of changes in tumor size. Tumor growth and drug-induced tumor regression were found to follow Gompertzian kinetics, with progressive retardation of the rate of change of tumor size in both of these circumstances. This retardation effect, describable with a constant α, may be caused by a shift in the proportion of tumor cells in the proliferative cycle. Drug sensitivity of the tumor could be described quantitatively with a calculation of BO, the tumor's initial sensitivity to a given drug regimen. Of particular clinical significance, the magnitude of a given patient's tumor regression could be predicted from the ratio of BO to α. Mathematical proof was obtained that the retardation constant determined during tumor regression also applied to the earlier period of tumor growth, and this constant was used to reconstruct the preclinical history of disease. In the average patient, fewer than 5 yr elapse from the initial tumor cell doubling to its clinical presentation with from 1011 to more than 1012 myeloma cells in the body. The reduction in total body tumor mass in most patients responding to therapy ranges from less than one to almost two orders of magnitude. Application of predictive kinetic analysis to the design of sequential drug regimens may lead to further improvement in the treatment of multiple myeloma and other tumors with similar growth characteristics. PMID:5040867

  7. Cholesterol masks membrane glycosphingolipid tumor-associated antigens to reduce their immunodetection in human cancer biopsies.

    PubMed

    Novak, Anton; Binnington, Beth; Ngan, Bo; Chadwick, Karen; Fleshner, Neil; Lingwood, Clifford A

    2013-11-01

    Glycosphingolipids (GSLs) are neoplastic and normal/cancer stem cell markers and GSL/cholesterol-containing membrane rafts are increased in cancer cell plasma membranes. We define a novel means by which cancer cells can restrict tumor-associated GSL immunoreactivity. The GSL-cholesterol complex reorients GSL carbohydrate to a membrane parallel, rather than perpendicular conformation, largely unavailable for antibody recognition. Methyl-β-cyclodextrin cholesterol extraction of all primary human tumor frozen sections tested (ovarian, testicular, neuroblastoma, prostate, breast, colon, pheochromocytoma and ganglioneuroma), unmasked previously "invisible" membrane GSLs for immunodetection. In ovarian carcinoma, globotriaosyl ceramide (Gb3), the GSL receptor for the antineoplastic Escherichia coli-derived verotoxin, was increased throughout the tumor. In colon carcinoma, Gb3 detection was vastly increased within the neovasculature and perivascular stroma. In tumors considered Gb3 negative (neuroblastoma, Leydig testicular tumor and pheochromocytoma), neovascular Gb3 was unmasked. Tumor-associated GSL stage-specific embryonic antigen (SSEA)-1, SSEA-3, SSEA-4 and globoH were unmasked according to tumor: SSEA-1 in prostate/colon; SSEA-3 in prostate; SSEA-4 in pheochromocytoma/some colon tumors; globoH in prostate/some colon tumors. In colon, anti-SSEA-1 was tumor cell specific. Within the GSL-cholesterol complex, filipin-cholesterol binding was also reduced. These results may relate to the ill-defined benefit of statins on cancer prognosis, for example, prostate carcinoma. We found novel anti-tumor GSL antibodies circulating in 3/5 statin-treated, but not untreated, prostate cancer patients. Lowering tumor membrane cholesterol may permit immune recognition of otherwise unavailable tumor-associated GSL carbohydrate, for more effective immunosurveillance and active/passive immunotherapy. Our results show standard immunodetection of tumor GSLs significantly under assesses

  8. IMP1 suppresses breast tumor growth and metastasis through the regulation of its target mRNAs

    PubMed Central

    Liu, Xin; Huang, Wenhe; Chen, Shaoying; Zhou, Yanchun; Li, Deling; Singer, Robert H.; Gu, Wei

    2016-01-01

    We have previously reported the ability of IMP1 in inhibiting proliferation and invasiveness of breast carcinoma cells in vitro. In the current study, we utilized a mouse xenograft model to further investigate the function of IMP1 in breast tumor progression and its underlying mechanism. We demonstrated that IMP1 expression significantly suppressed the growth of MDA231 cell-derived xenograft tumors and subsequent lung metastasis. Microarray analyses and differential gene expression identified handful mRNAs, many of which were involved in breast tumor-growth and metastasis. Further studies revealed that these mRNAs were directly interacted with the KH34 domain of IMP1 and this interaction post-transcriptionally regulated their corresponding protein expression. Either deletion of the KH34 domain of IMP1 or alteration of the expression of IMP1-bound mRNAs affected cell proliferation and tumor growth, producing the same phenotypes as IMP1 knockdown. Correlation of increased IMP1 expression with the reduced levels of its bound mRNAs, such as PTGS2, GDF15 and IGF-2 transcripts, was also observed in human breast tumors. Our studies provide insights into a molecular mechanism that the positive function of IMP1 to inhibit breast tumor growth and metastasis could be through the regulation of its target mRNAs. PMID:26910917

  9. Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo

    SciTech Connect

    Perryman, L.A.; Blair, J.M.; Kingsley, E.A.; Szymanska, B.; Ow, K.T.; Wen, V.W.; MacKenzie, K.L.; Vermeulen, P.B.; Jackson, P.; Russell, P.J. . E-mail: p.russell@unsw.edu.au

    2006-07-07

    This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous 'take rate' in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.

  10. Fragrant environment with α-pinene decreases tumor growth in mice.

    PubMed

    Kusuhara, Masatoshi; Urakami, Kenichi; Masuda, Yoko; Zangiacomi, Vincent; Ishii, Hidee; Tai, Sachiko; Maruyama, Koj; Yamaguchi, Ken

    2012-02-01

    Stress is believed to be harmful to not only mental but also physical health. However, proving a link between stress and disease is difficult. A recent study reported that an environmental enrichment reduced cancer growth via the hypothalamic-pituitary-adrenal axis and leptin. Here, we report that mice kept in a fragrant environment enriched with α-pinene show reduced melanoma growth. Tumor volume of mice under the α-pinene environment was about 40% smaller than that in the control mice. α-Pinene had no inhibitory effect on melanoma cell proliferation in vitro, suggesting that this effect was not a direct effect of α-pinene. These results suggest that the provision of a fragrant environment may be an important factor in the therapeutic approach to cancer.

  11. Patient-derived xenograft (PDX) tumors increase growth rate with time

    PubMed Central

    Pearson, Alexander T.; Finkel, Kelsey A.; Warner, Kristy A.; Nör, Felipe; Tice, David; Martins, Manoela D.; Jackson, Trachette L.; Nör, Jacques E.

    2016-01-01

    Patient-derived xenograft (PDX) models are frequently used for translational cancer research, and are assumed to behave consistently as the tumor ages. However, growth rate constancy as a function of time is unclear. Notably, variable PDX growth rates over time might have implications for the interpretation of translational studies. We characterized four PDX models through several in vivo passages from primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma. We developed a mathematical approach to merge growth data from different passages into a single measure of relative tumor volume normalized to study initiation size. We analyzed log-relative tumor volume increase with linear mixed effect models. Two oral pathologists analyzed the PDX tissues to determine if histopathological feature changes occurred over in vivo passages. Tumor growth rate increased over time. This was determined by repeated measures linear regression statistical analysis in four different PDX models. A quadratic statistical model for the temporal effect predicted the log-relative tumor volume significantly better than a linear time effect model. We found a significant correlation between passage number and histopathological features of higher tumor grade. Our mathematical treatment of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple passages. Non-linear tumor growth in our regression models revealed the exponential growth rate increased over time. The dynamic tumor growth rates correlated with quantifiable histopathological changes that related to passage number in multiple types of cancer. PMID:26783960

  12. Patient-derived xenograft (PDX) tumors increase growth rate with time.

    PubMed

    Pearson, Alexander T; Finkel, Kelsey A; Warner, Kristy A; Nör, Felipe; Tice, David; Martins, Manoela D; Jackson, Trachette L; Nör, Jacques E

    2016-02-16

    Patient-derived xenograft (PDX) models are frequently used for translational cancer research, and are assumed to behave consistently as the tumor ages. However, growth rate constancy as a function of time is unclear. Notably, variable PDX growth rates over time might have implications for the interpretation of translational studies. We characterized four PDX models through several in vivo passages from primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma. We developed a mathematical approach to merge growth data from different passages into a single measure of relative tumor volume normalized to study initiation size. We analyzed log-relative tumor volume increase with linear mixed effect models. Two oral pathologists analyzed the PDX tissues to determine if histopathological feature changes occurred over in vivo passages. Tumor growth rate increased over time. This was determined by repeated measures linear regression statistical analysis in four different PDX models. A quadratic statistical model for the temporal effect predicted the log-relative tumor volume significantly better than a linear time effect model. We found a significant correlation between passage number and histopathological features of higher tumor grade. Our mathematical treatment of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple passages. Non-linear tumor growth in our regression models revealed the exponential growth rate increased over time. The dynamic tumor growth rates correlated with quantifiable histopathological changes that related to passage number in multiple types of cancer.

  13. Challenge to the suppression of tumor growth by the β4-galactosyltransferase genes

    PubMed Central

    FURUKAWA, Kiyoshi

    2015-01-01

    It has been well established that structural changes in glycans attached to proteins and lipids are associated with malignant transformation of cells. We focused on galactose residues among the sugars since they are involved in the galectin-mediated biology, and many carbohydrate antigens are frequently expressed on this sugar. We found changes in the expression of the β4-galactosyltransferase (β4GalT) 2 and 5 genes in cancer cells: decreased expression of the β4GalT2 gene and increased expression of the β4GalT5 gene. The growth of mouse melanoma cells showing enhanced expression of the β4GalT2 gene or reduced expression of the β4GalT5 gene is inhibited remarkably in syngeneic mice. Tumor growth inhibition is probably caused by the induction of apoptosis, inhibition of angiogenesis, and/or reduced MAPK signals. Direct transduction of human β4GalT2 cDNA together with the adenovirus vector into human hepatocellular carcinoma cells grown in SCID mice results in marked growth retardation of the tumors. β4GalT gene-transfer appears to be a potential tool for cancer therapy. PMID:25743061

  14. Manufacturing process to reduce large grain growth in zirconium alloys

    DOEpatents

    Rosecrans, P.M.

    1984-08-01

    It is an object of the present invention to provide a procedure for desensitizing zirconium-based alloys to large grain growth (LGG) during thermal treatment above the recrystallization temperature of the alloy. It is a further object of the present invention to provide a method for treating zirconium-based alloys which have been cold-worked in the range of 2 to 8% strain to reduce large grain growth. It is another object of the present invention to provide a method for fabricating a zirconium alloy clad nuclear fuel element wherein the zirconium clad is resistant to large grain growth.

  15. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate

    PubMed Central

    Goldman, Corey K.; Kendall, Richard L.; Cabrera, Gustavo; Soroceanu, Liliana; Heike, Yuji; Gillespie, G. Yancey; Siegal, Gene P.; Mao, Xianzhi; Bett, Andrew J.; Huckle, William R.; Thomas, Kenneth A.; Curiel, David T.

    1998-01-01

    Vascular endothelial growth factor (VEGF) is a potent and selective vascular endothelial cell mitogen and angiogenic factor. VEGF expression is elevated in a wide variety of solid tumors and is thought to support their growth by enhancing tumor neovascularization. To block VEGF-dependent angiogenesis, tumor cells were transfected with cDNA encoding the native soluble FLT-1 (sFLT-1) truncated VEGF receptor which can function both by sequestering VEGF and, in a dominant negative fashion, by forming inactive heterodimers with membrane-spanning VEGF receptors. Transient transfection of HT-1080 human fibrosarcoma cells with a gene encoding sFLT-1 significantly inhibited their implantation and growth in the lungs of nude mice following i.v. injection and their growth as nodules from cells injected s.c. High sFLT-1 expressing stably transfected HT-1080 clones grew even slower as s.c. tumors. Finally, survival was significantly prolonged in mice injected intracranially with human glioblastoma cells stably transfected with the sflt-1 gene. The ability of sFLT-1 protein to inhibit tumor growth is presumably attributable to its paracrine inhibition of tumor angiogenesis in vivo, since it did not affect tumor cell mitogenesis in vitro. These results not only support VEGF receptors as antiangiogenic targets but also demonstrate that sflt-1 gene therapy might be a feasible approach for inhibiting tumor angiogenesis and growth. PMID:9671758

  16. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    SciTech Connect

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  17. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model.

    PubMed

    Kazmierczak, Robert A; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105-107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  18. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model

    PubMed Central

    Kazmierczak, Robert A.; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105–107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  19. Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis.

    PubMed

    Qi, Cuiling; Zhou, Qin; Li, Bin; Yang, Yang; Cao, Liu; Ye, Yuxiang; Li, Jiangchao; Ding, Yi; Wang, Huiping; Wang, Jintao; He, Xiaodong; Zhang, Qianqian; Lan, Tian; Lee, Kenneth Ka Ho; Li, Weidong; Song, Xiaoyu; Zhou, Jia; Yang, Xuesong; Wang, Lijing

    2014-10-30

    Angiogenesis is involved in the development, progression and metastasis of various human cancers. Herein, we report the discovery of glipizide, a widely used drug for type 2 diabetes mellitus, as a promising anticancer agent through the inhibition of tumor angiogenesis. By high-throughput screening (HTS) of an FDA approved drug library utilizing our in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, glipizide has been identified to significantly inhibit blood vessel formation and development. Moreover, glipizide was found to suppress tumor angiogenesis, tumor growth and metastasis using xenograft tumor and MMTV-PyMT transgenic mouse models. We further revealed that the anticancer capability of glipizide is not attributed to its antiproliferative effects, which are not significant against various human cancer cell lines. To investigate whether its anticancer efficacy is associated with the glucose level alteration induced by glipizide application, glimepiride, another medium to long-acting sulfonylurea antidiabetic drug in the same class, was employed for the comparison studies in the same fashion. Interestingly, glimepiride has demonstrated no significant impact on the tumor growth and metastasis, indicating that the anticancer effects of glipizide is not ascribed to its antidiabetic properties. Furthermore, glipizide suppresses endothelial cell migration and the formation of tubular structures, thereby inhibiting angiogenesis by up-regulating the expression of natriuretic peptide receptor A. These findings uncover a novel mechanism of glipizide as a potential cancer therapy, and also for the first time, provide direct evidence to support that treatment with glipizide may reduce the cancer risk for diabetic patients. PMID:25294818

  20. Impact of Stroma on the Growth, Microcirculation, and Metabolism of Experimental Prostate Tumors

    PubMed Central

    Zechmann, Christian M; Woenne, Eva C; Brix, Gunnar; Radzwill, Nicole; Ilg, Martin; Bachert, Peter; Peschke, Peter; Kirsch, Stefan; Kauczor, Hans-Ulrich; Delorme, Stefan; Semmler, Wolfhard; Kiessling, Fabian

    2007-01-01

    Abstract In prostate cancers (PCa), the formation of malignant stroma may substantially influence tumor phenotype and aggressiveness. Thus, the impact of the orthotopic and subcutaneous implantations of hormone-sensitive (H), hormone-insensitive (HI), and anaplastic (AT1) Dunning PCa in rats on growth, microcirculation, and metabolism was investigated. For this purpose, dynamic contrast-enhanced magnetic resonance imaging and 1H magnetic resonance spectroscopy ([1H]MRS) were applied in combination with histology. Consistent observations revealed that orthotopic H tumors grew significantly slower compared to subcutaneous ones, whereas the growth of HI and AT1 tumors was comparable at both locations. Histologic analysis indicated that glandular differentiation and a close interaction of tumor cells and smooth muscle cells (SMC) were associated with slow tumor growth. Furthermore, there was a significantly lower SMC density in subcutaneous H tumors than in orthotopic H tumors. Perfusion was observed to be significantly lower in orthotopic H tumors than in subcutaneous H tumors. Regional blood volume and permeability-surface area product showed no significant differences between tumor models and their implantation sites. Differences in growth between subcutaneous and orthotopic H tumors can be attributed to tumor-stroma interaction and perfusion. Here, SMC, may stabilize glandular structures and contribute to the maintenance of differentiated phenotype. PMID:17325744

  1. Protein interacting with C kinase 1 suppresses invasion and anchorage-independent growth of astrocytic tumor cells

    PubMed Central

    Cockbill, Louisa M. R.; Murk, Kai; Love, Seth; Hanley, Jonathan G.

    2015-01-01

    Astrocytic tumors are the most common form of primary brain tumor. Astrocytic tumor cells infiltrate the surrounding CNS tissue, allowing them to evade removal upon surgical resection of the primary tumor. Dynamic changes to the actin cytoskeleton are crucial to cancer cell invasion, but the specific mechanisms that underlie the particularly invasive phenotype of astrocytic tumor cells are unclear. Protein interacting with C kinase 1 (PICK1) is a PDZ and BAR domain–containing protein that inhibits actin-related protein 2/3 (Arp2/3)-dependent actin polymerization and is involved in regulating the trafficking of a number of cell-surface receptors. Here we report that, in contrast to other cancers, PICK1 expression is down-regulated in grade IV astrocytic tumor cell lines and also in clinical cases of the disease in which grade IV tumors have progressed from lower-grade tumors. Exogenous expression of PICK1 in the grade IV astrocytic cell line U251 reduces their capacity for anchorage-independent growth, two-dimensional migration, and invasion through a three-dimensional matrix, strongly suggesting that low PICK1 expression plays an important role in astrocytic tumorigenesis. We propose that PICK1 negatively regulates neoplastic infiltration of astrocytic tumors and that manipulation of PICK1 is an attractive possibility for therapeutic intervention. PMID:26466675

  2. Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth.

    PubMed

    Lewis, J W; Shavit, Y; Terman, G W; Nelson, L R; Gale, R P; Liebeskind, J C

    1983-01-01

    Exposure to stress has been associated with alterations in both immune function and tumor development in man and laboratory animals. In the present study, we investigated the effect of a particular type of inescapable footshock stress, known to cause an opioid mediated form of analgesia, on survival time of female Fischer 344 rats injected with a mammary ascites tumor. Rats subjected to inescapable footshock manifested an enhanced tumor growth indicated by a decreased survival time and decreased percent survival. This tumor enhancing effect of stress was prevented by the opiate antagonist, naltrexone, suggesting a role for endogenous opioid peptides in this process. In the absence of stress, naltrexone did not affect tumor growth.

  3. Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer.

    PubMed

    Hinsenkamp, Isabel; Schulz, Sandra; Roscher, Mareike; Suhr, Anne-Maria; Meyer, Björn; Munteanu, Bogdan; Fuchser, Jens; Schoenberg, Stefan O; Ebert, Matthias P A; Wängler, Björn; Hopf, Carsten; Burgermeister, Elke

    2016-08-01

    Gastric cancer (GC) remains a malignant disease with high mortality. Patients are frequently diagnosed in advanced stages where survival prognosis is poor. Thus, there is high medical need to find novel drug targets and treatment strategies. Recently, the comprehensive molecular characterization of GC subtypes revealed mutations in the small GTPase RHOA as a hallmark of diffuse-type GC. RHOA activates RHO-associated protein kinases (ROCK1/2) which regulate cell contractility, migration and growth and thus may play a role in cancer. However, therapeutic benefit of RHO-pathway inhibition in GC has not been shown so far. The ROCK1/2 inhibitor 1-(5-isoquinoline sulfonyl)-homopiperazine (HA-1077, fasudil) is approved for cerebrovascular bleeding in patients. We therefore investigated whether fasudil (i.p., 10 mg/kg per day, 4 times per week, 4 weeks) inhibits tumor growth in a preclinical model of GC. Fasudil evoked cell death in human GC cells and reduced the tumor size in the stomach of CEA424-SV40 TAg transgenic mice. Small animal PET/CT confirmed preclinical efficacy. Mass spectrometry imaging identified a translatable biomarker for mouse GC and suggested rapid but incomplete in situ distribution of the drug to gastric tumor tissue. RHOA expression was increased in the neoplastic murine stomach compared with normal non-malignant gastric tissue, and fasudil reduced (auto) phosphorylation of ROCK2 at THR249 in vivo and in human GC cells in vitro. In sum, our data suggest that RHO-pathway inhibition may constitute a novel strategy for treatment of GC and that enhanced distribution of future ROCK inhibitors into tumor tissue may further improve efficacy. PMID:27566106

  4. Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

    PubMed

    Fendrich, V; Lopez, C L; Manoharan, J; Maschuw, K; Wichmann, S; Baier, A; Holler, J P; Ramaswamy, A; Bartsch, D K; Waldmann, J

    2014-10-01

    Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

  5. Radiographically determined growth kinetics of primary lung tumors in the dog

    SciTech Connect

    Perry, R.E. . Coll. of Veterinary Medicine Pacific Northwest Lab., Richland, WA ); Weller, R.E.; Buschbom, R.L.; Dagle, G.E.; Park, J.F. )

    1989-10-01

    Tumor growth rate patterns especially tumor doubling time (TDT), have been extensively evaluated in man. Studies involving the determination of TDT in humans are limited, however, by the number of cases, time consistent radiographic tumor measurements, and inability to perform experimental procedures. In animals similar constraints do not exist. Lifespan animal models lend themselves well to tumor growth pattern analysis. Experimental studies have been designed to evaluate both the biological effects and growth patterns of induced and spontaneous tumors. The purpose of this study was to calculate the tumor volume doubling times (TCDT) for radiation-induced and spontaneous primary pulmonary neoplasms in dogs to see if differences existed due to etiology, sex or histologic cell type, and to determine if the time of tumor onset could be extrapolated from the TVDT. 3 refs.

  6. Impact of metabolic heterogeneity on tumor growth, invasion, and treatment outcomes

    PubMed Central

    Robertson-Tessi, Mark; Gillies, Robert J; Gatenby, Robert A; Anderson, Alexander RA

    2015-01-01

    Histopathological knowledge that extensive heterogeneity exists between and within tumors has been confirmed and deepened recently by molecular studies. However, the impact of tumor heterogeneity on prognosis and treatment remains as poorly understood as ever. Using a hybrid multi-scale mathematical model of tumor growth in vascularized tissue, we investigated the selection pressures exerted by spatial and temporal variations in tumor microenvironment and the resulting phenotypic adaptations. A key component of this model is normal and tumor metabolism and its interaction with microenvironmental factors. The metabolic phenotype of tumor cells is plastic, and microenvironmental selection leads to increased tumor glycolysis and decreased pH. Once this phenotype emerges, the tumor dramatically changes its behavior due to acid-mediated invasion, an effect that depends on both variations in the tumor cell phenotypes and their spatial distribution within the tumor. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the interior of the tumor. These cells then grow to the edge of the tumor and invade into the normal tissue using acidosis. Simulations suggest that diffusible cytotoxic treatments such as chemotherapy may increase the metabolic aggressiveness of a tumor due to drug-mediated selection. Chemotherapy removes the metabolic stratification of the tumor and allows more aggressive cells to grow towards blood vessels and normal tissue. Anti-angiogenic therapy also selects for aggressive phenotypes due to degradation of the tumor microenvironment, ultimately resulting in a more invasive tumor. In contrast, pH buffer therapy slows down the development of aggressive tumors, but only if administered when the tumor is still stratified. Overall, findings from this model highlight the risks of cytotoxic and anti-angiogenic treatments in the context of tumor heterogeneity resulting from a selection for more aggressive behaviors

  7. Pathology of growth hormone-producing tumors of the human pituitary.

    PubMed

    Kovacs, K; Horvath, E

    1986-02-01

    This paper reviews the morphologic features of growth hormone-producing tumors of the human pituitary. These tumors are associated with elevated blood growth hormone levels and acromegaly or gigantism and can be classified into the following morphologically distinct entities by the combined application of histology, immunocytology, and electron microscopy: densely granulated growth hormone cell adenoma; sparsely granulated growth hormone cell adenoma; mixed growth hormone cell- prolactin cell-adenoma; acidophil stem cell adenoma; mammosomatotroph cell adenoma; growth hormone cell carcinoma; plurihormonal adenoma with growth hormone production. PMID:3303228

  8. Preliminary investigation of the inhibitory effects of mechanical stress in tumor growth

    NASA Astrophysics Data System (ADS)

    Garg, Ishita; Miga, Michael I.

    2008-03-01

    In the past years different models have been formulated to explain the growth of gliomas in the brain. The most accepted model is based on a reaction-diffusion equation that describes the growth of the tumor as two separate components- a proliferative component and an invasive component. While many improvements have been made to this basic model, the work exploring the factors that naturally inhibit growth is insufficient. It is known that stress fields affect the growth of normal tissue. Due to the rigid skull surrounding the brain, mechanical stress might be an important factor in inhibiting the growth of gliomas. A realistic model of glioma growth would have to take that inhibitory effect into account. In this work a mathematical model based on the reaction-diffusion equation was used to describe tumor growth, and the affect of mechanical stresses caused by the mass effect of tumor cells was studied. An initial tumor cell concentration with a Gaussian distribution was assumed and tumor growth was simulated for two cases- one where growth was solely governed by the reaction-diffusion equation and second where mechanical stress inhibits growth by affecting the diffusivity. All the simulations were performed using the finite difference method. The results of simulations show that the proposed mechanism of inhibition could have a significant affect on tumor growth predictions. This could have implications for varied applications in the imaging field that use growth models, such as registration and model updated surgery.

  9. Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

    PubMed Central

    Dewaele, Michael; Tabaglio, Tommaso; Willekens, Karen; Bezzi, Marco; Teo, Shun Xie; Low, Diana H.P.; Koh, Cheryl M.; Rambow, Florian; Fiers, Mark; Rogiers, Aljosja; Radaelli, Enrico; Al-Haddawi, Muthafar; Tan, Soo Yong; Hermans, Els; Amant, Frederic; Yan, Hualong; Lakshmanan, Manikandan; Koumar, Ratnacaram Chandrahas; Lim, Soon Thye; Derheimer, Frederick A.; Campbell, Robert M.; Bonday, Zahid; Tergaonkar, Vinay; Shackleton, Mark; Blattner, Christine; Marine, Jean-Christophe; Guccione, Ernesto

    2015-01-01

    MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient–derived xenograft (PDX) mouse models, antisense oligonucleotide–mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target. PMID:26595814

  10. Inhibiting tumor growth by targeting liposomally encapsulated CDC20siRNA to tumor vasculature: therapeutic RNA interference.

    PubMed

    Majumder, Poulami; Bhunia, Sukanya; Bhattacharyya, Jayanta; Chaudhuri, Arabinda

    2014-04-28

    Many cancer cells over express CDC20 (Cell Division Cycle homologue 20), a key cell cycle regulator required for the completion of mitosis in organisms from yeast to human. A recent in vitro study showed that specific knockdown of CDC20 expression using CDC20siRNA can significantly inhibit growth of human pancreatic carcinoma cells. However, preclinical study aimed at demonstrating therapeutic potential of CDC20siRNA in inhibiting tumor growth has just begun. Using a syngeneic C57BL/6J mouse tumor model, herein we show that intravenous administration of a 19bp synthetic CDC20siRNA encapsulated within α5β1 integrin receptor selective liposomes of pegylated RGDK-lipopeptide inhibits melanoma tumor growth. Liposomally encapsulated CDC20siRNA was found to be efficient in silencing the expression of CDC20 in tumor and endothelial cells at both mRNA and protein levels under in vitro settings. Findings in the flow cytometric studies confirmed the presence of significantly enhanced populations of the G2/M phase in cells treated with liposomally encapsulated CDC20siRNA. Immunohistochemical staining of tumor cryosections from mice treated with liposomally encapsulated fluorescently labeled siRNAs revealed tumor vasculatures targeting capabilities of the present liposomal formulations. The colocalizations of the TUNEL and VE-cadherin positive cells in tumor cryosections are consistent with tumor growth inhibition being mediated via apoptosis of the tumor endothelial cells. In summary, the presently disclosed liposomal formulation of CDC20siRNA is a promising RNA interference tool for use in anti-angiogenic cancer therapy. PMID:24556418

  11. Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth

    PubMed Central

    Yang, Ming; Yu, Tao; Wang, Ying-Ying; Lai, Samuel K.; Zeng, Qi; Miao, Bolong; Tang, Benjamin C.; Simons, Brian W.; Ensign, Laura; Liu, Guanshu; Chan, Kannie W. Y.; Juang, Chih-Yin; Mert, Olcay; Wood, Joseph; Fu, Jie; McMahon, Michael T.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID:24339398

  12. Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth.

    PubMed

    Orr, Brent A; Bai, Haibo; Odia, Yazmin; Jain, Deepali; Anders, Robert A; Eberhart, Charles G

    2011-07-01

    The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.

  13. Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis.

    PubMed

    Cao, Yihai

    2013-08-01

    Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are frequently expressed in various tumors and their expression levels correlate with tumor growth, invasiveness, drug resistance, and poor clinical outcomes. Emerging experimental evidence demonstrates that PDGFs exhibit multiple functions in modulation of tumor growth, metastasis, and the tumor microenvironment by targeting malignant cells, vascular cells, and stromal cells. Understanding PDGF-PDGFR-mediated molecular signaling may provide new mechanistic rationales for optimizing current cancer therapies and the development of future novel therapeutic modalities.

  14. Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis.

    PubMed

    Xu, Ming; Xie, Yufeng; Sheng, Weihua; Miao, Jingcheng; Yang, Jicheng

    2015-08-01

    The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential tumor-suppressive effects via multiple pathways. However, the therapeutic effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer in human osteosarcoma is still unknown. In this study, we explored the in vitro and in vivo antitumor activity of Ad-ING4 in human osteosarcoma and its potential mechanism using a MG-63 human osteosarcoma cell line. We demonstrated that Ad-ING4 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27 and Bax, downregulated the Bcl-2 expression and activated Caspase-3 in MG-63 human osteosarcoma cells. Moreover, intratumoral injections of Ad-ING4 in athymic nude mice bearing MG-63 human osteosarcoma tumors significantly suppressed osteosarcoma xenografted tumor growth, increased the expression of P21, P27 and Bax, reduced the Bcl-2 and CD34 expression and microvessel density (MVD) in tumors. This retarded MG-63 osteosarcoma growth in vitro and in vivo in an athymic nude mouse model elicited by Ad-ING4 was closely associated with the increase in the expression of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to pro-apoptotic molecules Bcl-2/Bax followed by the activation of Caspase-3 leading to apoptosis via intrinsic apoptotic pathways, and the inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 is a potential candidate for human osteosarcoma gene therapy.

  15. On the Probability of Random Genetic Mutations for Various Types of Tumor Growth

    PubMed Central

    2013-01-01

    In this work, we consider the problem of estimating the probability for a specific random genetic mutation to be present in a tumor of a given size. Previous mathematical models have been based on stochastic methods where the tumor was assumed to be homogeneous and, on average, growing exponentially. In contrast, we are able to obtain analytical results for cases where the exponential growth of cancer has been replaced by other, arguably more realistic types of growth of a heterogeneous tumor cell population. Our main result is that the probability that a given random mutation will be present by the time a tumor reaches a certain size, is independent of the type of curve assumed for the average growth of the tumor, at least for a general class of growth curves. The same is true for the related estimate of the expected number of mutants present in a tumor of a given size, if mutants are indeed present. PMID:22311065

  16. A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth.

    PubMed

    Lebron, Maria B; Brennan, Laura; Damoci, Christopher B; Prewett, Marie C; O'Mahony, Marguerita; Duignan, Inga J; Credille, Kelly M; DeLigio, James T; Starodubtseva, Marina; Amatulli, Michael; Zhang, Yiwei; Schwartz, Kaben D; Burtrum, Douglas; Balderes, Paul; Persaud, Kris; Surguladze, David; Loizos, Nick; Paz, Keren; Kotanides, Helen

    2014-09-01

    Stem cell factor receptor (c-Kit) exerts multiple biological effects on target cells upon binding its ligand stem cell factor (SCF). Aberrant activation of c-Kit results in dysregulated signaling and is implicated in the pathogenesis of numerous cancers. The development of more specific and effective c-Kit therapies is warranted given its essential role in tumorigenesis. In this study, we describe the biological properties of CK6, a fully human IgG1 monoclonal antibody against the extracellular region of human c-Kit. CK6 specifically binds c-Kit receptor with high affinity (EC 50 = 0.06 nM) and strongly blocks its interaction with SCF (IC 50 = 0.41 nM) in solid phase assays. Flow cytometry shows CK6 binding to c-Kit on the cell surface of human small cell lung carcinoma (SCLC), melanoma, and leukemia tumor cell lines. Furthermore, exposure to CK6 inhibits SCF stimulation of c-Kit tyrosine kinase activity and downstream signaling pathways such as mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), in addition to reducing tumor cell line growth in vitro. CK6 treatment significantly decreases human xenograft tumor growth in NCI-H526 SCLC (T/C% = 57) and Malme-3M melanoma (T/C% = 58) models in vivo. The combination of CK6 with standard of care chemotherapy agents, cisplatin and etoposide for SCLC or dacarbazine for melanoma, more potently reduces tumor growth (SCLC T/C% = 24, melanoma T/C% = 38) compared with CK6 or chemotherapy alone. In summary, our results demonstrate that CK6 is a c-Kit antagonist antibody with tumor growth neutralizing properties and are highly suggestive of potential therapeutic application in treating human malignancies harboring c-Kit receptor. PMID:24921944

  17. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells.

    PubMed

    Müller, Philipp; Rothschild, Sacha I; Arnold, Walter; Hirschmann, Petra; Horvath, Lukas; Bubendorf, Lukas; Savic, Spasenija; Zippelius, Alfred

    2016-01-01

    Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4(+) and CD8(+) T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8(+) T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c(+) cells and CD68(+) as well as CD163(+) macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8(+) T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.

  18. Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

    PubMed Central

    Laukkanen, Mikko O.

    2016-01-01

    Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2−) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction. PMID:27293512

  19. Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

    PubMed

    Laukkanen, Mikko O

    2016-01-01

    Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2 (-)) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction. PMID:27293512

  20. TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3

    PubMed Central

    Murphy, Matthew; Chatterjee, Sujash S.; Jain, Sidharth; Katari, Manpreet; DasGupta, Ramanuj

    2016-01-01

    Dysregulation of the Wnt pathway leading to accumulation of β-catenin (CTNNB1) is a hallmark of colorectal cancer (CRC). Nuclear CTNNB1 acts as a transcriptional coactivator with TCF/LEF transcription factors, promoting expression of a broad set of target genes, some of which promote tumor growth. However, it remains poorly understood how CTNNB1 interacts with different transcription factors in different contexts to promote different outcomes. While some CTNNB1 target genes are oncogenic, others regulate differentiation. Here, we found that TCF7L1, a Wnt pathway repressor, buffers CTNNB1/TCF target gene expression to promote CRC growth. Loss of TCF7L1 impaired growth and colony formation of HCT116 CRC cells and reduced tumor growth in a mouse xenograft model. We identified a group of CTNNB1/TCF target genes that are activated in the absence of TCF7L1, including EPHB3, a marker of Paneth cell differentiation that has also been implicated as a tumor suppressor in CRC. Knockdown of EPHB3 partially restores growth and normal cell cycle progression of TCF7L1-Null cells. These findings suggest that while CTNNB1 accumulation is critical for CRC progression, activation of specific Wnt target genes in certain contexts may in fact inhibit tumor growth. PMID:27333864

  1. TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3.

    PubMed

    Murphy, Matthew; Chatterjee, Sujash S; Jain, Sidharth; Katari, Manpreet; DasGupta, Ramanuj

    2016-01-01

    Dysregulation of the Wnt pathway leading to accumulation of β-catenin (CTNNB1) is a hallmark of colorectal cancer (CRC). Nuclear CTNNB1 acts as a transcriptional coactivator with TCF/LEF transcription factors, promoting expression of a broad set of target genes, some of which promote tumor growth. However, it remains poorly understood how CTNNB1 interacts with different transcription factors in different contexts to promote different outcomes. While some CTNNB1 target genes are oncogenic, others regulate differentiation. Here, we found that TCF7L1, a Wnt pathway repressor, buffers CTNNB1/TCF target gene expression to promote CRC growth. Loss of TCF7L1 impaired growth and colony formation of HCT116 CRC cells and reduced tumor growth in a mouse xenograft model. We identified a group of CTNNB1/TCF target genes that are activated in the absence of TCF7L1, including EPHB3, a marker of Paneth cell differentiation that has also been implicated as a tumor suppressor in CRC. Knockdown of EPHB3 partially restores growth and normal cell cycle progression of TCF7L1-Null cells. These findings suggest that while CTNNB1 accumulation is critical for CRC progression, activation of specific Wnt target genes in certain contexts may in fact inhibit tumor growth. PMID:27333864

  2. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.

    PubMed

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D; Shetake, Neena; Balla, Murali M S; Kumar, Amit; Ray, Pritha; Ghosh, Anu; Pandey, B N

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  3. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.

    PubMed

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D; Shetake, Neena; Balla, Murali M S; Kumar, Amit; Ray, Pritha; Ghosh, Anu; Pandey, B N

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  4. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

    PubMed Central

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D.; Shetake, Neena; Balla, Murali M. S.; Kumar, Amit; Ray, Pritha; Ghosh, Anu

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  5. Promoter mutation and reduced expression of BRCA1 in canine mammary tumors.

    PubMed

    Qiu, H B; Sun, W D; Yang, X; Jiang, Q Y; Chen, S; Lin, D G

    2015-12-01

    Breast cancer 1, early onset (BRCA1) is one of the most important genes in human familial breast cancer, which also plays an important role in canine mammary tumors. The objectives of this study were to determine the promoter sequence of canine BRCA1, to investigate its promoter mutation status and to describe BRCA1 expression pattern in canine mammary tumors. The promoter sequence of canine BRCA1 was acquired by aligning human BRCA1 promoter sequence with canine genomic sequence and confirmed by standard promoter activity analysis. Same as human BRCA1 promoter, the CAAT box and G/C box were found in canine BRCA1 promoter. In order to explore the mutation status of the promoter region and to investigate the expression pattern of this gene, 10 normal canine mammary tissues, 15 benign mammary tumors and 15 malignant mammary tumors were used. By sequencing, 46.7% of the malignant mammary tumors were found with a deletion of one cytosine in the promoter region. The mRNA expression of BRCA1 was significantly reduced in benign and malignant mammary tumors (P<0.05), and the protein expression of BRCA1 was significantly reduced in malignant mammary tumors (P<0.05). This study is the first time to determine the canine BRCA1 promoter sequence and to describe the promoter mutation status in canine mammary tumors. PMID:26679809

  6. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    PubMed

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  7. Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

    PubMed Central

    Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel F.; Shiku, Hiroshi; Mineno, Junichi; Okamoto, Sachiko; Old, Lloyd J.; Shrikant, Protul; Gnjatic, Sacha; Odunsi, Kunle

    2015-01-01

    Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4+ T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients. PMID:26447332

  8. Can Arbuscular Mycorrhizal Fungi Reduce the Growth of Agricultural Weeds?

    PubMed Central

    Veiga, Rita S. L.; Jansa, Jan; Frossard, Emmanuel; van der Heijden, Marcel G. A.

    2011-01-01

    Background Arbuscular mycorrhizal fungi (AMF) are known for their beneficial effects on plants. However, there is increasing evidence that some ruderal plants, including several agricultural weeds, respond negatively to AMF colonization. Here, we investigated the effect of AMF on the growth of individual weed species and on weed-crop interactions. Methodology/Principal Findings First, under controlled glasshouse conditions, we screened growth responses of nine weed species and three crops to a widespread AMF, Glomus intraradices. None of the weeds screened showed a significant positive mycorrhizal growth response and four weed species were significantly reduced by the AMF (growth responses between −22 and −35%). In a subsequent experiment, we selected three of the negatively responding weed species – Echinochloa crus-galli, Setaria viridis and Solanum nigrum – and analyzed their responses to a combination of three AMF (Glomus intraradices, Glomus mosseae and Glomus claroideum). Finally, we tested whether the presence of a crop (maize) enhanced the suppressive effect of AMF on weeds. We found that the growth of the three selected weed species was also reduced by a combination of AMF and that the presence of maize amplified the negative effect of AMF on the growth of E. crus-galli. Conclusions/Significance Our results show that AMF can negatively influence the growth of some weed species indicating that AMF have the potential to act as determinants of weed community structure. Furthermore, mycorrhizal weed growth reductions can be amplified in the presence of a crop. Previous studies have shown that AMF provide a number of beneficial ecosystem services. Taken together with our current results, the maintenance and promotion of AMF activity may thereby contribute to sustainable management of agroecosystems. However, in order to further the practical and ecological relevance of our findings, additional experiments should be performed under field conditions. PMID

  9. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor

    PubMed Central

    1980-01-01

    The results of this paper are consistent with the hypothesis that progressive growth of the Meth A fibrosarcoma evokes the generation of a T-cell-mediated mechanism of immunosuppression that prevents this highly immunogenic tumor from being rejected by its immunocompetent host. It was shown that it is possible to cause the regression of large, established Meth A tumors by intravenous infusion of tumor- sensitized T cells from immune donors, but only if the tumors are growing in T-cell-deficient recipients. It was also shown that the adoptive T-cell-mediated regression of tumors in such recipients can be prevented by prior infusion of splenic T cells from T-cell-intact, tumor-bearing donors. The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression. Because the presence of suppressor T cells generated in response to the Meth A did not suppress the capacity of Meth A-bearing mice to generate and express immunity against a tumor allograft, it is obvious that they were not in a state of generalized immunosuppression. PMID:6444236

  10. Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase1

    PubMed Central

    Jackson, Kenneth W.; Christiansen, Victoria J.; Yadav, Vivek R.; Silasi-Mansat, Robert; Lupu, Florea; Awasthi, Vibhudutta; Zhang, Roy R.; McKee, Patrick A.

    2015-01-01

    Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth > 90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs. PMID:25622898

  11. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

    PubMed Central

    Keunen, Olivier; Johansson, Mikael; Oudin, Anaïs; Sanzey, Morgane; Rahim, Siti A. Abdul; Fack, Fred; Thorsen, Frits; Taxt, Torfinn; Bartos, Michal; Jirik, Radovan; Miletic, Hrvoje; Wang, Jian; Stieber, Daniel; Stuhr, Linda; Moen, Ingrid; Rygh, Cecilie Brekke; Bjerkvig, Rolf; Niclou, Simone P.

    2011-01-01

    Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype. PMID:21321221

  12. Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator

    PubMed Central

    Zhou, Xiang; Hao, Qian; Liao, Peng; Luo, Shiwen; Zhang, Minhong; Hu, Guohui; Liu, Hongbing; Zhang, Yiwei; Cao, Bo; Baddoo, Melody; Flemington, Erik K; Zeng, Shelya X; Lu, Hua

    2016-01-01

    Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53. DOI: http://dx.doi.org/10.7554/eLife.15099.001 PMID:27282385

  13. Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence.

    PubMed

    Andrew, Angeline S; Marsit, Carmen J; Schned, Alan R; Seigne, John D; Kelsey, Karl T; Moore, Jason H; Perreard, Laurent; Karagas, Margaret R; Sempere, Lorenzo F

    2015-09-01

    Bladder cancer is the fourth most common cancer among men in the United States and more than half of patients experience recurrences within 5 years after initial diagnosis. Additional clinically informative and actionable biomarkers of the recurrent bladder cancer phenotypes are needed to improve screening and molecular therapeutic approaches for recurrence prevention. MicroRNA-34a (miR-34a) is a short noncoding regulatory RNA with tumor suppressive attributes. We leveraged our unique, large, population-based prognostic study of bladder cancer in New Hampshire, United States to evaluate miR-34a expression levels in individual tumor cells to assess prognostic value. We collected detailed exposure and medical history data, as well as tumor tissue specimens from bladder patients and followed them long-term for recurrence, progression and survival. Fluorescence-based in situ hybridization assays were performed on urothelial carcinoma tissue specimens (n = 229). A larger proportion of the nonmuscle invasive tumors had high levels of miR-34a within the carcinoma cells compared to those tumors that were muscle invasive. Patients with high miR-34a levels in their baseline nonmuscle invasive tumors experienced lower risks of recurrence (adjusted hazard ratio 0.57, 95% confidence interval 0.34-0.93). Consistent with these observations, we demonstrated a functional tumor suppressive role for miR-34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar. Our results highlight the need for further clinical studies of miR-34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder.

  14. PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species.

    PubMed

    Warfel, Noel A; Sainz, Alva G; Song, Jin H; Kraft, Andrew S

    2016-07-01

    Intratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it is highly correlated with metastasis, therapeutic resistance, and disease recurrence in cancer patients. As a result, there is an urgent need to develop effective therapies that target hypoxic cells within the tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a prosurvival pathway that is upregulated in response to hypoxia, in a HIF-1-independent manner. We demonstrate that pharmacologic or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia as compared with normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors prevent Nrf2 from accumulating in the nucleus, reducing the transcription of cytoprotective genes and leading to the build-up of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be successfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediated therapeutic resistance and induce cell death in the hypoxic tumor microenvironment. Mol Cancer Ther; 15(7); 1637-47. ©2016 AACR. PMID:27196781

  15. Myristica fragrans Suppresses Tumor Growth and Metabolism by Inhibiting Lactate Dehydrogenase A.

    PubMed

    Kim, Eun-Yeong; Choi, Hee-Jung; Park, Mi-Ju; Jung, Yeon-Seop; Lee, Syng-Ook; Kim, Keuk-Jun; Choi, Jung-Hye; Chung, Tae-Wook; Ha, Ki-Tae

    2016-01-01

    Most cancer cells predominantly produce ATP by maintaining a high rate of lactate fermentation, rather than by maintaining a comparatively low rate of tricarboxylic acid cycle, i.e., Warburg's effect. In the pathway, the pyruvate produced by glycolysis is converted to lactic acid by lactate dehydrogenase (LDH). Here, we demonstrated that water extracts from the seeds of Myristica fragrans Houtt. (MF) inhibit the in vitro enzymatic activity of LDH. MF effectively suppressed cell growth and the overall Warburg effect in HT29 human colon cancer cells. Although the expression of LDH-A was not changed by MF, both lactate production and LDH activity were decreased in MF-treated cells under both normoxic and hypoxic conditions. In addition, intracellular ATP levels were also decreased by MF treatment, and the uptake of glucose was also reduced by MF treatment. Furthermore, the experiment on tumor growth in the in vivo mice model revealed that MF effectively reduced the growth of allotransplanted Lewis lung carcinoma cells. Taken together, these results suggest that MF effectively inhibits cancer growth and metabolism by inhibiting the activity of LDH, a major enzyme responsible for regulating cancer metabolism. These results implicate MF as a potential candidate for development into a novel drug against cancer through inhibition of LDH activity.

  16. Myristica fragrans Suppresses Tumor Growth and Metabolism by Inhibiting Lactate Dehydrogenase A.

    PubMed

    Kim, Eun-Yeong; Choi, Hee-Jung; Park, Mi-Ju; Jung, Yeon-Seop; Lee, Syng-Ook; Kim, Keuk-Jun; Choi, Jung-Hye; Chung, Tae-Wook; Ha, Ki-Tae

    2016-01-01

    Most cancer cells predominantly produce ATP by maintaining a high rate of lactate fermentation, rather than by maintaining a comparatively low rate of tricarboxylic acid cycle, i.e., Warburg's effect. In the pathway, the pyruvate produced by glycolysis is converted to lactic acid by lactate dehydrogenase (LDH). Here, we demonstrated that water extracts from the seeds of Myristica fragrans Houtt. (MF) inhibit the in vitro enzymatic activity of LDH. MF effectively suppressed cell growth and the overall Warburg effect in HT29 human colon cancer cells. Although the expression of LDH-A was not changed by MF, both lactate production and LDH activity were decreased in MF-treated cells under both normoxic and hypoxic conditions. In addition, intracellular ATP levels were also decreased by MF treatment, and the uptake of glucose was also reduced by MF treatment. Furthermore, the experiment on tumor growth in the in vivo mice model revealed that MF effectively reduced the growth of allotransplanted Lewis lung carcinoma cells. Taken together, these results suggest that MF effectively inhibits cancer growth and metabolism by inhibiting the activity of LDH, a major enzyme responsible for regulating cancer metabolism. These results implicate MF as a potential candidate for development into a novel drug against cancer through inhibition of LDH activity. PMID:27430914

  17. Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism.

    PubMed

    Hollander, Lindsay; Guo, Xiaojia; Velazquez, Heino; Chang, John; Safirstein, Robert; Kluger, Harriet; Cha, Charles; Desir, Gary V

    2016-07-01

    To sustain their proliferation, cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163(+) tumor-associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies, or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell-cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163(+) TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma. Cancer Res; 76(13); 3884-94. ©2016 AACR. PMID:27197188

  18. Constructing Tumor Vaccines Targeting for Vascular Endothelial Growth Factor (VEGF) by DNA Shuffling.

    PubMed

    Bie, Nana; Zhao, Xiuyun; Li, Zhitao; Qi, Gaofu

    2016-09-01

    Most of tumor antigens are self-proteins with poor antigenicity because of immune tolerance. Here, we describe DNA shuffling for overcoming the tolerance of tumor antigens such as vascular endothelial growth factor (VEGF), a growth factor associated with tumor angiogenesis. VEGF genes from mouse, rat, human, and chicken were randomly assembled to chimeric genes by DNA shuffling for constructing an expression library, then screened by PCR, SDS-PAGE, and immunization. A chimeric protein named as No. 46 was selected from the library with the strongest immunotherapy effects on mouse H22 hepatocellular carcinoma, which could induce long-lasted and high level of antibodies recognizing VEGF in mice. Immunization with this chimeric protein could significantly inhibit tumor angiogenesis, slow down tumor growth, increase the survival rate of tumor-bearing mice, and inhibit the lung metastases of tumor in mouse. Treatment with the anti-VEGF IgG induced by this chimeric protein also significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice, by blocking the tyrosine phosphorylation of ERK1/2 pathway of VEGF-VEGFR interaction. Our study provides an efficient approach to overcome the immune tolerance of self-antigens for developing novel tumor vaccines. PMID:27428264

  19. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    SciTech Connect

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, Andre; Gnanasekar, Munirathinam

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. Black-Right-Pointing-Pointer Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. Black-Right-Pointing-Pointer Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. Black-Right-Pointing-Pointer Knock down of RAGE abrogates prostate tumor growth in vivo. Black-Right-Pointing-Pointer Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  20. Tumor growth reduction is regulated at the gene level in Walker 256 tumor-bearing rats supplemented with fish oil rich in EPA and DHA.

    PubMed

    Borghetti, G; Yamazaki, R K; Coelho, I; Pequito, D C T; Schiessel, D L; Kryczyk, M; Mamus, R; Naliwaiko, K; Fernandes, L C

    2013-08-01

    We investigated the effect of fish oil (FO) supplementation on tumor growth, cyclooxygenase 2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARγ), and RelA gene and protein expression in Walker 256 tumor-bearing rats. Male Wistar rats (70 days old) were fed with regular chow (group W) or chow supplemented with 1 g/kg body weight FO daily (group WFO) until they reached 100 days of age. Both groups were then inoculated with a suspension of Walker 256 ascitic tumor cells (3 × 10(7) cells/mL). After 14 days the rats were killed, total RNA was isolated from the tumor tissue, and relative mRNA expression was measured using the 2(-ΔΔCT) method. FO significantly decreased tumor growth (W=13.18 ± 1.58 vs WFO=5.40 ± 0.88 g, P<0.05). FO supplementation also resulted in a significant decrease in COX-2 (W=100.1 ± 1.62 vs WFO=59.39 ± 5.53, P<0.001) and PPARγ (W=100.4 ± 1.04 vs WFO=88.22 ± 1.46, P<0.05) protein expression. Relative mRNA expression was W=1.06 ± 0.022 vs WFO=0.31 ± 0.04 (P<0.001) for COX-2, W=1.08 ± 0.02 vs WFO=0.52 ± 0.08 (P<0.001) for PPARγ, and W=1.04 ± 0.02 vs WFO=0.82 ± 0.04 (P<0.05) for RelA. FO reduced tumor growth by attenuating inflammatory gene expression associated with carcinogenesis.

  1. Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors

    PubMed Central

    Jiménez-Triana, Clímaco Andres; Castelán-Martínez, Osvaldo D.; Rivas-Ruiz, Rodolfo; Jiménez-Méndez, Ricardo; Medina, Aurora; Clark, Patricia; Rassekh, Rod; Castañeda-Hernández, Gilberto; Carleton, Bruce; Medeiros, Mara

    2015-01-01

    Abstract Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight. We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4). Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07–24.3, P = 0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r = −0.527, P = <0.001). PMID:26313789

  2. Coupled Hybrid Continuum-Discrete Model of Tumor Angiogenesis and Growth

    PubMed Central

    Lyu, Jie; Cao, Jinfeng; Zhang, Peiming; Liu, Yang; Cheng, Hongtao

    2016-01-01

    The processes governing tumor growth and angiogenesis are codependent. To study the relationship between them, we proposed a coupled hybrid continuum-discrete model. In this model, tumor cells, their microenvironment (extracellular matrixes, matrix-degrading enzymes, and tumor angiogenic factors), and their network of blood vessels, described by a series of discrete points, were considered. The results of numerical simulation reveal the process of tumor growth and the change in microenvironment from avascular to vascular stage, indicating that the network of blood vessels develops gradually as the tumor grows. Our findings also reveal that a tumor is divided into three regions: necrotic, semi-necrotic, and well-vascularized. The results agree well with the previous relevant studies and physiological facts, and this model represents a platform for further investigations of tumor therapy. PMID:27701426

  3. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.

    PubMed

    Mei, H; Sun, S; Bai, Y; Chen, Y; Chai, R; Li, H

    2015-04-02

    Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors.

  4. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs

    PubMed Central

    Mei, H; Sun, S; Bai, Y; Chen, Y; Chai, R; Li, H

    2015-01-01

    Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors. PMID:25837486

  5. p53 status in stromal fibroblasts modulates tumor growth in an SDF1-dependent manner

    PubMed Central

    Addadi, Yoseph; Moskovits, Neta; Granot, Dorit; Lozano, Guillermina; Carmi, Yaron; Apte, Ron N.; Neeman, Michal; Oren, Moshe

    2010-01-01

    The p53 tumor suppressor exerts a variety of cell-autonomous effects that are aimed to thwart tumor development. In addition, however, there is growing evidence for cell non-autonomous tumor suppressor effects of p53. In the present study, we investigated the impact of stromal p53 on tumor growth. Specifically, we found that ablation of p53 in fibroblasts enabled them to promote more efficiently the growth of tumors initiated by PC3 prostate cancer-derived cells. This stimulatory effect was dependent on the increased expression of the chemokine SDF-1 in the p53-deficient fibroblasts. Notably, fibroblasts harboring mutant p53 protein were more effective than p53-null fibroblasts in promoting tumor growth. The presence of either p53-null or p53-mutant fibroblasts led also to a markedly elevated rate of metastatic spread of the PC3 tumors. These findings implicate p53 in a cell non-autonomous tumor suppressor role within stromal fibroblasts, through suppressing the production of tumor-stimulatory factors by these cells. Moreover, expression of mutant p53 by tumor stroma fibroblasts might exert a gain of function effect, further accelerating tumor development. PMID:20952507

  6. Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo.

    PubMed

    Arcella, Antonietta; Carpinelli, Giulia; Battaglia, Giuseppe; D'Onofrio, Mara; Santoro, Filippo; Ngomba, Richard Teke; Bruno, Valeria; Casolini, Paola; Giangaspero, Felice; Nicoletti, Ferdinando

    2005-07-01

    U87MG human glioma cells in cultures expressed metabotropic glutamate (mGlu) receptors mGlu2 and mGlu3. Addition of the mGlu2/3 receptor antagonist LY341495 to the cultures reduced cell growth, expression of cyclin D1/2, and activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. This is in line with the evidence that activation of mGlu2/3 receptors sustains glioma cell proliferation. U87MG cells were either implanted under the skin (1x10(6) cells/0.5 ml) or infused into the caudate nucleus (0.5x10(6) cells/5 microl) of nude mice. Animals were treated for 28 days with mGlu receptor antagonists by means of subcutaneous osmotic minipumps. Treatments with LY341495 or (2S)-alpha-ethylglutamate (both infused at a rate of 1 mg/kg per day) reduced the size of tumors growing under the skin. Infusion of LY341495 (10 mg/kg per day) also reduced the growth of brain tumors, as assessed by magnetic resonance imaging analysis carried out every seven days. The effect of drug treatment was particularly evident during the exponential phase of tumor growth, that is, between the third and the fourth week following cell implantation. Immunohistochemical analysis showed that U87MG cells retained the expression of mGlu2/3 receptors when implanted into the brain of nude mice. These data suggest that mGlu2/3 receptor antagonists are of potential use in the experimental treatment of malignant gliomas. PMID:16053698

  7. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Casey, Trimmer; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G; Sotgia, Federica; Lisanti, Michael P

    2010-11-01

    The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an

  8. Mathematical models of tumor growth using Voronoi tessellations in pathology slides of kidney cancer.

    PubMed

    Saribudak, Aydin; Yiyu Dong; Gundry, Stephen; Hsieh, James; Uyar, M Umit

    2015-08-01

    The impact of patient-specific spatial distribution features of cell nuclei on tumor growth characteristics was analyzed. Tumor tissues from kidney cancer patients were allowed to grow in mice to apply H&E staining and to measure tumor volume during preclinical phase of our study. Imaging the H&E stained slides under a digital light microscope, the morphological characteristics of nuclei positions were determined. Using artificial intelligence based techniques, Voronoi features were derived from diagrams, where cell nuclei were considered as distinct nodes. By identifying the effect of each Voronoi feature, tumor growth was expressed mathematically. Consistency between the computed growth curves and preclinical measurements indicates that the information obtained from the H&E slides can be used as biomarkers to build personalized mathematical models for tumor growth. PMID:26737283

  9. 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. PMID:12659668

  10. 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

  11. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages.

    PubMed

    Nandi, Bisweswar; Shapiro, Mia; Samur, Mehmet K; Pai, Christine; Frank, Natasha Y; Yoon, Charles; Prabhala, Rao H; Munshi, Nikhil C; Gold, Jason S

    2016-08-01

    Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer. PMID:27622061

  12. The novel Aryl hydrocarbon receptor inhibitor biseugenol inhibits gastric tumor growth and peritoneal dissemination

    PubMed Central

    Lai, De-Wei; Karlsson, Anna Isabella; Wang, Keh-Bin; Chen, Yi-Ching; Shen, Chin-Chang; Wu, Sheng-Mao; Liu, Chia-Yu; Tien, Hsing-Ru; Peng, Yen-Chun; Jan, Yee-Jee; Chao, Te-Hsin; Lan, Keng-Hsin; Arbiser, Jack L.; Sheu, Meei-Ling

    2014-01-01

    Biseugenol (Eug) is known to antiproliferative of cancer cells; however, to date, the antiperitoneal dissemination effects have not been studied in any mouse cancer model. In this study, Aryl hydrocarbon receptor (AhR) expression was associated with lymph node and distant metastasis in patients with gastric cancer and was correlated with clinicolpathological pattern. We evaluated the antiperitoneal dissemination potential of knockdown AhR and Biseugenol in cancer mouse model and assessed mesenchymal characteristics. Our results demonstrate that tumor growth, peritoneal dissemination and peritoneum or organ metastasis implanted MKN45 cells were significantly decreased in shAhR and Biseugenol-treated mice and that endoplasmic reticulum (ER) stress was caused. Biseugenol-exposure tumors showed acquired epithelial features such as phosphorylation of E-cadherin, cytokeratin-18 and loss mesenchymal signature Snail, but not vimentin regulation. Snail expression, through AhR activation, is an epithelial-to-mesenchymal transition (EMT) determinant. Moreover, Biseugenol enhanced Calpain-10 (Calp-10) and AhR interaction resulted in Snail downregulation. The effect of shCalpain-10 in cancer cells was associated with inactivation of AhR/Snail promoter binding activity. Inhibition of Calpain-10 in gastric cancer cells by short hairpin RNA or pharmacological inhibitor was found to effectively reduced growth ability and vessel density in vivo. Importantly, knockdown of AhR completed abrogated peritoneal dissemination. Herein, Biseugenol targeting ER stress provokes Calpain-10 activity, sequentially induces reversal of EMT and apoptosis via AhR may involve the paralleling processes. Taken together, these data suggest that Calpain-10 activation and AhR inhibition by Biseugenol impedes both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT. PMID:25226618

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

    PubMed Central

    Mohamad, Nora A; Cricco, Graciela P; Sambuco, Lorena A; Croci, Máximo; Medina, Vanina A; Gutiérrez, Alicia S; Bergoc, Rosa M; Rivera, Elena S; Martín, Gabriela A

    2009-01-01

    AIM: To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization. METHODS: Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression. RESULTS: Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change. CONCLUSION: The antitumoral action of aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes. PMID:19266598

  14. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways

    PubMed Central

    GAO, JIAN-LI; LV, GUI-YUAN; HE, BAI-CHENG; ZHANG, BING-QIANG; ZHANG, HONGYU; WANG, NING; WANG, CHONG-ZHI; DU, WEI; YUAN, CHUN-SU; HE, TONG-CHUAN

    2013-01-01

    Plant-derived active constituents and their semi-synthetic or synthetic analogs have served as major sources of anticancer drugs. 20(S)-protopanaxadiol (PPD) is a metabolite of ginseng saponin of both American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A. Meyer). We previously demonstrated that ginsenoside Rg3, a glucoside precursor of PPD, exhibits anti-proliferative effects on HCT116 cells and reduces tumor size in a xenograft model. Our subsequent study indicated that PPD has more potent antitumor activity than that of Rg3 in vitro although the mechanism underlying the anticancer activity of PPD remains to be defined. Here, we investigated the mechanism underlying the anticancer activity of PPD in human cancer cells in vitro and in vivo. PPD was shown to inhibit growth and induce cell cycle arrest in HCT116 cells. The in vivo studies indicate that PPD inhibits xenograft tumor growth in athymic nude mice bearing HCT116 cells. The xenograft tumor size was significantly reduced when the animals were treated with PPD (30 mg/kg body weight) for 3 weeks. When the expression of previously identified Rg3 targets, A kinase (PRKA) anchor protein 8 (AKAP8L) and phosphatidylinositol transfer protein α (PITPNA), was analyzed, PPD was shown to inhibit the expression of PITPNA while upregulating AKAP8L expression in HCT116 cells. Pathway-specific reporter assays indicated that PPD effectively suppressed the NF-κB, JNK and MAPK/ERK signaling pathways. Taken together, our results suggest that the anticancer activity of PPD in colon cancer cells may be mediated through targeting NF-κB, JNK and MAPK/ERK signaling pathways, although the detailed mechanisms underlying the anticancer mode of PPD action need to be fully elucidated. PMID:23633038

  15. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

    PubMed Central

    Coutinho de Souza, Patricia; Mallory, Samantha; Smith, Nataliya; Saunders, Debra; Li, Xiao-Nan; McNall-Knapp, Rene Y.; Fung, Kar-Ming; Towner, Rheal A.

    2015-01-01

    Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  16. Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance

    PubMed Central

    Naumov, George N.; Nilsson, Monique B.; Cascone, Tina; Briggs, Alexandra; Straume, Oddbjorn; Akslen, Lars A.; Lifshits, Eugene; Byers, Lauren Averett; Xu, Li; Wu, Hua-kang; Jänne, Pasi; Kobayashi, Susumu; Halmos, Balazs; Tenen, Daniel; Tang, Xi M.; Engelman, Jeffrey; Yeap, Beow; Folkman, Judah; Johnson, Bruce E.; Heymach, John V.

    2010-01-01

    Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib benefit some non–small cell lung cancer (NSCLC) patients, but most do not respond (primary resistance) and those who initially respond eventually progress (acquired resistance). EGFR TKI resistance is not completely understood and has been associated with certain EGFR and K-RAS mutations and MET amplification. Experimental Design We hypothesized that dual inhibition of the vascular endothelial growth factor (VEGF) and EGFR pathways may overcome primary and acquired resistance. We investigated the VEGF receptor/EGFR TKI vandetanib, and the combination of bevacizumab and erlotinib in vivo using xenograft models of EGFR TKI sensitivity, primary resistance, and three models of acquired resistance, including models with mutated K-RAS and secondary EGFR T790M mutation. Results Vandetanib, gefitinib, and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model. In all four resistant models, vandetanib and bevacizumab/erlotinib were significantly more effective than erlotinib or gefitinib alone. Erlotinib resistance was associated with a rise in both host and tumor-derived VEGF but not EGFR secondary mutations in the KRAS mutant-bearing A549 xenografts. Dual inhibition reduced tumor endothelial proliferation compared with VEGF or EGFR blockade alone, suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects. Conclusion These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal VEGF and that combined blockade of the VEGFR and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs. This approach merits further evaluation in NSCLC patients. PMID:19447865

  17. Metronomic topotecan impedes tumor growth of MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence.

    PubMed

    Taschner-Mandl, Sabine; Schwarz, Magdalena; Blaha, Johanna; Kauer, Maximilian; Kromp, Florian; Frank, Nelli; Rifatbegovic, Fikret; Weiss, Tamara; Ladenstein, Ruth; Hohenegger, Martin; Ambros, Inge M; Ambros, Peter F

    2016-01-19

    Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth-arrest and act immune-stimulatory, while others are tumor-promoting. We evaluated whether metronomic, i.e. long-term, repetitive low-dose, drug treatment induces senescence in vitro and in vivo. And importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified.We demonstrate that metronomic application of chemotherapeutic drugs induces therapy-induced senescence, characterized by cell cycle arrest, p21(WAF/CIP1) up-regulation and DNA double-strand breaks selectively in MYCN-amplified NB. Low-dose topotecan (TPT) was identified as an inducer of a favorable SASP while lacking NFKB1/p50 activation. In contrast, Bromo-deoxy-uridine induced senescent NB-cells secret a tumor-promoting SASP in a NFKB1/p50-dependent manner. Importantly, TPT-treated senescent tumor cells act growth-inhibitory in a dose-dependent manner on non-senescent tumor cells and MYCN expression is significantly reduced in vitro and in vivo. Furthermore, in a mouse xenotransplant-model for MYCN-amplified NB metronomic TPT leads to senescence selectively in tumor cells, complete or partial remission, prolonged survival and a favorable SASP.This new mode-of-action of metronomic TPT treatment, i.e. promoting a tumor-inhibiting type of senescence in MYCN-amplified tumors, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles. PMID:26657295

  18. Metronomic topotecan impedes tumor growth of MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence

    PubMed Central

    Taschner-Mandl, Sabine; Schwarz, Magdalena; Blaha, Johanna; Kauer, Maximilian; Kromp, Florian; Frank, Nelli; Rifatbegovic, Fikret; Weiss, Tamara; Ladenstein, Ruth; Hohenegger, Martin; Ambros, Inge M.; Ambros, Peter F.

    2016-01-01

    Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth-arrest and act immune-stimulatory, while others are tumor-promoting. We evaluated whether metronomic, i.e. long-term, repetitive low-dose, drug treatment induces senescence in vitro and in vivo. And importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified. We demonstrate that metronomic application of chemotherapeutic drugs induces therapy-induced senescence, characterized by cell cycle arrest, p21WAF/CIP1 up-regulation and DNA double-strand breaks selectively in MYCN-amplified NB. Low-dose topotecan (TPT) was identified as an inducer of a favorable SASP while lacking NFKB1/p50 activation. In contrast, Bromo-deoxy-uridine induced senescent NB-cells secret a tumor-promoting SASP in a NFKB1/p50-dependent manner. Importantly, TPT-treated senescent tumor cells act growth-inhibitory in a dose-dependent manner on non-senescent tumor cells and MYCN expression is significantly reduced in vitro and in vivo. Furthermore, in a mouse xenotransplant-model for MYCN-amplified NB metronomic TPT leads to senescence selectively in tumor cells, complete or partial remission, prolonged survival and a favorable SASP. This new mode-of-action of metronomic TPT treatment, i.e. promoting a tumor-inhibiting type of senescence in MYCN-amplified tumors, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles. PMID:26657295

  19. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis.

    PubMed

    Lim, Sharon; Hosaka, Kayoko; Nakamura, Masaki; Cao, Yihai

    2016-06-21

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

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

    PubMed Central

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

    2015-01-01

    Introduction 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. Methods 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). Results 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. Conclusions Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting

  1. Crystalline silica-induced leukotrieneB4-dependent inflammation promotes lung tumor growth

    PubMed Central

    Satpathy, Shuchismita R.; Jala, Venkatakrishna R.; Bodduluri, Sobha R.; Krishnan, Elangovan; Hegde, Bindu; Hoyle, Gary; Fraig, Mostafa; Luster, Andrew D.; Haribabu, Bodduluri

    2015-01-01

    Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-rasLA1 mice, CS exposure markedly enhances the lung tumor burden and genetic deletion of leukotriene B4 receptor1 (BLT1−/−) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1−/−K-rasLA1 mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumor model, CS exposure results in rapid tumor growth and decrease survival that is attenuated in the absence of BLT1. These results suggest that LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge will facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer. PMID:25923988

  2. Suppression of KSHV-induced angiopoietin-2 inhibits angiogenesis, infiltration of inflammatory cells, and tumor growth.

    PubMed

    Yu, Xiaolan; Sha, Jingfeng; Xiang, Shao; Qin, Sanhai; Conrad, Patricia; Ghosh, Santosh K; Weinberg, Aaron; Ye, Fengchun

    2016-08-01

    Kaposi's sarcoma (KS) is a highly angiogenic and inflammatory neoplasia. The angiogenic and inflammatory cytokine angiopoietin-2 (Ang-2) is strongly expressed in KS due to Kaposi's sarcoma-associated herpesvirus (KSHV) infection. In the present study, we determined how Ang-2 contributes to development of KS by using telomerase-immortalized human umbilical vein endothelial cells (TIVE) as a model, which become malignantly transformed and express increased levels of Ang-2 following KSHV infection. Ang-2 released from TIVE-KSHV cells induces tyrosine phosphorylation of Tie-2 receptor from both human and mouse endothelial cells and promotes angiogenesis in nude mice. Functional inhibition or expressional "knock-down" of Ang-2 in these cells blocks angiogenesis and inhibits tumor growth. Ang-2 suppression also reduces the numbers of infiltrating monocytes/macrophages in tumors. In transwell-based cell migration assays, Ang-2 indeed enhances migration of human monocytes in a dose-dependent manner. These results underscore a pivotal role of KSHV-induced Ang-2 in KS tumor development by promoting both angiogenesis and inflammation. Our data also suggest that selective drug targeting of Ang-2 may be used for treatment of KS. PMID:27294705

  3. An Atypical Acidophil Cell Line Tumor Showing Focal Differentiation Toward Both Growth Hormone and Prolactin Cells.

    PubMed

    Naritaka, Heiji; Kameya, Toru; Sato, Yuichi; Furuhata, Shigeru; Okui, Junichi; Kamiguchi, Yuji; Otani, Mitsuhiro; Toya, Shigeo

    1995-01-01

    We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactive in situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells. PMID:12114745

  4. Loss of stromal JUNB does not affect tumor growth and angiogenesis.

    PubMed

    Braun, Jennifer; Strittmatter, Karin; Nübel, Tobias; Komljenovic, Dorde; Sator-Schmitt, Melanie; Bäuerle, Tobias; Angel, Peter; Schorpp-Kistner, Marina

    2014-03-15

    The transcription factor AP-1 subunit JUNB has been shown to play a pivotal role in angiogenesis. It positively controls angiogenesis by regulating Vegfa as well as the transcriptional regulator Cbfb and its target Mmp13. In line with these findings, it has been demonstrated that tumor cell-derived JUNB promotes tumor growth and angiogenesis. In contrast to JUNB's function in tumor cells, the role of host-derived stromal JUNB has not been elucidated so far. Here, we show that ablation of Junb in stromal cells including endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts does not affect tumor growth in two different syngeneic mouse models, the B16-F1 melanoma and the Lewis lung carcinoma model. In-depth analyses of the tumors revealed that tumor angiogenesis remains unaffected as assessed by measurements of the microvascular density and relative blood volume in the tumor. Furthermore, we could show that the maturation status of the tumor vasculature, analyzed by the SMC marker expression, α-smooth muscle actin and Desmin, as well as the attachment of pericytes to the endothelium, is not changed upon ablation of Junb. Taken together, these results indicate that the pro-angiogenic functions of stromal JUNB are well compensated with regard to tumor angiogenesis and tumor growth. PMID:24027048

  5. NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts

    PubMed Central

    Fan, Xing; Khaki, Leila; Zhu, Thant S.; Soules, Mary E.; Talsma, Caroline E.; Gul, Naheed; Koh, Cheryl; Zhang, Jiangyang; Li, Yue-Ming; Maciaczyk, Jarek; Nikkhah, Guido; DiMeco, Francesco; Piccirillo, Sara; Vescovi, Angelo L.; Eberhart, Charles G.

    2010-01-01

    Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by γ-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas. PMID:19904829

  6. EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF.

    PubMed

    Chen, Yanke; Gou, Xingchun; Kong, Derek Kai; Wang, Xiaofei; Wang, Jianhui; Chen, Zeming; Huang, Chen; Zhou, Jiangbing

    2015-10-20

    EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down-regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.

  7. Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.

    PubMed

    Holopainen, Tanja; López-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari

    2012-07-15

    Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth. PMID:22593188

  8. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions

    PubMed Central

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C.; Adams, Ralf H.; Duarte, António

    2015-01-01

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy. PMID:26213336

  9. Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis

    PubMed Central

    Mehndiratta, Samir; Lai, Ssu-Chia; Liou, Jing-Ping; Yang, Chia-Ron

    2015-01-01

    Histone deacetylases (HDACs) display multifaceted functions by coordinating the interaction of signal pathways with chromatin structure remodeling and the activation of non-histone proteins; these epigenetic regulations play an important role during malignancy progression. HDAC inhibition shows promise as a new strategy for cancer therapy; three HDAC inhibitors have been approved. We previously reported that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157), a novel indole-3-ethylsulfamoylphenylacrylamide compound, demonstrated potent HDAC inhibition and anti-inflammatory effects. In this study, we evaluated its anti-cancer activity in vitro and in vivo. MPT0G157 treatment significantly inhibited different tumor growth at submicromolar concentration and was particularly potent in human colorectal cancer (HCT116) cells. Apoptosis and inhibited HDACs activity induced by MPT0G157 was more potent than that by the marketed drugs PXD101 (Belinostat) and SAHA (Vorinostat). In an in vivo model, MPT0G157 markedly inhibited HCT116 xenograft tumor volume and reduced matrigel-induced angiogenesis. The anti-angiogenetic effect of MPT0G157 was found to increase the hyperacetylation of heat shock protein 90 (Hsp90) and promote hypoxia-inducible factor-1α (HIF-1α) degradation followed by down-regulation of vascular endothelial growth factor (VEGF) expression. Our results demonstrate that MPT0G157 has potential as a new drug candidate for cancer therapy. PMID:26087180

  10. INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma.

    PubMed

    Zhou, Bingying; Wang, Li; Zhang, Shu; Bennett, Brian D; He, Fan; Zhang, Yan; Xiong, Chengliang; Han, Leng; Diao, Lixia; Li, Pishun; Fargo, David C; Cox, Adrienne D; Hu, Guang

    2016-06-15

    Superenhancers (SEs) are large genomic regions with a high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, a chromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi. Furthermore, Ino80 silencing selectively inhibits melanoma cell proliferation, anchorage-independent growth, tumorigenesis, and tumor maintenance in mouse xenografts. Mechanistically, Ino80 occupies >90% of SEs, and its occupancy is dependent on transcription factors such as MITF and Sox9. Ino80 binding reduces nucleosome occupancy and facilitates Mediator recruitment, thus promoting oncogenic transcription. Consistently, genes co-occupied by Ino80 and Med1 are selectively expressed in melanomas compared with melanocytes. Together, our results reveal an essential role of INO80-dependent chromatin remodeling in SE function and suggest a novel strategy for disrupting SEs in cancer treatment. PMID:27340176

  11. Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis.

    PubMed

    Huang, Yen-Chia; Huang, Fang-I; Mehndiratta, Samir; Lai, Ssu-Chia; Liou, Jing-Ping; Yang, Chia-Ron

    2015-07-30

    Histone deacetylases (HDACs) display multifaceted functions by coordinating the interaction of signal pathways with chromatin structure remodeling and the activation of non-histone proteins; these epigenetic regulations play an important role during malignancy progression. HDAC inhibition shows promise as a new strategy for cancer therapy; three HDAC inhibitors have been approved. We previously reported that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157), a novel indole-3-ethylsulfamoylphenylacrylamide compound, demonstrated potent HDAC inhibition and anti-inflammatory effects. In this study, we evaluated its anti-cancer activity in vitro and in vivo. MPT0G157 treatment significantly inhibited different tumor growth at submicromolar concentration and was particularly potent in human colorectal cancer (HCT116) cells. Apoptosis and inhibited HDACs activity induced by MPT0G157 was more potent than that by the marketed drugs PXD101 (Belinostat) and SAHA (Vorinostat). In an in vivo model, MPT0G157 markedly inhibited HCT116 xenograft tumor volume and reduced matrigel-induced angiogenesis. The anti-angiogenetic effect of MPT0G157 was found to increase the hyperacetylation of heat shock protein 90 (Hsp90) and promote hypoxia-inducible factor-1α (HIF-1α) degradation followed by down-regulation of vascular endothelial growth factor (VEGF) expression. Our results demonstrate that MPT0G157 has potential as a new drug candidate for cancer therapy. PMID:26087180

  12. EF24 inhibits tumor growth and metastasis via suppressing NF-kappaB dependent pathways in human cholangiocarcinoma

    PubMed Central

    Yin, Da-long; Liang, Ying-jian; Zheng, Tong-sen; Song, Rui-peng; Wang, Jia-bei; Sun, Bo-shi; Pan, Shang-ha; Qu, Lian-dong; Liu, Jia-ren; Jiang, Hong-chi; Liu, Lian-xin

    2016-01-01

    A synthetic monoketone analog of curcumin, termed 3, 5-bis (2-flurobenzylidene) piperidin-4-one (EF24), has been reported to inhibit the growth of a variety of cancer cells both in vitro and in vivo. However, whether EF24 has anticancer effects on cholangiocarcinoma (CCA) cells and the mechanisms remain to be investigated. The aim of our study was to evaluate the molecular mechanisms underlying the anticancer effects of EF24 on CCA tumor growth and metastasis. Cell proliferation, apoptosis, migration, invasion, tumorigenesis and metastasis were examined. EF24 exhibited time- and dose-dependent inhibitory effects on HuCCT-1, TFK-1 and HuH28 human CCA cell lines. EF24 inhibited CCA cell proliferation, migration, and induced G2/M phase arrest. EF24 induced cell apoptosis along with negative regulation of NF-κB- X-linked inhibitor of apoptosis protein (XIAP) signaling pathway. XIAP inhibition by lentivirus mediated RNA interference enhanced EF24-induced apoptosis, while XIAP overexpression reduced it in CCA cells. In vivo, EF24 significantly suppressed the growth of CCA tumor xenografts and tumor metastasis while displaying low toxicity levels. Our findings indicate that EF24 is a potent antitumor agent that inhibits tumor growth and metastasis by inhibiting NF-κB dependent signaling pathways. EF24 may represent a novel approach for CCA treatment. PMID:27571770

  13. EF24 inhibits tumor growth and metastasis via suppressing NF-kappaB dependent pathways in human cholangiocarcinoma.

    PubMed

    Yin, Da-Long; Liang, Ying-Jian; Zheng, Tong-Sen; Song, Rui-Peng; Wang, Jia-Bei; Sun, Bo-Shi; Pan, Shang-Ha; Qu, Lian-Dong; Liu, Jia-Ren; Jiang, Hong-Chi; Liu, Lian-Xin

    2016-01-01

    A synthetic monoketone analog of curcumin, termed 3, 5-bis (2-flurobenzylidene) piperidin-4-one (EF24), has been reported to inhibit the growth of a variety of cancer cells both in vitro and in vivo. However, whether EF24 has anticancer effects on cholangiocarcinoma (CCA) cells and the mechanisms remain to be investigated. The aim of our study was to evaluate the molecular mechanisms underlying the anticancer effects of EF24 on CCA tumor growth and metastasis. Cell proliferation, apoptosis, migration, invasion, tumorigenesis and metastasis were examined. EF24 exhibited time- and dose-dependent inhibitory effects on HuCCT-1, TFK-1 and HuH28 human CCA cell lines. EF24 inhibited CCA cell proliferation, migration, and induced G2/M phase arrest. EF24 induced cell apoptosis along with negative regulation of NF-κB- X-linked inhibitor of apoptosis protein (XIAP) signaling pathway. XIAP inhibition by lentivirus mediated RNA interference enhanced EF24-induced apoptosis, while XIAP overexpression reduced it in CCA cells. In vivo, EF24 significantly suppressed the growth of CCA tumor xenografts and tumor metastasis while displaying low toxicity levels. Our findings indicate that EF24 is a potent antitumor agent that inhibits tumor growth and metastasis by inhibiting NF-κB dependent signaling pathways. EF24 may represent a novel approach for CCA treatment. PMID:27571770

  14. Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.

    PubMed

    Sills, A K; Williams, J I; Tyler, B M; Epstein, D S; Sipos, E P; Davis, J D; McLane, M P; Pitchford, S; Cheshire, K; Gannon, F H; Kinney, W A; Chao, T L; Donowitz, M; Laterra, J; Zasloff, M; Brem, H

    1998-07-01

    The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, and has no obvious effects on the growth of newborn vertebrates. Squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans. PMID:9661892

  15. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth

    PubMed Central

    Rao, Xiongjian; Duan, Xiaotao; Mao, Weimin; Li, Xuexia; Li, Zhonghua; Li, Qian; Zheng, Zhiguo; Xu, Haimiao; Chen, Min; Wang, Peng G.; Wang, Yingjie; Shen, Binghui; Yi, Wen

    2015-01-01

    The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours. PMID:26399441

  16. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth.

    PubMed

    Rao, Xiongjian; Duan, Xiaotao; Mao, Weimin; Li, Xuexia; Li, Zhonghua; Li, Qian; Zheng, Zhiguo; Xu, Haimiao; Chen, Min; Wang, Peng G; Wang, Yingjie; Shen, Binghui; Yi, Wen

    2015-09-24

    The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours.

  17. Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth.

    PubMed

    Lin, P; Polverini, P; Dewhirst, M; Shan, S; Rao, P S; Peters, K

    1997-10-15

    Tie2 is a novel receptor tyrosine kinase that is expressed almost exclusively by vascular endothelium. Disruption of Tie2 function in transgenic mice resulted in embryonic lethality secondary to characteristic vascular defects; similar defects occurred after disruption of the Tie2 ligand. These findings indicate that the Tie2/Tie2 ligand pathway plays important roles during development of the embryonic vasculature. To determine whether the Tie2 pathway was involved in pathologic angiogenesis in adult tissues, a soluble form of the extracellular domain of murine Tie2 (ExTek.6His) was developed and used as a Tie2 inhibitor. After a single application of the ExTek.6His protein into a rat cutaneous window chamber, growth of a mammary tumor inside the chamber was reduced by > 75% (P < 0.005), and tumor vascular length density was reduced by 40% when compared with control-treated tumors (P < 0.01). In the rat cornea, ExTek.6His blocked angiogenesis stimulated by tumor cell conditioned media. ExTek.6His protein did not affect the viability of cultured tumor cells, indicating that the antitumor effect of ExTek.6His was due to the inhibition of tumor angiogenesis. These data demonstrate a role for the Tie2 pathway in pathologic angiogenesis, suggesting that targeting this pathway may yield effective antiangiogenic agents for treatment of cancer and other angiogenic diseases.

  18. 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.

  19. Update on a tumor-associated NADH oxidase in gastric cancer cell growth

    PubMed Central

    Cheng, Hsiao-Ling; Lee, Yi-Hui; Yuan, Tein-Ming; Chen, Shi-Wen; Chueh, Pin-Ju

    2016-01-01

    Gastric cancer is one of the most common human malignancies, and its prevalence has been shown to be well-correlated with cancer-related deaths worldwide. Regrettably, the poor prognosis of this disease is mainly due to its late diagnosis at advanced stages after the cancer has already metastasized. Recent research has emphasized the identification of cancer biomarkers in the hope of diagnosing cancer early and designing targeted therapies to reverse cancer progression. One member of a family of growth-related nicotinamide adenine dinucleotide (NADH or hydroquinone) oxidases is tumor-associated NADH oxidase (tNOX; ENOX2). Unlike its counterpart CNOX (ENOX1), identified in normal rat liver plasma membranes and shown to be stimulated by growth factors and hormones, tNOX activity purified from rat hepatoma cells is constitutively active. Its activity is detectable in the sera of cancer patients but not in those of healthy volunteers, suggesting its clinical relevance. Interestingly, tNOX expression was shown to be present in an array of cancer cell lines. More importantly, inhibition of tNOX was well correlated with reduced cancer cell growth and induction of apoptosis. RNA interference targeting tNOX expression in cancer cells effectively restored non-cancerous phenotypes, further supporting the vital role of tNOX in cancer cells. Here, we review the regulatory role of tNOX in gastric cancer cell growth. PMID:26973386

  20. Toxicology across scales: Cell population growth in vitro predicts reduced fish growth

    PubMed Central

    Stadnicka-Michalak, Julita; Schirmer, Kristin; Ashauer, Roman

    2015-01-01

    Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace tests with juvenile fish. Hundreds of thousands of fish at this developmental stage are annually used to assess the influence of chemicals on growth. Juveniles are more sensitive than adult fish, and their growth can affect their chances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical impact on fish growth based on in vitro data. Our model predicts reduced fish growth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration. PMID:26601229

  1. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.

    PubMed

    Lemos, Henrique; Mohamed, Eslam; Huang, Lei; Ou, Rong; Pacholczyk, Gabriela; Arbab, Ali S; Munn, David; Mellor, Andrew L

    2016-04-15

    Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8(+) T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8(+) T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8(+) T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076-81. ©2016 AACR.

  2. 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

  3. Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors.

    PubMed Central

    Hatva, E.; Kaipainen, A.; Mentula, P.; Jääskeläinen, J.; Paetau, A.; Haltia, M.; Alitalo, K.

    1995-01-01

    Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7856749

  4. Comparing immune-tumor growth models with drug therapy using optimal control

    NASA Astrophysics Data System (ADS)

    Martins, Marisa C.; Rocha, Ana Maria A. C.; Costa, M. Fernanda P.; Fernandes, Edite M. G. P.

    2016-06-01

    In this paper we compare the dynamics of three tumor growth models that include an immune system and a drug administration therapy using optimal control. The objective is to minimize a combined function of the total of tumor cells over time and a chemotherapeutic drug administration.

  5. THE INFLUENCE OF LECITHIN AND CHOLESTERIN UPON THE GROWTH OF TUMORS.

    PubMed

    Robertson, T B; Burnett, T C

    1913-03-01

    1. Cholesterin, whether suspended in dilute alcohol or in sodium oleate solution, when injected directly into tumors causes a marked acceleration both of the primary and of the metastatic growth. 2. The acceleration of the growth of the primary tumor by cholesterin is most evident in the premetastatic stage. 3. Lecithin, when injected in the form of an aqueous emulsion directly into tumors, diminishes the tendency to form metastases, retards the metastatic growth when it does occur, and in some instances also retards the primary growth. 4. The retardation due to lecithin is most evident in the metastatic stage. 5. Simultaneous injection of M/6 strontium chloride solution into the tumors does not appreciably affect the action of the lecithin.

  6. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique.

    PubMed

    Ni, Jie; Cozzi, Paul; Hung, Tzong-Tyng; Hao, Jingli; Graham, Peter; Li, Yong

    2016-02-01

    Prostate cancer (CaP) is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D) ultrasound system equipped with photoacoustic (PA) imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8). Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r(2) = 0.948, 0.955, and 0.953, respectively) and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001). The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research.

  7. Does Economic Growth Reduce Childhood Undernutrition in Ethiopia?

    PubMed Central

    Biadgilign, Sibhatu; Shumetie, Arega; Yesigat, Habtamu

    2016-01-01

    Background Policy discussions and debates in the last couple of decades emphasized efficiency of development policies for translating economic growth to development. One of the key aspects in this regard in the developing world is achieving improved nutrition through economic development. Nonetheless, there is a dearth of literature that empirically verifies the association between economic growth and reduction of childhood undernutrition in low- and middle-income countries. Thus, the aim of the study is to assess the interplay between economic growth and reduction of childhood undernutrition in Ethiopia. Methods The study used pooled data of three rounds (2000, 2005 and 2010) from the Demographic and Health Surveys (DHS) of Ethiopia. A multilevel mixed logistic regression model with robust standard errors was utilized in order to account for the hierarchical nature of the data. The dependent variables were stunting, underweight, and wasting in children in the household. The main independent variable was real per capita income (PCI) that was adjusted for purchasing power parity. This information was obtained from World Bank. Results A total of 32,610 children were included in the pooled analysis. Overall, 11,296 (46.7%) [46.0%-47.3%], 8,197(33.8%) [33.2%-34.4%] and 3,175(13.1%) [12.7%-13.5%] were stunted, underweight, and wasted, respectively. We found a strong correlation between prevalence of early childhood undernutrition outcomes and real per capita income (PCI). The proportions of stunting (r = -0.1207, p<0.0001), wasting (r = -0.0338, p<0.0001) and underweight (r = -0.1035, p<0.0001) from the total children in the household were negatively correlated with the PCI. In the final model adjustment with all the covariates, economic growth substantially reduced stunting [β = -0.0016, SE = 0.00013, p<0.0001], underweight [β = -0.0014, SE = 0.0002, p<0.0001] and wasting [β = -0.0008, SE = 0.0002, p<0.0001] in Ethiopia over a decade. Conclusion Economic growth

  8. Upregulation of serum vascular endothelial growth factor in patients with salivary gland tumor.

    PubMed

    Andisheh Tadbir, Azadeh; Khademi, Bijan; Malekzadeh, Mahyar; Mardani, Maryam; Khademi, Bahar

    2013-01-01

    Neoangiogenesis is essential for tumor development, invasion, and dissemination. The most potent of the cytokines associated with angiogenesis is vascular endothelial growth factor (VEGF). The aim of the present study was to determine VEGF serum level in patients with salivary gland tumor. Using an ELISA kit, the circulating levels of VEGF in sera from 58 patients with salivary gland tumor and 30 healthy controls were assessed. Mean VEGF levels in sera of patients with salivary gland tumors (574.9 ± 414.3) were significantly higher than those in controls (263.9 ± 310.0) (P = 0.009). Within the salivary gland tumor group, mean serum VEGF concentration in malignant tumors (n = 27) was 727.3 ± 441.8 pg/mL, and that in benign tumors (n = 31) was 442.2 ± 343.3 pg/mL. Mean serum VEGF concentration was significantly higher in malignant tumors than in benign tumors (P = 0.008) and was higher in benign tumors than in controls (P = 0.03). The data in the present study clearly show that VEGF level was consistently upregulated in benign and malignant tumors in comparison to healthy controls. However, the role of VEGF as a prognostic factor in salivary gland tumor and its application in antiangiogenic therapy require further clinical research.

  9. Graphene growth from reduced graphene oxide by chemical vapour deposition: seeded growth accompanied by restoration

    PubMed Central

    Chang, Sung-Jin; Hyun, Moon Seop; Myung, Sung; Kang, Min-A; Yoo, Jung Ho; Lee, Kyoung G.; Choi, Bong Gill; Cho, Youngji; Lee, Gaehang; Park, Tae Jung

    2016-01-01

    Understanding the underlying mechanisms involved in graphene growth via chemical vapour deposition (CVD) is critical for precise control of the characteristics of graphene. Despite much effort, the actual processes behind graphene synthesis still remain to be elucidated in a large number of aspects. Herein, we report the evolution of graphene properties during in-plane growth of graphene from reduced graphene oxide (RGO) on copper (Cu) via methane CVD. While graphene is laterally grown from RGO flakes on Cu foils up to a few hundred nanometres during CVD process, it shows appreciable improvement in structural quality. The monotonous enhancement of the structural quality of the graphene with increasing length of the graphene growth from RGO suggests that seeded CVD growth of graphene from RGO on Cu surface is accompanied by the restoration of graphitic structure. The finding provides insight into graphene growth and defect reconstruction useful for the production of tailored carbon nanostructures with required properties. PMID:26961409

  10. Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer.

    PubMed

    He, Bai-Cheng; Gao, Jian-Li; Zhang, Bing-Qiang; Luo, Qing; Shi, Qiong; Kim, Stephanie H; Huang, Enyi; Gao, Yanhong; Yang, Ke; Wagner, Eric R; Wang, Linyuan; Tang, Ni; Luo, Jinyong; Liu, Xing; Li, Mi; Bi, Yang; Shen, Jikun; Luther, Gaurav; Hu, Ning; Zhou, Qixin; Luu, Hue H; Haydon, Rex C; Zhao, Yingming; He, Tong-Chuan

    2011-02-01

    As one of the most common malignancies, colon cancer is initiated by abnormal activation of the Wnt/β-catenin pathway. Although the treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We have found that bisbenzylisoquinoline alkaloid tetrandrine (TET) exhibits anticancer activity. TET is used as a calcium channel blocker to treat hypertensive and arrhythmic conditions in Chinese medicine. Here, we investigate the molecular basis underlying TET's anticancer activity. We compare TET with six chemotherapy drugs in eight cancer lines and find that TET exhibits comparable anticancer activities with camptothecin, vincristine, paclitaxel, and doxorubicin, and better than that of 5-fluorouracil (5-FU) and carboplatin. TET IC₅₀ is ≤5 μM in most of the tested cancer lines. TET exhibits synergistic anticancer activity with 5-FU and reduces migration and invasion capabilities of HCT116 cells. Furthermore, TET induces apoptosis and inhibits xenograft tumor growth of colon cancer. TET treatment leads to a decrease in β-catenin protein level in xenograft tumors, which is confirmed by T-cell factor/lymphocyte enhancer factor and c-Myc reporter assays. It is noteworthy that HCT116 cells with allelic oncogenic β-catenin deleted are less sensitive to TET-mediated inhibition of proliferation, viability, and xenograft tumor growth. Thus, our findings strongly suggest that the anticancer effect of TET in colon cancer may be at least in part mediated by targeting β-catenin activity. Therefore, TET may be used alone or in combination as an effective anticancer agent. PMID:20978119

  11. Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts.

    PubMed

    Chen, Guohua; Fillebeen, Carine; Wang, Jian; Pantopoulos, Kostas

    2007-04-01

    Iron is essential for proliferation of normal and neoplastic cells. Cellular iron uptake, utilization and storage are regulated by transcriptional and post-transcriptional mechanisms. We hypothesized that the disruption of iron homeostasis may modulate the growth properties of cancer cells. To address this, we employed H1299 lung cancer cells engineered for tetracycline-inducible overexpression of the post-transcriptional regulator iron regulatory protein 1 (IRP1). The induction of IRP1 (wild-type or the constitutive IRP1(C437S) mutant) did not affect the proliferation of the cells in culture, and only modestly reduced their efficiency to form colonies in soft agar. However, IRP1 dramatically impaired the capacity of the cells to form solid tumor xenografts in nude mice. Tumors derived from IRP1-transfectants were <20% in size compared to those from parent cells. IRP1 coordinately controls the expression of transferrin receptor 1 (TfR1) and ferritin by binding to iron-responsive elements (IREs) within their mRNAs. Biochemical analysis revealed high expression of epitope-tagged IRP1 in tumor tissue, which was associated with a profound increase in IRE-binding activity. As expected, this response misregulated iron metabolism by increasing TfR1 levels. Surprisingly, IRP1 failed to suppress ferritin expression and did not affect the levels of the iron transporter ferroportin. Our results show that the overexpression of IRP1 is associated with an apparent tumor suppressor phenotype and provide a direct regulatory link between the IRE/IRP system and cancer.

  12. Effects of vatalanib on tumor growth can be potentiated by mTOR blockade in vivo.

    PubMed

    Jaeger-Lansky, Agnes; Cejka, Daniel; Ying, Liu; Preusser, Matthias; Hoeflmayer, Doris; Fuereder, Thorsten; Koehrer, Stefan; Wacheck, Volker

    2010-06-01

    The vascular endothelial growth factor (VEGF) is a central mediator of tumor-induced angiogenesis. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, decreases VEGF-secretion of cancer cells. Vatalanib is a selective inhibitor of VEGF receptors 1-3. In the present study it was hypothesized that dual inhibition of VEGF signaling by inhibition of VEGF production and VEGF receptor signaling leads to synergistic anti-tumor effects. In vitro, effects of vatalanib and everolimus on cell proliferation, cell cycle, apoptosis and signal transduction were examined in three gastric cancer cell lines. Effects on angiogenesis were assessed using tube formation assays of cultured human umbilical vein endothelial cells (HUVECs). In vivo, the antitumor effect of compounds was studied using a gastric cancer xenograft nude mouse model. VEGF of murine origin (mVEGF) and human cancer cell-derived VEGF (hVEGF) were studied separately by specific ELISAs. Tumor vascularization and proliferation were quantified by immunohistochemistry. In vitro, everolimus but not vatalanib decreased gastric cancer proliferation without inducing apoptosis. Vatalanib abolished endothelial cell tube formation, whereas inhibition of tube formation by everolimus was incomplete. In vivo, the combination of vatalanib with everolimus was superior to single agent treatments and reduced tumor size by about 50% relative to everolimus monotherapy (p < 0.005). Pharmacodynamic analysis of VEGF plasma level showed a decrease of hVEGF by everolimus and indicated a trend towards lower mVEGF level only in the combination group. In line, there was a tendency for lower vascular density and proliferation for combination treatment. We conclude that in a preclinical model of gastric cancer the antitumor activity of vatalanib can be augmented by everolimus. PMID:20404549

  13. Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope.

    PubMed

    Caron, Jennifer M; Ames, Jacquelyn J; Contois, Liangru; Liebes, Leonard; Friesel, Robert; Muggia, Franco; Vary, Calvin P H; Oxburgh, Leif; Brooks, Peter C

    2016-06-01

    Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of α-smooth muscle actin-expressing stromal cells. Integrin α10β1 can serve as a receptor for the HU177 epitope in α-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized α10β1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.

  14. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

    PubMed Central

    Ward, Kristy K.; Tancioni, Isabelle; Lawson, Christine; Miller, Nichol L.G.; Jean, Christine; Chen, Xiao Lei; Uryu, Sean; Kim, Josephine; Tarin, David; Stupack, Dwayne G.; Plaxe, Steven C.; Schlaepfer, David D.

    2013-01-01

    Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer. PMID:23275034

  15. Midkine expression correlating with growth activity and tooth morphogenesis in odontogenic tumors.

    PubMed

    Fujita, Shuichi; Seki, Sachiko; Fujiwara, Mutsunori; Ikeda, Tohru

    2008-05-01

    Midkine (MK; a low molecular weight heparin-binding growth factor) is a multifunctional cytokine. MK plays a role in morphogenesis of many organs including teeth through epithelial-mesenchymal interactions. We immunohistochemically examined MK expression in various human odontogenic tumors. There was no difference in positive rate and intensity of MK between benign odontogenic tumors and their malignant counterparts. Ameloblastoma showed MK localization in the peripheral columnar cells in budding processes from the parenchyma, which frequently expressed proliferating cell nuclear antigen. MK was also preferentially expressed in keratinized cells in acanthomatous ameloblastoma and keratocystic odontogenic tumor. In odontogenic mixed tumors except for odontoma, intense immunoreactivity to MK was found in epithelial follicles, the surrounding odontogenic ectomesenchymal tissue, and the basement membrane between them. Intensity in the odontogenic ectomesenchyme decreased in relation to distance from the epithelial follicles. No expression was found in tumor cells associated with production of dental hard tissues in odontogenic mixed tumors including odontoma. These findings suggested that MK is involved in the reciprocal interaction between odontogenic epithelium and odontogenic ectomesenchymal tissue in areas without dental hard tissue formation in odontogenic mixed tumors. Coexpression of MK and proliferating cell nuclear antigen was also observed in epithelial follicles and highly cellular nodules in the ectomesenchyme of odontogenic mixed tumors. MK is considered to mediate growth activity of odontogenic tumors and cell differentiation of odontogenic mixed tumors through molecular mechanisms similar to those involved in morphogenesis of the tooth.

  16. Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways

    SciTech Connect

    Tong, Qingyi; Qing, Yong; Wu, Yang; Hu, Xiaojuan; Jiang, Lei; Wu, Xiaohua

    2014-12-01

    Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways. - Highlights: • Dioscin inhibits tumor growth in vivo and does not exhibit any toxicity. • Dioscin inhibits angiogenesis within solid tumors. • Dioscin inhibits the proliferation, migration, invasion, and tube formation of HUVECs. • Dioscin inhibits VEGF–induced blood vessel formation in vivo. • Dioscin inhibits VEGFR2 signaling pathway as well as AKT/MAPK pathway.

  17. 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.

  18. 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

  19. Tumor Localization Using Cone-Beam CT Reduces Setup Margins in Conventionally Fractionated Radiotherapy for Lung Tumors

    SciTech Connect

    Yeung, Anamaria R.; Li, Jonathan G.; Shi Wenyin; Newlin, Heather E.; Chvetsov, Alexei; Liu, Chihray; Palta, Jatinder R.; Olivier, Kenneth

    2009-07-15

    Purpose: To determine whether setup margins can be reduced using cone-beam computed tomography (CBCT) to localize tumor in conventionally fractionated radiotherapy for lung tumors. Methods and Materials: A total of 22 lung cancer patients were treated with curative intent with conventionally fractionated radiotherapy using daily image guidance with CBCT. Of these, 13 lung cancer patients had sufficient CBCT scans for analysis (389 CBCT scans). The patients underwent treatment simulation in the BodyFix immobilization system using four-dimensional CT to account for respiratory motion. Daily alignment was first done according to skin tattoos, followed by CBCT. All 389 CBCT scans were retrospectively registered to the planning CT scans using automated soft-tissue and bony registration; the resulting couch shifts in three dimensions were recorded. Results: The daily alignment to skin tattoos with no image guidance resulted in systematic ({sigma}) and random ({sigma}) errors of 3.2-5.6 mm and 2.0-3.5 mm, respectively. The margin required to account for the setup error introduced by aligning to skin tattoos with no image guidance was approximately 1-1.6 cm. The difference in the couch shifts obtained from the bone and soft-tissue registration resulted in systematic ({sigma}) and random ({sigma}) errors of 1.5-4.1 mm and 1.8-5.3 mm, respectively. The margin required to account for the setup error introduced using bony anatomy as a surrogate for the target, instead of localizing the target itself, was 0.5-1.4 cm. Conclusion: Using daily CBCT soft-tissue registration to localize the tumor in conventionally fractionated radiotherapy reduced the required setup margin by up to approximately 1.5 cm compared with both no image guidance and image guidance using bony anatomy as a surrogate for the target.

  20. Tumor growth in complex, evolving microenvironmental geometries: A diffuse domain approach

    PubMed Central

    Chen, Ying; Lowengrub, John S.

    2014-01-01

    We develop a mathematical model of tumor growth in complex, dynamic microenvironments with active, deformable membranes. Using a diffuse domain approach, the complex domain is captured implicitly using an auxiliary function and the governing equations are appropriately modified, extended and solved in a larger, regular domain. The diffuse domain method enables us to develop an efficient numerical implementation that does not depend on the space dimension or the microenvironmental geometry. We model homotypic cell-cell adhesion and heterotypic cell-basement membrane (BM) adhesion with the latter being implemented via a membrane energy that models cell-BM interactions. We incorporate simple models of elastic forces and the degradation of the BM and ECM by tumor-secreted matrix degrading enzymes. We investigate tumor progression and BM response as a function of cell-BM adhesion and the stiffness of the BM. We find tumor sizes tend to be positively correlated with cell-BM adhesion since increasing cell-BM adhesion results in thinner, more elongated tumors. Prior to invasion of the tumor into the stroma, we find a negative correlation between tumor size and BM stiffness as the elastic restoring forces tend to inhibit tumor growth. In order to model tumor invasion of the stroma, we find it necessary to downregulate cell-BM adhesiveness, which is consistent with experimental observations. A stiff BM promotes invasiveness because at early stages the opening in the BM created by MDE degradation from tumor cells tends to be narrower when the BM is stiffer. This requires invading cells to squeeze through the narrow opening and thus promotes fragmentation that then leads to enhanced growth and invasion. In three dimensions, the opening in the BM was found to increase in size even when the BM is stiff because of pressure induced by growing tumor clusters. A larger opening in the BM can increase the potential for further invasiveness by increasing the possibility that additional

  1. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    SciTech Connect

    Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  2. The vermetid gastropod Dendropoma maximum reduces coral growth and survival

    PubMed Central

    Shima, Jeffrey S.; Osenberg, Craig W.; Stier, Adrian C.

    2010-01-01

    Coral reefs are one of the most diverse systems on the planet; yet, only a small fraction of coral reef species have attracted scientific study. Here, we document strong deleterious effects of an often overlooked species—the vermetid gastropod, Dendropoma maximum—on growth and survival of reef-building corals. Our surveys of vermetids on Moorea (French Polynesia) revealed a negative correlation between the density of vermetids and the per cent cover of live coral. Furthermore, the incidence of flattened coral growth forms was associated with the presence of vermetids. We transplanted and followed the fates of focal colonies of four species of corals on natural reefs where we also manipulated presence/absence of vermetids. Vermetids reduced skeletal growth of focal corals by up to 81 per cent and survival by up to 52 per cent. Susceptibility to vermetids varied among coral species, suggesting that vermetids could shift coral community composition. Our work highlights the potential importance of a poorly studied gastropod to coral dynamics. PMID:20484230

  3. Reduced placental volume and flow in severe growth restricted fetuses

    PubMed Central

    Abulé, Renata Montes Dourado; Bernardes, Lisandra Stein; Doro, Giovana Farina; Miyadahira, Seizo; Francisco, Rossana Pulcinelli Vieira

    2016-01-01

    OBJECTIVES: To evaluate placental volume and vascular indices in pregnancies with severe fetal growth restriction and determine their correlations to normal reference ranges and Doppler velocimetry results of uterine and umbilical arteries. METHODS: Twenty-seven fetuses with estimated weights below the 3rd percentile for gestational age were evaluated. Placental volume and vascular indices, including vascularization, flow, and vascularization flow indices, were measured by three-dimensional ultrasound using a rotational technique and compared to a previously described nomogram. The observed-to-expected placental volume ratio for gestational age and observed-to-expected placental volume ratio for fetal weight were calculated. Placental parameters correlated with the Doppler velocimetry results of uterine and umbilical arteries. RESULTS: The mean uterine artery pulsatility index was negatively correlated with the observed-to-expected placental volume ratio for gestational age, vascularization index and vascularization flow index. The observed-to-expected placental volume ratio for gestational age and observed-to-expected placental volume ratio for fetal weight and vascularization index were significantly lower in the group with a bilateral protodiastolic notch. No placental parameter correlated with the umbilical artery pulsatility index. CONCLUSIONS: Pregnancies complicated by severe fetal growth restriction are associated with reduced placental volume and vascularization. These findings are related to changes in uterine artery Doppler velocimetry. Future studies on managing severe fetal growth restriction should focus on combined results of placental three-dimensional ultrasound and Doppler studies of uterine arteries. PMID:27438567

  4. Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice

    PubMed Central

    Tuomela, Johanna M; Valta, Maija P; Väänänen, Kalervo; Härkönen, Pirkko L

    2008-01-01

    Background Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. Methods PC-3 cells (5 × 105) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. Results Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96–485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209–1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed. Conclusion Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by

  5. The inhibition of tumor growth and metastasis by self-assembled nanofibers of taxol.

    PubMed

    Wang, Huaimin; Wei, Jun; Yang, Chengbiao; Zhao, Huiyuan; Li, Dongxia; Yin, Zhinan; Yang, Zhimou

    2012-08-01

    Molecular hydrogels have big potential for local delivery and sustained release of therapeutic agents. In this paper, we reported on a molecular hydrogel mainly formed by the widely used anti-cancer drug of taxol. The hydrogel was formed by an ester bond hydrolysis process from a taxol derivative (Taxol-SA-GSSG, 1) and could be administrated into solid tumors to dramatically hinder their growths and prevent their metastasis. Besides the improved anti-cancer effect compared to the clinically used intravenous (i.v.) injection of Taxol(®), the concentration of taxol in blood was low due to the local administration of taxol hydrogels, which greatly enhanced the dosage tolerance of mice to taxol and might reduce side effects of taxol during chemotherapy. Our observations suggested that the hydrogel mainly composed of taxol would have great potential for its practical applications.

  6. The Bone Microenvironment: a Fertile Soil for Tumor Growth.

    PubMed

    Buenrostro, Denise; Mulcrone, Patrick L; Owens, Philip; Sterling, Julie A

    2016-08-01

    Bone metastatic disease remains a significant and frequent problem for cancer patients that can lead to increased morbidity and mortality. Unfortunately, despite decades of research, bone metastases remain incurable. Current studies have demonstrated that many properties and cell types within the bone and bone marrow microenvironment contribute to tumor-induced bone disease. Furthermore, they have pointed to the importance of understanding how tumor cells interact with their microenvironment in order to help improve both the development of new therapeutics and the prediction of response to therapy. PMID:27255469

  7. Knockdown of PKM2 Suppresses Tumor Growth and Invasion in Lung Adenocarcinoma.

    PubMed

    Sun, Hong; Zhu, Anyou; Zhang, Lunjun; Zhang, Jie; Zhong, Zhengrong; Wang, Fengchao

    2015-01-01

    Accumulating evidence shows that activity of the pyruvate kinase M2 (PKM2) isoform is closely related to tumorigenesis. In this study, we investigated the relationship between PKM2 expression, tumor invasion, and the prognosis of patients with lung adenocarcinoma. We retrospectively analyzed 65 cases of patients with lung adenocarcinoma who were divided into low and a high expression groups based on PKM2 immunohistochemical staining. High PKM2 expression was significantly associated with reduced patient survival. We used small interfering RNA (siRNA) technology to investigate the effect of targeted PKM2-knockout on tumor growth at the cellular level. In vitro, siRNA-mediated PKM2-knockdown significantly inhibited the proliferation, glucose uptake (25%), ATP generation (20%) and fatty acid synthesis of A549 cells, while the mitochondrial respiratory capacity of the cells increased (13%).Western blotting analysis showed that PKM2-knockout significantly inhibited the expression of the glucose transporter GLUT1 and ATP citrate lyase, which is critical for fatty acid synthesis. Further Western blotting analysis showed that PKM2-knockdown inhibited the expression of matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF), which are important in degradation of the extracellular matrix and angiogenesis, respectively. These observations show that PKM2 activates both glycolysis and lipid synthesis, thereby regulating cell proliferation and invasion. This information is important in elucidating the mechanisms by which PKM2 influences the growth and metastasis of lung adenocarcinoma at the cellular and molecular level, thereby providing the basic data required for the development of PKM2-targeted gene therapy.

  8. 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

  9. The effect of housing temperature on the growth of CT26 tumor expressing fluorescent protein EGFP

    NASA Astrophysics Data System (ADS)

    Yuzhakova, Diana V.; Shirmanova, Marina V.; Lapkina, Irina V.; Serebrovskaya, Ekaterina O.; Lukyanov, Sergey A.; Zagaynova, Elena V.

    2016-04-01

    To date, the effect of housing temperature on tumor development in the immunocompetent mice has been studied on poorly immunogenic cancer models. Standard housing temperature 20-26°C was shown to cause chronic metabolic cold stress and promote tumor progression via suppression of the antitumor immune response, whereas a thermoneutral temperature 30-31°C was more preferable for normal metabolism of mice and inhibited tumor growth. Our work represents the first attempt to discover the potential effect of housing temperature on the development of highly immunogenic tumor. EGFP-expressing murine colon carcinoma CT26 generated in Balb/c mice was used as a tumor model. No statistically significant differences were shown in tumor incidences and growth rates at 20°C, 25°C and 30°C for non-modified CT26. Maintaining mice challenged with CT26-EGFP cells at 30°C led to complete inhibition of tumor development. In summary, we demonstrated that the housing temperature is important for the regulation of growth of highly immunogenic tumors in mice through antitumor immunity.

  10. Temperature-dependent growth and regression of epidermal tumors in the european eel (Anguilla anguilla L.).

    PubMed

    Peters, G; Peters, N

    1978-09-29

    The population of eels in the Elbe estuary showed a high rate of affliction with epidermal papillomas. Distinct seasonal fluctuations were observed in the frequency of occurrence and tumor size. In spring and autumn, the frequency was low, and the tumors were relatively small. In summer, the tumors reached a maximum in both frequency and size. A distinct influence of water temperature on tumor growth was demonstrated experimentally. Summer temperatures of 15--22 degrees C caused very rapid growth. In the field and in the laboratory, the tumors exhibited a fourfold increase in average volume within 3 months. These fast-growing neoplasms had certain relatively uniform histologic features. The tumor cells were separated by wide intercellular spaces. The basal layer was composed of tall columnar cells, while the surface layer was composed of slightly flattened cells. Winter water temperatures (5--10 degrees C) inhibited tumor growth and even caused tumor regression. In 3 months, the papillomas shrank to half of their initial size. Histologic and ultrastructural examinations revealed signs of tissue degeneration: necrobiotic processes in the epidermal region, cellular and nuclear polymorphisms, dissolution of membranes, loss of cell integrity, and loosening and reduction in size of the basal cell layer. PMID:280183

  11. Physical Activity Counteracts Tumor Cell Growth in Colon Carcinoma C26-Injected Muscles: An Interim Report

    PubMed Central

    Hiroux, Charlotte; Vandoorne, Tijs; Koppo, Katrien; De Smet, Stefan; Hespel, Peter; Berardi, Emanuele

    2016-01-01

    Skeletal muscle tissue is a rare site of tumor metastasis but is the main target of the degenerative processes occurring in cancer-associated cachexia syndrome. Beneficial effects of physical activity in counteracting cancer-related muscle wasting have been described in the last decades. Recently it has been shown that, in tumor xeno-transplanted mouse models, physical activity is able to directly affect tumor growth by modulating inflammatory responses in the tumor mass microenvironment. Here, we investigated the effect of physical activity on tumor cell growth in colon carcinoma C26 cells injected tibialis anterior muscles of BALB/c mice. Histological analyses revealed that 4 days of voluntary wheel running significantly counteracts tumor cell growth in C26-injected muscles compared to the non-injected sedentary controls. Since striated skeletal muscle tissue is the site of voluntary contraction, our results confirm that physical activity can also directly counteract tumor cell growth in a metabolically active tissue that is usually not a target for metastasis. PMID:27478560

  12. Insulin and acivicin improve host nutrition and prevent tumor growth during total parenteral nutrition.

    PubMed Central

    Chance, W T; Cao, L; Fischer, J E

    1988-01-01

    The effect that a 14-day treatment program of total parenteral nutrition (TPN) combined with the glutamine antimetabolite, acivicin, and anabolic hormone, insulin, has on carcass weight and muscle sparing was investigated in tumor-bearing rats. Although TPN resulted in increased carcass weight gain as compared to chow-fed tumor-bearing rats, no savings in gastrocnemius muscle could be demonstrated. The combination of TPN with daily insulin treatment elicited significant increases in both carcass weight and muscle savings, with no alteration in tumor growth. Although combining acivicin with TPN halted tumor growth and increased carcass weight, the change in carcass weight was less than that observed with the insulin-TPN combination. No muscle savings were observed in the acivicin-TPN-treated rats. Yet when acivicin and insulin were combined with TPN, tumor growth was stopped, carcass weight was gained, and muscle mass was saved. Therefore, these experiments suggest that it is possible to add lean body tissue and stabilize tumor growth in rats that receive TPN through anabolic hormone treatment combined with an inhibitor of tumor metabolism. PMID:3140745

  13. Gramicidin A blocks tumor growth and angiogenesis through inhibition of hypoxia-inducible factor in renal cell carcinoma.

    PubMed

    David, Justin M; Owens, Tori A; Inge, Landon J; Bremner, Ross M; Rajasekaran, Ayyappan K

    2014-04-01

    Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel-forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1α and HIF-2α proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O(2)-dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHL-expressing RCC.

  14. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    PubMed Central

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  15. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer.

    PubMed

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  16. 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

    2015-01-01

    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

  17. 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

  18. 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.

  19. Overexpression of caudal-related homeobox transcription factor 2 inhibits the growth of transplanted colorectal tumors in nude mice.

    PubMed

    Zheng, Jian-Bao; Qiao, Li-Na; Sun, Xue-Jun; Qi, Jie; Ren, Hai-Liang; Wei, Guang-Bing; Zhou, Pei-Hua; Yao, Jian-Feng; Zhang, Li; Jia, Peng-Bo

    2015-09-01

    EGFP‑C1‑CDX2 group, and the gene expression of MMP‑2 was reduced. These results indicate that CDX2 inhibited the growth of colorectal tumor cells, possibly by downregulating the gene expression.

  20. Overexpression of caudal-related homeobox transcription factor 2 inhibits the growth of transplanted colorectal tumors in nude mice

    PubMed Central

    ZHENG, JIAN-BAO; QIAO, LI-NA; SUN, XUE-JUN; QI, JIE; REN, HAI-LIANG; WEI, GUANG-BING; ZHOU, PEI-HUA; YAO, JIAN-FENG; ZHANG, LI; JIA, PENG-BO

    2015-01-01

    reduced. These results indicate that CDX2 inhibited the growth of colorectal tumor cells, possibly by downregulating the gene expression. PMID:26005051

  1. Blocking tumor growth by targeting autophagy and SQSTM1 in vivo.

    PubMed

    Wei, Huijun; Guan, Jun-Lin

    2015-01-01

    Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials in response to starvation and maintenance of cellular homeostasis. Dysfunction of autophagy is implicated in a variety of diseases including cancer. In a recent study, we devised a system for inducible deletion of an essential autophagy gene Rb1cc1/Fip200 in established tumor cells in vivo and showed that Rb1cc1 is required for maintaining tumor growth. We further investigated the role of the accumulated SQSTM1 in Rb1cc1-null autophagy-deficient tumor cells. To our surprise, the increased SQSTM1 was not responsible for the inhibition of tumor growth, but rather supported the residual growth of tumors (i.e., partially compensated for the defective growth caused by Rb1cc1 deletion). Further analysis indicated that SQSTM1 promoted tumor growth in autophagy-deficient cells at least partially through its activation of the NFKB signaling pathway. A working model is proposed to account for our findings, which suggest that targeting both autophagy and the consequently increased SQSTM1 may be exploited for developing more effective cancer therapies.

  2. Brain tumor regulates neuromuscular synapse growth and endocytosis in Drosophila by suppressing mad expression.

    PubMed

    Shi, Wenwen; Chen, Yan; Gan, Guangming; Wang, Dan; Ren, Jinqi; Wang, Qifu; Xu, Zhiheng; Xie, Wei; Zhang, Yong Q

    2013-07-24

    The precise regulation of synaptic growth is critical for the proper formation and plasticity of functional neural circuits. Identification and characterization of factors that regulate synaptic growth and function have been under intensive investigation. Here we report that brain tumor (brat), which was identified as a translational repressor in multiple biological processes, plays a crucial role at Drosophila neuromuscular junction (NMJ) synapses. Immunohistochemical analysis demonstrated that brat mutants exhibited synaptic overgrowth characterized by excess satellite boutons at NMJ terminals, whereas electron microscopy revealed increased synaptic vesicle size but reduced density at active zones compared with wild-types. Spontaneous miniature excitatory junctional potential amplitudes were larger and evoked quantal content was lower at brat mutant NMJs. In agreement with the morphological and physiological phenotypes, loss of Brat resulted in reduced FM1-43 uptake at the NMJ terminals, indicating that brat regulates synaptic endocytosis. Genetic analysis revealed that the actions of Brat at synapses are mediated through mothers against decapentaplegic (Mad), the signal transduction effector of the bone morphogenetic protein (BMP) signaling pathway. Furthermore, biochemical analyses showed upregulated levels of Mad protein but normal mRNA levels in the larval brains of brat mutants, suggesting that Brat suppresses Mad translation. Consistently, knockdown of brat by RNA interference in Drosophila S2 cells also increased Mad protein level. These results together reveal an important and previously unidentified role for Brat in synaptic development and endocytosis mediated by suppression of BMP signaling. PMID:23884941

  3. 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

  4. The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors.

    PubMed

    Mizoguchi, H; Komiyama, S; Matsui, K; Hamanaka, R; Ono, M; Kiue, A; Kobayashi, M; Shimizu, N; Welgus, H G; Kuwano, M

    1991-11-11

    Three cancer cell lines, IMC-2, IMC-3 and IMC-4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC-2 in nude mice was markedly faster than that of the IMC-3 and IMC-4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC-2 cells in response to EGF, but no change for IMC-3 and IMC-4 cells. We examined response to EGF of IMC-2 cells with regard to expression of a growth-related oncogene (c-fos), proteinases and their inhibitors. Expression of c-fos was transiently increased in IMC-2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase-type plasminogen activator and 72-kDa type-IV collagenase in IMC-2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor-I (PAI-I) and tissue inhibitor of metalloproteinases-I (TIMP-I) in IMC-2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.

  5. TetraMabs: simultaneous targeting of four oncogenic receptor tyrosine kinases for tumor growth inhibition in heterogeneous tumor cell populations

    PubMed Central

    Castoldi, Raffaella; Schanzer, Jürgen; Panke, Christian; Jucknischke, Ute; Neubert, Natalie J.; Croasdale, Rebecca; Scheuer, Werner; Auer, Johannes; Klein, Christian; Niederfellner, Gerhard; Kobold, Sebastian; Sustmann, Claudio

    2016-01-01

    Monoclonal antibody-based targeted tumor therapy has greatly improved treatment options for patients. Antibodies against oncogenic receptor tyrosine kinases (RTKs), especially the ErbB receptor family, are prominent examples. However, long-term efficacy of such antibodies is limited by resistance mechanisms. Tumor evasion by a priori or acquired activation of other kinases is often causative for this phenomenon. These findings led to an increasing number of combination approaches either within a protein family, e.g. the ErbB family or by targeting RTKs of different phylogenetic origin like HER1 and cMet or HER1 and IGF1R. Progress in antibody engineering technology enabled generation of clinical grade bispecific antibodies (BsAbs) to design drugs inherently addressing such resistance mechanisms. Limited data are available on multi-specific antibodies targeting three or more RTKs. In the present study, we have evaluated the cloning, eukaryotic expression and purification of tetraspecific, tetravalent Fc-containing antibodies targeting HER3, cMet, HER1 and IGF1R. The antibodies are based on the combination of single-chain Fab and Fv fragments in an IgG1 antibody format enhanced by the knob-into-hole technology. They are non-agonistic and inhibit tumor cell growth comparable to the combination of four parental antibodies. Importantly, TetraMabs show improved apoptosis induction and tumor growth inhibition over individual monospecific or BsAbs in cellular assays. In addition, a mimicry assay to reflect heterogeneous expression of antigens in a tumor mass was established. With this novel in vitro assay, we can demonstrate the superiority of a tetraspecific antibody to bispecific tumor antigen-binding antibodies in early pre-clinical development. PMID:27578890

  6. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  7. IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden.

    PubMed

    van der Zee, Marten; Sacchetti, Andrea; Cansoy, Medine; Joosten, Rosalie; Teeuwssen, Miriam; Heijmans-Antonissen, Claudia; Ewing-Graham, Patricia C; Burger, Curt W; Blok, Leen J; Fodde, Riccardo

    2015-09-01

    Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH(hi)) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDH(hi) cells in immunodeficient mice. ALDH(hi) cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDH(lo) cells. Notably, the number of ALDH(hi) cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDH(hi) endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer.

  8. 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

    2016-09-01

    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. PMID:27259386

  9. 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

    2016-09-01

    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.

  10. Correlation between antioxidant activity of garlic extracts and WEHI-164 fibrosarcoma tumor growth in BALB/c mice.

    PubMed

    Shirzad, Hedayatollah; Taji, Fatemeh; Rafieian-Kopaei, Mahmoud

    2011-09-01

    The biological activities of garlic may be affected by different processing methods. This study, therefore, aimed to evaluate potential anticancer effects of different type of processed garlic extracts on WEHI-164 tumor cells in inbred BALB/c mice and correlate the tumor growth rates with some garlic constituents. In a preclinical trial 60 BALB/c mice were injected with WEHI-164 tumor cells and divided into six groups of 10 animals. Group 1 mice received 200 μL of saline, and groups 2-6 were injected intraperitoneally with fresh, microwaved, 3-month-old, leaves, and boiled garlic extracts, respectively, at 20 mg/kg/0.2 mL. Three weeks following tumor inoculation, the mean tumor size in garlic extract-treated groups was reduced with significant reductions observed in the fresh and microwaved extract groups compared with the control group (P<.05). The antioxidant capacity and the amounts of allicin, flavonoids, and phenolic compounds in differentially processed garlic were evaluated and correlated with their anticancer activities. There was a linear correlation between the amounts of allicin, flavonoids, or phenolic components derived from fresh, microwaved, 3-month-old, leaves, and boiled garlic and cancer growth prevention. In conclusion, garlic has anticancer activity against WEHI-164 tumor cells, and processing such as heating reduces its effect dramatically. The anticancer activities of different kinds of garlic are related to the level of allicin, flavonoids, and phenolic components. Therefore, fresh garlic has the highest content of bioactive components and the greatest anticancer efficacy.

  11. Anti-bevacizumab idiotype antibody vaccination is effective in inducing vascular endothelial growth factor-binding response, impairing tumor outgrowth.

    PubMed

    Sanches, Jéssica de Souza; de Aguiar, Rodrigo Barbosa; Parise, Carolina Bellini; Suzuki, Juliana Mayumi; Chammas, Roger; de Moraes, Jane Zveiter

    2016-04-01

    Tumors require blood supply and, to overcome this restriction, induce angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in this process, which explains the great number of antiangiogenic therapies targeting VEGF. The research and development of targeted therapy has led to the approval of bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), in clinical settings. However, side effects have been reported, usually as a consequence of bolus-dose administration of the antibody. This limitation could be circumvented through the use of anti-idiotype (Id) antibodies. In the present study, we evaluated the efficacy of an active VEGF-binding immune response generated by an anti-bevacizumab idiotype mAb, 10.D7. The 10.D7 anti-Id mAb vaccination led to detectable levels of VEGF-binding anti-anti-Id antibodies. In order to examine whether this humoral immune response could have implications for tumor development, 10.D7-immunized mice were challenged with B16-F10 tumor cells. Mice immunized with 10.D7 anti-Id mAb revealed reduced tumor growth when compared to control groups. Histological analyses of tumor sections from 10.D7-immunized mice showed increased necrotic areas, decreased CD31-positive vascular density and reduced CD68-positive cell infiltration. Our results encourage further therapeutic studies, particularly if one considers that the anti-Id therapeutic vaccination maintains stable levels of VEGF-binding antibodies, which might be useful in the control of tumor relapse.

  12. The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells: therapeutic implications in tumor angiogenesis.

    PubMed

    Zou, Gang-Ming; Karikari, Collins; Kabe, Yasuaki; Handa, Hiroshi; Anders, Robert A; Maitra, Anirban

    2009-04-01

    The apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape-1/Ref-1) is a multi-functional protein, involved in DNA repair and the activation of redox-sensitive transcription factors. The Ape-1/Ref-1 redox domain acts as a cytoprotective element in normal endothelial cells, mitigating the deleterious effects of apoptotic stimuli through induction of survival signals. We explored the role of the Ape-1/Ref-1 redox domain in the maintenance of tumor-associated endothelium, and of endothelial progenitor cells (EPCs), which contribute to tumor angiogenesis. We demonstrate that E3330, a small molecule inhibitor of the Ape-1/Ref-1 redox domain, blocks the in vitro growth of pancreatic cancer-associated endothelial cells (PCECs) and EPCs, which is recapitulated by stable expression of a dominant-negative redox domain mutant. Further, E3330 blocks the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into CD31(+) endothelial progeny. Exposure of PCECs to E3330 results in a reduction of H-ras expression and intracellular nitric oxide (NO) levels, as well as decreased DNA-binding activity of the hypoxia-inducible transcription factor, HIF-1alpha. E3330 also reduces secreted and intracellular vascular endothelial growth factor expression by pancreatic cancer cells, while concomitantly downregulating the cognate receptor Flk-1/KDR on PCECs. Inhibition of the Ape-1/Ref-1 redox domain with E3330 or comparable angiogenesis inhibitors might be a potent therapeutic strategy in solid tumors.

  13. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.

    PubMed

    Atapattu, Lakmali; Saha, Nayanendu; Chheang, Chanly; Eissman, Moritz F; Xu, Kai; Vail, Mary E; Hii, Linda; Llerena, Carmen; Liu, Zhanqi; Horvay, Katja; Abud, Helen E; Kusebauch, Ulrike; Moritz, Robert L; Ding, Bi-Sen; Cao, Zhongwei; Rafii, Shahin; Ernst, Matthias; Scott, Andrew M; Nikolov, Dimitar B; Lackmann, Martin; Janes, Peter W

    2016-08-22

    The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID:27503072

  14. DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling.

    PubMed

    Han, Na; Yuan, Xun; Wu, Hua; Xu, Hanxiao; Chu, Qian; Guo, Mingzhou; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2015-03-20

    Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival. PMID:25788272

  15. SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth.

    PubMed

    Park, Seong-Hoon; Ozden, Ozkan; Liu, Guoxiang; Song, Ha Yong; Zhu, Yueming; Yan, Yufan; Zou, Xianghui; Kang, Hong-Jun; Jiang, Haiyan; Principe, Daniel R; Cha, Yong-Il; Roh, Meejeon; Vassilopoulos, Athanassios; Gius, David

    2016-07-01

    Sirtuins participate in sensing nutrient availability and directing metabolic activity to match energy needs with energy production and consumption. However, the pivotal targets for sirtuins in cancer are mainly unknown. In this study, we identify the M2 isoform of pyruvate kinase (PKM2) as a critical target of the sirtuin SIRT2 implicated in cancer. PKM2 directs the synthesis of pyruvate and acetyl-CoA, the latter of which is transported to mitochondria for use in the Krebs cycle to generate ATP. Enabled by a shotgun mass spectrometry analysis founded on tissue culture models, we identified a candidate SIRT2 deacetylation target at PKM2 lysine 305 (K305). Biochemical experiments including site-directed mutants that mimicked constitutive acetylation suggested that acetylation reduced PKM2 activity by preventing tetramerization to the active enzymatic form. Notably, ectopic overexpression of a deacetylated PKM2 mutant in Sirt2-deficient mammary tumor cells altered glucose metabolism and inhibited malignant growth. Taken together, our results argued that loss of SIRT2 function in cancer cells reprograms their glycolytic metabolism via PKM2 regulation, partially explaining the tumor-permissive phenotype of mice lacking Sirt2 Cancer Res; 76(13); 3802-12. ©2016 AACR. PMID:27197174

  16. Effect of host age on the transplantation, growth, and radiation response of EMT6 tumors

    SciTech Connect

    Rockwell, S.

    1981-02-01

    The characteristics of EMT6 tumors in young adult and aged BALB/c KaRw mice were compared. The number of tumor cells implanted s.c. necessary to cause tumors in 50% of the injection sites was lower in aging than in young adult mice. The latent period of intradermally implanted tumors was shorter in aging mice than in young animals; however, the growth curves of established tumors were similar. The number and appearance of lung colonies after injection of cells i.v. and the pattern of spontaneous metastases were similar in young and aged animals. Radiation dose-response curves for the cells of tumors in young and aging mice were different and suggested that the proportion of hypoxic cells was higher in tumors on aging animals. These findings suggest that both immunological and nonimmunological tumor-host interactions differ in young and aged animals and that such factors may influence the natural history of the tumor and the response of the tumor to treatment.

  17. Magnitude of malate-aspartate reduced nicotinamide adenine dinucleotide shuttle activity in intact respiring tumor cells.

    PubMed

    Greenhouse, W V; Lehninger, A L

    1977-11-01

    Measurements of respiration, CO2 and lactate production, and changes in the levels of various key metabolites of the glycolytic sequence and tricarboxylic acid cycle were made on five lines of rodent ascites tumor cells (two strains of Ehrlich ascites tumor cells, Krebs II carcinoma, AS-30D carcinoma, and L1210 cells) incubated aerobically in the presence of uniformly labeled D-[14C]glucose. From these data, as well as earlier evidence demonstrating that the reduced nicotinamide adenine dinucleotide (NADH) shuttle in these cells requires a transaminase step and is thus identified as the malate-aspartate shuttle (W.V.V. Greenhouse and A.L. Lehninger, Cancer Res., 36: 1392-1396, 1976), metabolic flux diagrams were constructed for the five cell lines. These diagrams show the relative rates of glycolysis, the tricarboxylic acid cycle, electron transport, and the malate-aspartate shuttle in these tumors. Large amounts of cytosolic NADH were oxidized by the mitochondrial respiratory chain via the NADH shuttle, comprising anywhere from about 20 to 80% of the total flow of reducing equivalents to oxygen in these tumors. Calculations of the sources of energy for adenosine triphosphate synthesis indicated that on the average about one-third of the respiratory adenosine triphosphate is generated by electron flow originating from cytosolic NADH via the malate-aspartate shuttle.

  18. Reduced Wind Speed Improves Plant Growth in a Desert City

    PubMed Central

    Bang, Christofer; Sabo, John L.; Faeth, Stanley H.

    2010-01-01

    Background The often dramatic effects of urbanization on community and ecosystem properties, such as primary productivity, abundances, and diversity are now well-established. In most cities local primary productivity increases and this extra energy flows upwards to alter diversity and relative abundances in higher trophic levels. The abiotic mechanisms thought to be responsible for increases in urban productivity are altered temperatures and light regimes, and increased nutrient and water inputs. However, another abiotic factor, wind speed, is also influenced by urbanization and well known for altering primary productivity in agricultural systems. Wind effects on primary productivity have heretofore not been studied in the context of urbanization. Methodology/Principal Findings We designed a field experiment to test if increased plant growth often observed in cities is explained by the sheltering effects of built structures. Wind speed was reduced by protecting Encelia farinosa (brittlebush) plants in urban, desert remnant and outlying desert localities via windbreaks while controlling for water availability and nutrient content. In all three habitats, we compared E. farinosa growth when protected by experimental windbreaks and in the open. E. farinosa plants protected against ambient wind in the desert and remnant areas grew faster in terms of biomass and height than exposed plants. As predicted, sheltered plants did not differ from unprotected plants in urban areas where wind speed is already reduced. Conclusion/Significance Our results indicate that reductions in wind speed due to built structures in cities contribute to increased plant productivity and thus also to changes in abundances and diversity of higher trophic levels. Our study emphasizes the need to incorporate wind speed in future urban ecological studies, as well as in planning for green space and sustainable cities. PMID:20548790

  19. Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β

    PubMed Central

    Kim, Jung-Eun; Phan, Thuy Xuan; Nguyen, Vu Hong; Dinh-Vu, Hong-Van; Zheng, Jin Hai; Yun, Misun; Park, Sung-Gyoo; Hong, Yeongjin; Choy, Hyon E.; Szardenings, Michael; Hwang, Won; Park, Jin-A; Park, SunHee; Im, Sin-Hyeog; Min, Jung-Joon

    2015-01-01

    Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (ΔppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ΔppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1β and TNF-α were markedly increased in tumors colonized by ΔppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1β and TNF-α returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1β and TNF-α. We found that macrophages and dendritic cells were the main producers of TNF-α and IL-1β. Inhibiting IL-1β production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1β or TNF-α in conjunction with Salmonella therapy. These findings suggested that IL-1β and TNF-α play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy. PMID:26516371

  20. Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo

    PubMed Central

    Wyche, Thomas P.; Dammalapati, Ajitha; Cho, Hyunah; Harrison, April D.; Kwon, Glen S.; Chen, Herbert; Bugni, Tim S.; Jaskula-Sztul, Renata

    2014-01-01

    Carcinoids are slow-growing neuroendocrine tumors (NETs) that are characterized by hormone overproduction; surgery is currently the only option for treatment. Activation of the Notch pathway has previously been shown to have a role in tumor suppression in NETs. The marine-derived thiodepsipeptide thiocoraline was investigated in vitro in two carcinoid cell lines (BON and H727). Carcinoid cells treated with nanomolar concentrations of thiocoraline resulted in a decrease in cell proliferation and an alteration of malignant phenotype evidenced by decrease of NET markers, ASCL-1, CgA, and NSE. Western blot analysis demonstrated the activation of Notch1 on the protein level in BON cells. Additionally, thiocoraline activated downstream Notch targets HES1, HES5, and HEY2. Thiocoraline effectively suppressed carcinoid cell growth by promoting cell cycle arrest in BON and H727 cells. An in vivo study demonstrated that thiocoraline, formulated with polymeric micelles, slowed carcinoid tumor progression. Thus, the therapeutic potential of thiocoraline, which induced activation of the Notch pathway, in carcinoid tumors was demonstrated. PMID:25412645

  1. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    PubMed Central

    Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

    2016-01-01

    Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials. PMID:27485515

  2. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    PubMed

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models.

  3. Annexin-V promotes anti-tumor immunity and inhibits neuroblastoma growth in vivo.

    PubMed

    Yan, Xiaocai; Doffek, Kara; Yin, Chaobo; Krein, Michael; Phillips, Michael; Sugg, Sonia L; Johnson, Bryon; Shilyansky, Joel

    2012-11-01

    The goal of the current study is to determine the effects of blocking phosphatidylserine (PS) on the growth of neuroblastoma in mice. PS, an anionic phospholipid restricted to the cytoplasmic surface of plasma membranes in most cells, is externalized to the surface of apoptotic cells. PS has been shown to induce immune tolerance to self-antigens. PS can also be found on the surface of live cells and in particular tumor cells. Annexin-V (AnV) is a protein that specifically binds and blocks PS. To determine the effects of blocking PS with AnV on tumor growth and immunogenicity, mice were inoculated with AGN2a, a poorly immunogenic murine neuroblastoma that expresses high level of PS on the cell surface. Survival and anti-tumor T cell response were determined. AGN2a were engineered to secrete AnV. Secreted protein effectively blocked tumor PS. 40 % of mice inoculated with AnV-expressing AGN2a cells survived free of tumor, whereas none of the mice inoculated with control cells survived (p = 0.0062). The benefits of AnV were lost when mice were depleted of T cells. The findings suggest that AnV could protect mice from tumor challenge through an immune mediated mechanism. Mice were then immunized with irradiated AnV-secreting or control cells, and challenged with wild-type AGN2a cells. AnV-secreting cell vaccine protected 80 % of mice from AGN2a challenge, while control cell vaccine prevented tumor growth in only 30 % of animals (p = 0.012). ELISPOT analysis demonstrated that AnV-secreting cell vaccine induced a greater frequency of interferon-gamma producing splenic T cells. T cells isolated from mice immunized with AnV-secreting but not control vaccine lysed AGN2a. In summary, AnV blocked PS, enhanced T cell mediated tumor immunity, and inhibited tumor growth.

  4. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types. PMID:26568031

  5. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types.

  6. 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.

  7. Morphology and growth characteristics of epithelial cells from classic Wilms' tumors.

    PubMed Central

    Hazen-Martin, D. J.; Garvin, A. J.; Gansler, T.; Tarnowski, B. I.; Sens, D. A.

    1993-01-01

    The ability to establish cell cultures representing the epithelial component of Wilms' tumor was determined for 18 cases of classic Wilms' tumors. From these 18 cases only two resulted in the culture of epithelial cells. Although the tumors from both cases were composed of a prominent epithelial component, other classic tumors not producing epithelial cell cultures also possessed appreciable epithelial components. Likewise, heterotransplants of these two primary tumors failed to give rise to epithelial cell cultures, although cultures of the blastemal element were produced. This suggests that Wilms' tumors may be prone to differentiate in different directions at varying times during tumor growth, possibly dependent on local tumor environment. Epithelial cells from these two classic cases were grown in culture in basal medium composed of a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 medium, supplemented with selenium, insulin, transferrin, hydrocortisone, tri-iodothyronine, and epidermal growth factor, on a collagen type I matrix with absorbed fetal calf serum proteins. One of the two cases also required the addition of bovine pituitary extract, ethanolamine, prostaglandin E1, and putrescine for optimum growth. Morphological analysis disclosed that the cultured cells were very similar to normal renal tubular cells in culture, except that the cells displayed little evidence for differentiated active ion transport and tended to grow in a multilayered arrangement. The culture of the epithelial cells from classic Wilms' tumors provides a model system for the study of tumor differentiation and progression. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 PMID:8384407

  8. Non-invasive optical imaging of tumor growth in intact animals

    NASA Astrophysics Data System (ADS)

    Lu, Jinling; Li, Pengcheng; Luo, Qingming; Zhu, Dan

    2003-12-01

    We describe here a system for rapidly visualizing tumor growth in intact rodent mice that is simple, rapid, and eminently accessible and repeatable. We have established new rodent tumor cell line -- SP2/0-GFP cells that stably express high level of green fluorescent protein (GFP) by transfected with a plasmid that encoded GFP using electroporation and selected with G418 for 3 weeks. 1 x 104 - 1x107 SP2/0-GFP mouse melanoma cells were injected s.c. in the ears and legs of 6- to 7-week-old syngeneic male BALB/c mice, and optical images visualized real-time the engrafted tumor growth. The tumor burden was monitored over time by cryogenically cooled charge coupled device (CCD) camera focused through a stereo microscope. The results show that the fluorescence intensity of GFP-expressing tumor is comparably with the tumor growth and/or depress. This in vivo optical imaging based on GFP is sensitive, external, and noninvasive. It affords continuous visual monitoring of malignant growth within intact animals, and may comprise an ideal tool for evaluating antineoplastic therapies.

  9. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  10. Monoclonal Antibodies Targeting Tumor Growth | NCI Technology Transfer Center | TTC

    Cancer.gov

    The NCI Nanobiology Program, Protein Interaction Group is seeking parties to license or co-develop, evaluate, or commercialize monoclonal antibodies against the insulin-like growth factor for the treatment of cancer.

  11. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    SciTech Connect

    Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin; Cai, Liuxin

    2010-12-17

    Research highlights: {yields} Reconstitution of ARHI suppresses the growth of HCC xenografts. {yields} ARHI reexpression impairs tumor angiogenesis in vivo. {yields} Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. {yields} Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  12. Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

    PubMed Central

    ZHAO, DAHANG; LIU, XIANGJIE; ZHANG, YUNGE; DING, ZHAOMING; DONG, FENG; XU, HONGWEI; WANG, BAOXIN; WANG, WENBO

    2016-01-01

    Osteosarcoma is the most prevalent type of primary malignant bone tumor. Inhibitor of growth 4 (ING4) has been demonstrated to function as a tumor suppressor through multiple pathways, and is its expression is understood to be suppressed or reduced in various malignancies. The present study aimed to investigate the expression of ING4 and to determine its prognostic value in osteosarcoma tissue. Formalin-fixed, paraffin-embedded tissue microarrays were analyzed, and contained 41 osteosarcoma specimens and 11 normal bone tissue specimens with duplicate cores. ING4 expression was evaluated by immunohistochemical staining. The association between ING4 expression in the osteosarcoma and normal bone tissues was analyzed, in addition to the association between ING4 expression and Enneking classification of the osteosarcoma tissues. A significant statistical difference was observed in the ING4 immunohistochemical staining score between the osteosarcoma and normal bone tissues (P<0.001). Furthermore, a significant negative correlation was detected between the ING4 immunohistochemical staining scores and the Enneking classification results of the 41 osteosarcoma tissues (P=0.002). Low expression of ING4 was observed in the osteosarcoma specimens, and this reduced expression of ING4 was negatively correlated with Enneking classification. Thus, the results of the present study indicate that ING4 may serve as a promising prognostic marker in osteosarcoma. PMID:27073567

  13. The transcription factor Ets21C drives tumor growth by cooperating with AP-1

    PubMed Central

    Toggweiler, Janine; Willecke, Maria; Basler, Konrad

    2016-01-01

    Tumorigenesis is driven by genetic alterations that perturb the signaling networks regulating proliferation or cell death. In order to block tumor growth, one has to precisely know how these signaling pathways function and interplay. Here, we identified the transcription factor Ets21C as a pivotal regulator of tumor growth and propose a new model of how Ets21C could affect this process. We demonstrate that a depletion of Ets21C strongly suppressed tumor growth while ectopic expression of Ets21C further increased tumor size. We confirm that Ets21C expression is regulated by the JNK pathway and show that Ets21C acts via a positive feed-forward mechanism to induce a specific set of target genes that is critical for tumor growth. These genes are known downstream targets of the JNK pathway and we demonstrate that their expression not only depends on the transcription factor AP-1, but also on Ets21C suggesting a cooperative transcriptional activation mechanism. Taken together we show that Ets21C is a crucial player in regulating the transcriptional program of the JNK pathway and enhances our understanding of the mechanisms that govern neoplastic growth. PMID:27713480

  14. Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma

    PubMed Central

    Hrynyk, Michael; Ellis, Jordon P; Haxho, Fiona; Allison, Stephanie; Steele, Joseph AM; Abdulkhalek, Samar; Neufeld, Ronald J; Szewczuk, Myron R

    2015-01-01

    Poly (lactic-co-glycolic acid) (PLGA) copolymers have been extensively used in cancer research. PLGA can be chemically engineered for conjugation or encapsulation of drugs in a particle formulation. We reported that oseltamivir phosphate (OP) treatment of human pancreatic tumor-bearing mice disrupted the tumor vasculature with daily injections. Here, the controlled release of OP from a biodegradable PLGA cylinder (PLGA-OP) implanted at tumor site was investigated for its role in limiting tumor neovascularization, growth, and metastasis. PLGA-OP cylinders over 30 days in vitro indicated 20%–25% release profiles within 48 hours followed by a continuous metronomic low dose release of 30%–50% OP for an additional 16 days. All OP was released by day 30. Surgically implanted PLGA-OP containing 20 mg OP and blank PLGA cylinders at the tumor site of heterotopic xenografts of human pancreatic PANC1 tumors in RAGxCγ double mutant mice impeded tumor neovascularization, growth rate, and spread to the liver and lungs compared with the untreated cohort. Xenograft tumors from PLGA and PLGA-OP-treated cohorts expressed significant higher levels of human E-cadherin with concomitant reduced N-cadherin and host CD31+ endothelial cells compared with the untreated cohort. These results clearly indicate that OP delivered from PLGA cylinders surgically implanted at the site of the solid tumor show promise as an effective treatment therapy for cancer. PMID:26309402

  15. Combined therapeutic effects of vinblastine and Astragalus saponins in human colon cancer cells and tumor xenograft via inhibition of tumor growth and proangiogenic factors.

    PubMed

    Auyeung, Kathy K W; Law, P C; Ko, Joshua K S

    2014-01-01

    Our previous study had demonstrated that Astragalus saponins (AST) could reduce the side effects of orthodox chemotherapeutic drugs, while concurrently promote antitumor activity. In the present study, we attempted to investigate the potential synergistic anticarcinogenic effects of AST and a vinca alkaloid vinblastine (VBL). Reduced expression of key proangiogenic and metastatic factors including VEGF, bFGF, metalloproteinase (MMP)-2, and MMP-9 was detected in VBL-treated colon cancer cells, with further downregulation by combined VBL/AST treatment. Subsequently, VBL or AST decreased LoVo cell invasiveness, with further reduction when the drugs were cotreated. Significant growth inhibition and cell cycle arrest at G2/M phase were achieved by either drug treatment with apparent synergistic effects. VBL-induced apoptosis was confirmed but found to be unrelated to induction of the novel apoptotic protein NSAID-activated gene 1. In vivo study in tumor xenograft indicates that combined VBL/AST treatment resulted in sustained regression of tumor growth, with attenuation of the neutropenic and anemic effects of VBL. In addition, downregulation of proangiogenic and proliferative factors was also visualized, with boosting effect by combined drug treatment. These findings have provided evidence that AST combined with adjuvant chemotherapeutics like VBL could alleviate cancer development through diversified modes of action, including the regulation of angiogenesis.

  16. Growth-inhibitory Activity and Downregulation of the Class II Tumor-suppressor Gene H-rev107 in Tumor Cell Lines and Experimental Tumors

    PubMed Central

    Sers, Christine; Emmenegger, Urban; Husmann, Knut; Bucher, Katharina; Andres, Ann-Catherine; Schäfer, Reinhold

    1997-01-01

    The H-rev107 gene is a new class II tumor suppressor, as defined by its reversible downregulation and growth-inhibiting capacity in HRAS transformed cell lines. Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation. Cell populations of H-rev107 transfectants showed an attenuated tumor formation in nude mice. Cells explanted from tumors or maintained in cell culture for an extended period of time no longer exhibited detectable levels of the H-rev107 protein, suggesting strong selection against H-rev107 expression in vitro and in vivo. Expression of the truncated form of H-rev107 lacking the COOH-terminal membrane associated domain of 25 amino acids, had a weaker inhibitory effect on proliferation in vitro and was unable to attenuate tumor growth in nude mice. The H-rev107 mRNA is expressed in most adult rat tissues, and immunohistochemical analysis showed expression of the protein in differentiated epithelial cells of stomach, of colon and small intestine, in kidney, bladder, esophagus, and in tracheal and bronchial epithelium. H-rev107 gene transcription is downregulated in rat cell lines derived from liver, kidney, and pancreatic tumors and also in experimental mammary tumors expressing a RAS transgene. In colon carcinoma cell lines only minute amounts of protein were detectable. Thus, downregulation of H-rev107 expression may occur at the level of mRNA or protein. PMID:9049257

  17. Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer.

    PubMed

    Liu, Meng; Sjogren, Anna-Karin M; Karlsson, Christin; Ibrahim, Mohamed X; Andersson, Karin M E; Olofsson, Frida J; Wahlstrom, Annika M; Dalin, Martin; Yu, Huiming; Chen, Zhenggang; Yang, Shao H; Young, Stephen G; Bergo, Martin O

    2010-04-01

    RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS(G12D)-expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.

  18. Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2

    PubMed Central

    Wu, Florence TH; Lee, Christina R; Bogdanovic, Elena; Prodeus, Aaron; Gariépy, Jean; Kerbel, Robert S

    2015-01-01

    Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)—a purported Ang1 mimetic, Tie2 agonist—can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231•LM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined. PMID:25851538

  19. The Importance of Neighborhood Scheme Selection in Agent-based Tumor Growth Modeling

    PubMed Central

    Tzedakis, Georgios; Tzamali, Eleftheria; Marias, Kostas; Sakkalis, Vangelis

    2015-01-01

    Modeling tumor growth has proven a very challenging problem, mainly due to the fact that tumors are highly complex systems that involve dynamic interactions spanning multiple scales both in time and space. The desire to describe interactions in various scales has given rise to modeling approaches that use both continuous and discrete variables, known as hybrid approaches. This work refers to a hybrid model on a 2D square lattice focusing on cell movement dynamics as they play an important role in tumor morphology, invasion and metastasis and are considered as indicators for the stage of malignancy used for early prognosis and effective treatment. Considering various distributions of the microenvironment, we explore how Neumann vs. Moore neighborhood schemes affects tumor growth and morphology. The results indicate that the importance of neighborhood selection is critical under specific conditions that include i) increased hapto/chemo-tactic coefficient, ii) a rugged microenvironment and iii) ECM degradation. PMID:26396490

  20. Targeting matriptase in breast cancer abrogates tumor progression via impairment of stromal-epithelial growth factor signaling

    PubMed Central

    Zoratti, Gina L.; Tanabe, Lauren M.; Varela, Fausto A.; Murray, Andrew S.; Bergum, Christopher; Colombo, Eloic; Lang, Julie; Molinolo, Alfredo A.; Leduc, Richard; Marsault, Eric; Boerner, Julie; List, Karin

    2015-01-01

    Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years due to its consistent dysregulation in human epithelial tumors, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumor formation and blunted tumor growth. The abated tumor growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signaling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer. PMID:25873032

  1. Suppressing tumor growth of nasopharyngeal carcinoma by hTERTC27 polypeptide delivered through adeno-associated virus plus adenovirus vector cocktail

    PubMed Central

    Liu, Xiong; Li, Xiang-Ping; Peng, Ying; Ng, Samuel S.; Yao, Hong; Wang, Zi-Feng; Wang, Xiao-Mei; Kung, Hsiang-Fu; Lin, Marie C.M.

    2012-01-01

    Nasopharyngeal carcinoma (NPC) is a metastatic carcinoma that is highly prevalent in Southeast Asia. Our laboratory has previously demonstrated that the C-terminal 27-kDa polypeptide of human telomerase reverse transcriptase (hTERTC27) inhibits the growth and tumorigenicity of human glioblastoma and melanoma cells. In this study, we investigated the antitumor effect of hTERTC27 in human C666-1 NPC cells xenografted in a nude mouse model. A cocktail of vectors comprising recombinant adeno-associated virus (rAAV) and recombinant adenovirus (rAdv) that each carry hTERTC27 (rAAV-hTERTC27 and rAdv-hTERTC27; the cocktail was abbreviated to rAAV/rAdv-hTERTC27) was more effective than either rAAV-hTERTC27 or rAdv-hTERTC27 alone in inhibiting the growth of C666-1 NPC xenografts. Furthermore, we established three tumors on each mouse and injected rAAV/rAdv-hTERTC27 into one tumor per mouse. Although hTERTC27 expression could only be detected in the injected tumors, reduced tumor growth was observed in the injected tumor as well as the uninjected tumors, demonstrating that the vector cocktail could provoke an antitumor effect on distant, metastasized tumors. Further studies showed the observed antitumor effects included inducing necrosis and apoptosis and reducing microvessel density. Together, our data suggest that the rAAV/rAdv-hTERTC27 cocktail can potently inhibit NPC tumor growth in both local and metastasized tumors and should be further developed as a novel gene therapy strategy for NPC. PMID:23149313

  2. Vaccination with OVA-bound nanoparticles encapsulating IL-7 inhibits the growth of OVA-expressing E.G7 tumor cells in vivo.

    PubMed

    Toyota, Hiroko; Yanase, Noriko; Yoshimoto, Takayuki; Harada, Mitsunori; Kato, Yasuki; Mizuguchi, Junichiro

    2015-01-01

    Immunotherapy has gained special attention due to its specific effects on tumor cells and systemic action to block metastasis. We recently demonstrated that ovalbumin (OVA) conjugated to the surface of nanoparticles (NPs) (OVA‑NPs) can manipulate humoral immune responses. In the present study, we aimed to ascertain whether vaccination with OVA-NPs entrapping IL-7 (OVA-NPs-IL-7) are able to induce antitumor immune responses in vivo. Pretreatment with a subcutaneous inoculation of OVA-NPs delayed the growth of thymic lymphoma cells expressing a model tumor antigen OVA (E.G7-OVA), and OVA-NPs-IL-7 substantially blocked the growth of E.G7-OVA tumor cells, although NPs-IL-7 alone had a meager effect, as assessed by the mean tumor size and the percentage of tumor-free mice. However, pretreatment with OVA-NPs-IL-7 failed to reduce the growth of parental thymic tumor cells, suggesting that the antitumor effect was antigen-specific. A tetramer assay revealed that vaccination with OVA-NPs-IL-7 tended to enhance the proportion of cytotoxic T cells (CTLs) specific for OVA. When the tumor-free mice inoculated with OVA-NPs-IL-7 plus EG.7 cells were rechallenged with E.G7-OVA cells, they demonstrated reduced growth compared with that in the control mice. Thus, a single subcutaneous injection of OVA-NPs-IL-7 into mice induced tumor-specific and also memory-like immune responses, resulting in regression of tumor cells. Antigens on NPs entrapping IL-7 would be a promising carrier to develop and enhance immune responses, including humoral and cellular immunity as well as a method of drug delivery to a specific target of interest.

  3. Decreased Warburg effect induced by ATP citrate lyase suppression inhibits tumor growth in pancreatic cancer.

    PubMed

    Zong, Haifeng; Zhang, Yang; You, Yong; Cai, Tiantian; Wang, Yehuang

    2015-03-01

    ATP citrate lyase (ACLY) is responsible for the conversion of cytosolic citrate into acetyl-CoA and oxaloacetate, and the first rate-limiting enzyme involved in de novo lipogenesis. Recent studies have demonstrated that inhibition of elevated ACLY results in growth arrest and apoptosis in a subset of cancers; however, the expression pattern and underlying biological function of ACLY in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, overexpressed ACLY was more commonly observed in PDAC compared to normal pancreatic tissues. Kaplan-Meier survival analysis showed that high expression level of ACLY resulted in a poor prognosis of PDAC patients. Silencing of endogenous ACLY expression by siRNA in PANC-1 cells led to reduced cell viability and increased cell apoptosis. Furthermore, significant decrease in glucose uptake and lactate production was observed after ACLY was knocked down, and this effect was blocked by 2-deoxy-D-glucose, indicating that ACLY functions in the Warburg effect affect PDAC cell growth. Collectively, this study reveals that suppression of ACLY plays an anti-tumor role through decreased Warburg effect, and ACLY-related inhibitors might be potential therapeutic approaches for PDAC. PMID:25701462

  4. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    SciTech Connect

    Lyu, Qing; Tou, Fangfang; Su, Hong; Wu, Xiaoyong; Chen, Xinyi; Zheng, Zhi

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  5. The Growth of SGC-7901 Tumor Xenografts Was Suppressed by Chinese Bayberry Anthocyanin Extract through Upregulating KLF6 Gene Expression

    PubMed Central

    Wang, Yue; Zhang, Xia-nan; Xie, Wen-hua; Zheng, Yi-xiong; Cao, Jin-ping; Cao, Pei-rang; Chen, Qing-jun; Li, Xian; Sun, Chong-de

    2016-01-01

    To investigate the antitumor effect of anthocyanins extracted from Chinese bayberry fruit (Myrica rubra Sieb. et Zucc.), a nude mouse tumor xenograft model was established. Treatments with C3G (cyanidin-3-glucoside, an anthocyanin) significantly suppressed the growth of SGC-7901 tumor xenografts in a dose-dependent manner. Immunohistochemical staining showed a significant increase in p21 expression, indicating that the cell cycle of tumor xenografts was inhibited. qPCR screening showed that C3G treatment up-regulated the expression of the KLF6 gene, which is an important tumor suppressor gene inactivated in many human cancers. Western blot showed that C3G treatments markedly increased KLF6 and p21 protein levels, inhibited CDK4 and Cyclin D1 expression, but did not notably change the expression of p53. These results indicated that KLF6 up-regulates p21 in a p53-independent manner and significantly reduces tumor proliferation. This study provides important information for the possible mechanism of C3G-induced antitumor activity against gastric adenocarcinoma in vivo. PMID:27690088

  6. RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment

    PubMed Central

    Nasser, Mohd W.; Wani, Nissar Ahmad; Ahirwar, Dinesh K.; Powell, Catherine A.; Ravi, Janani; Elbaz, Mohamad; Zhao, Helong; Padilla, Laura; Zhang, Xiaoli; Shilo, Konstantin; Ostrowski, Michael; Shapiro, Charles; Carson, William E.; Ganju, Ramesh K.

    2015-01-01

    RAGE is a multi-functional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer cells, both in primary tumors and lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the pro-inflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidat