cyclic-gmp and Neoplasm-Metastasis

Topics: Calcium; Cell Division; Cyclic AMP; Cyclic GMP; Energy Metabolism; Mitogens; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms, Experimental

Topics: Animals; Binding Sites; Cell Adhesion; Cell Division; Cell Membrane; Cell Transformation, Neoplastic; Chick Embryo; Cricetinae; Cyclic AMP; Cyclic GMP; Erythrocytes; Glycolipids; Glycoproteins; Humans; Intercellular Junctions; Kidney Tubules, Proximal; Lectins; Lipid Metabolism; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Proteins

Drug resistance mechanisms still characterize metastatic melanoma, despite the new treatments that have been recently developed. Targeting of the cGMP/protein kinase G pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric-linked dimeric cGMP analogs able to bind and activate protein kinase G, called protein kinase G activators (PAs) 4 and 5. PA5 was identified as the most effective compound on melanoma cell lines as well as on patient-derived metastatic melanoma cells cultured as three-dimensional spheroids and in a zebrafish melanoma model. PA5 was able to significantly reduce cell viability, size, and invasion of melanoma spheroids. Importantly, PA5 showed a tumor-specific outcome because no toxic effect was observed in healthy melanocytes exposed to the cGMP analog. We defined that by triggering protein kinase G, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of protein kinase B and extracellular signal‒regulated kinase 1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analog PA5 as a potential therapeutic strategy for melanoma.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Humans; Melanocytes; Melanoma; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Zebrafish

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer and the 5-year survival rate is only 5%. Several studies have suggested that cancer stem cells (CSCs) are thought to be involved in recurrence and metastasis and so it is essential to establish an approach targeting CSCs. Here we have demonstrated that cyclic guanosine monophosphate (cGMP) suppressed CD44 expression and the properties of CSCs in PDAC. Microarray analysis suggested that cGMP inhibited Forkhead box O3 (FOXO3), which is known as a tumor suppressor. Surprisingly, our data demonstrated that FOXO3 is essential for CD44 expression and the properties of CSCs. Our data also indicated that patients with high FOXO3 activation signatures had poor prognoses. This evidence suggested that cGMP induction and FOXO3 inhibition could be ideal candidates for pancreatic CSC.

Topics: Adenocarcinoma; Animals; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cyclic GMP; Forkhead Box Protein O3; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Mice; Microarray Analysis; Neoplasm Metastasis; Neoplastic Stem Cells; Prognosis; Xenograft Model Antitumor Assays

Malignant melanomas escape immunosurveillance via the loss/down-regulation of MHC-I expression. Natural killer (NK) cells have the potential to function as essential effector cells for eliminating melanomas. Cyclic di-GMP (c-di-GMP), a ligand of the stimulator of interferon genes (STING) signal pathway, can be thought of as a new class of adjuvant against cancer. However, it is yet to be tested, because technologies for delivering c-di-GMP to the cytosol are required. Herein, we report that c-di-GMP efficiently activates NK cells and induces antitumor effects against malignant melanomas when loaded in YSK05 lipid containing liposomes, by assisting in the efficient delivery of c-di-GMP to the cytosol. The intravenous administration of c-di-GMP encapsulated within YSK05-liposomes (c-di-GMP/YSK05-Lip) into mice efficiently induced the production of type I interferon (IFN) as well as the activation of NK cells, resulting in a significant antitumor effect in a lung metastasis mouse model using B16-F10. This antitumor effect was dominated by NK cells. The infiltration of NK cells was observed in the lungs with B16-F10 melanomas. These findings indicate that the c-di-GMP/YSK05-Lip induces MHC-I non-restricted antitumor immunity mediated by NK cells. Consequently, c-di-GMP/YSK05-Lip represents a potentially new adjuvant system for use in immunotherapy against malignant melanomas.

Topics: Animals; Chemotherapy, Adjuvant; Cyclic GMP; Cytokines; Cytosol; Drug Delivery Systems; Immunotherapy; Injections, Intravenous; Killer Cells, Natural; Ligands; Lipids; Liposomes; Lung; Macrophage Activation; Melanoma, Experimental; Membrane Proteins; Mice; Neoplasm Metastasis; Piperidines

Matrix metalloproteinase-9 (MMP-9) produced by colorectal cancer cells is a critical determinant of metastatic disease progression and an attractive target for antimetastatic strategies to reduce colon cancer mortality. Cellular signaling by cyclic GMP (cGMP) regulates MMP-9 dynamics in various cell systems, and the bacterial enterotoxin receptor guanylyl cyclase C (GCC), the principle source of cGMP in colonocytes, which is overexpressed in colorectal cancers, inhibits tumor initiation and progression in the intestine. Here, we show that ligand-dependent GCC signaling through cGMP induces functional remodeling of cancer cell MMP-9 reflected by a compartmental redistribution of this gelatinase, in which intracellular retention resulted in reciprocal extracellular depletion. Functional remodeling of MMP-9 by GCC signaling reduced the ability of colon cancer cells to degrade matrix components, organize the actin cytoskeleton to form locomotory organelles and spread, and hematogenously seed distant organs. Of significance, GCC effects on cancer cell MMP-9 prevented establishment of metastatic colonies by colorectal cancer cells in the mouse peritoneum in vivo. Because endogenous hormones for GCC are uniformly deficient in intestinal tumors, reactivation of dormant GCC signaling with exogenous administration of GCC agonists may represent a specific intervention to target MMP-9 functions in colon cancer cells. The notion that GCC-mediated regulation of cancer cell MMP-9 disrupts metastasis, in turn, underscores the unexplored utility of GCC hormone replacement therapy in the chemoprevention of colorectal cancer progression.

Topics: Caco-2 Cells; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Cyclic GMP; Epithelial Cells; Guanylate Cyclase; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasm Metastasis; Peritoneal Neoplasms; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction

Tumour hypoxia is associated with resistance to therapy and with increased invasion and metastatic potential. Recent studies in our laboratory have shown that the hypoxic up-regulation of tumour cell invasiveness and chemoresistance is in part due to reduced nitric oxide (NO) signaling. Using B16F10 murine melanoma cells, we demonstrate here that the increased metastatic potential associated with exposure to hypoxia is mediated by a reduction in cGMP-dependent NO-signaling. Pre-incubation of B16F10 cells in hypoxia (1% vs. 20% O(2)) for 12 hr increased lung colonization ability by over 4-fold. This effect of hypoxia on metastasis was inhibited by co-incubation with low concentrations of the NO-mimetic drugs glyceryl trinitrate (GTN) and diethylenetriamine NO adduct (DETA/NO). In a manner similar to hypoxia, pharmacological inhibition of NO synthesis resulted in a significant increase in lung nodule formation, an effect that was prevented by co-incubation with GTN. An important NO-signaling pathway involves the activation of soluble guanylyl cyclase and the consequential generation of cGMP. Culture in the presence of a non-hydrolysable cGMP analogue (8-Br-cGMP) abrogated the hypoxia-induced lung nodule formation, suggesting that the effects of NO on metastasis are mediated via a cGMP-dependent pathway. These findings suggest that a novel mechanism whereby hypoxia regulates metastatic potential involves a downstream inhibition of cGMP-dependent NO signaling.

Topics: Animals; Cyclic GMP; Female; Hypoxia; Lung Neoplasms; Melanoma, Experimental; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Nitric Oxide; Signal Transduction; Tumor Cells, Cultured; Tumor Stem Cell Assay

The present study examined the effect of hepatoma-associated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca(2+) mobilization and metastatic process of human hepatoma cells. HAb18G/CD147 cDNA was transfected into human 7721 hepatoma cells to obtain a cell line stably expressing HAb18G/CD147, T7721, as demonstrated by Northern blot and immunocytochemical studies. 8-Bromo-cGMP (cGMP) inhibited the thapsigargin-induced Ca(2+) entry in a concentration-dependent manner in 7721 cells. The cGMP-induced inhibition was abolished by an inhibitor of protein kinase G, KT5823 (1 microm). However, expression of HAb18G/CD147 in T7721 cells decreased the inhibitory response to cGMP. A similar concentration-dependent inhibitory effect on the Ca(2+) entry was observed in 7721 cells in response to a NO donor, (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca(2+) entry was significantly reduced in HAb18G/CD147-expressing T7721 cells, indicating a role for HAb18G/CD147 in NO/cGMP-regulated Ca(2+) entry. Experiments investigating metastatic potentials demonstrated that HAb18G/CD147-expressing T7721 cells attached to the Matrigel-coated culture plates and invaded through Matrigel-coated permeable filters at the rate significantly greater than that observed in 7721 cells. Both the attachment and invasion rates could be suppressed by SNAP, and the inhibitory effect of SNAP could be reversed by NO inhibitor, N(G)-nitro-l-arginine methyl ester. The sensitivity of the attachment and invasion rates to cGMP was significantly reduced in T7721 cells as compared with 7721 cells when cells were pretreated with thapsigargin. The difference in the sensitivity between the two cells could be abolished by a Ca(2+) channel blocker, Ni(2+) (3 mm). These results suggest that HAb18G/CD147 enhances metastatic potentials in human hepatoma cells by disrupting the regulation of store-operated Ca(2+) entry by NO/cGMP.

Topics: Alkaloids; Antigens, CD; Antigens, Neoplasm; Antigens, Surface; Avian Proteins; Basigin; Blood Proteins; Blotting, Northern; Calcium; Carbazoles; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line; Cell Movement; Collagen; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; DNA, Complementary; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Humans; Immunohistochemistry; Indoles; Laminin; Liver Neoplasms; Membrane Glycoproteins; Neoplasm Metastasis; NG-Nitroarginine Methyl Ester; Nickel; Nitric Oxide; Penicillamine; Proteoglycans; Signal Transduction; Thapsigargin; Time Factors; Transfection; Tumor Cells, Cultured

The effects of prostaglandin E1(PGE1), prostaglandin synthesis inhibitor and indomethacin (IN) on the growth and metastasis of Lewis lung carcinoma (LLC) were studied and their mechanisms of action were investigated. Seventy-five C57BL mice of both sexes were utilized in the experiment. It was found that both PGE1 and IN could significantly retard the growth of transplanted LLC and reduce the number of pulmonary metastatic foci. PGE1 obviously decreased the acid phosphatase (ACP) activity of LLC cells while IN showed no such effect. Besides, PGE1 could markedly elevate the plasma cAMP level of LLC-bearing mice, but not normal controls. Meanwhile, it could decrease plasma cGMP concentration of both normal and tumor-bearing mice. IN, like PGE1, could increase plasma cAMP and decrease plasma cGMP levels of LLC-bearing animals. TEM observation revealed that tumor cells treated with PGE1 and IN presented a series of degenerative and destructive changes. In addition, PGE1 and IN exhibited a different effect on several cell-mediated immune responses of the tumored hosts, the former inhibitory and the latter stimulatory. The possible mechanisms of action of the two chemicals are discussed.

Topics: Adolescent; Alprostadil; Animals; Child; Cyclic AMP; Cyclic GMP; Female; Humans; Indomethacin; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation

Levels of urine excretion of cAMP and cGMP and their ratio were studied in patients with colorectal cancer in the course of a 3-year follow-up. At 12-36 months after surgery, the cAMP/cGMP ratio was higher (mainly due to decreased cGMP level) in disease-free patients than in those with recurrence or metastases. Preoperative level of cyclic nucleotide excretion cannot serve as prognostic factor for recurrence or metastasis development whereas levels of cAMP and cGMP measured within a follow-up period may be used for monitoring the course of colorectal cancer. The cAMP/cGMP ratio tended to rise in application of drugs controlling hyperlipidemia and other signs of cancrophilia.

Topics: Adult; Colonic Neoplasms; Cyclic AMP; Cyclic GMP; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Rectal Neoplasms; Time Factors

It is shown that zymosan, prodigiosan, tiloron and levamisol have a different effect on the level of cyclic nucleotides and the cAMP/cGMP correlation in the lungs, thymus and spleen of mice during metastatic spreading of the Lewis carcinoma. A more pronounced antimetastatic effect after administration of immunomodulators is accompanied by a more considerable increase in the cAMP/cAMP coefficient in immunocompetent organs. There exists a close negative correlation between the increase in the cAMP/cGMP coefficient in the thymus and spleen, on the one hand, and inhibition of the metastatic spreading in the lungs under the effect of levamisol and zymosan, on the other.

Topics: Adjuvants, Immunologic; Animals; Cyclic AMP; Cyclic GMP; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Spleen; Thymus Gland

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Blood; Carcinogens; Cell Communication; Cell Cycle; Cell Division; Cells, Cultured; Cyclic AMP; Cyclic GMP; DNA; Fibroblasts; Mice; Neoplasm Metastasis; Neoplasms; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Xanthines

Plasma and 24-h urinary adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 12 normal subjects, 33 patients with six types of non-neoplastic disease (cholelithiasis, peptic ulcer, coronary heart disease, hypertension, regional ileitis, and cirrhosis), and 34 patients with five types of disseminated neoplastic disease (acute myelocytic leukemia; Hodgkin's disease; and metastatic cancer of the lung, colon, and breast). In patients with non-neoplastic disease, cyclic nucleotide values in plasma and urine did not differ significantly (P greater than 0.05) from those in normal subjects. In patients with disseminated cancer, cyclic AMP values in plasma and urine likewise did not differ significantly from those in normal subjects. Plasma cyclic GMP, in contrast, was significantly elevated in all five types of cancer patients, and urinary cyclic GMP was significantly elevated (five times the normal mean) in patients with acute myelogenous leukemia and Hodgkin's disease.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Metastasis; Neoplasms

The portion of B- and T-lymphocytes at the whole white blood count have been estimated in patients with malignant melanoma. An elevation of the B-lymphocytes and a decrease of the T-lymphocytes could be observed in comparison to controls. The CAMP and CGMP level in lymphocytes of patients suffering from melanoma shows a correlation to the degree of metastasing changes. The cyclic nucleotides by mealanoma patients are influenced differently than by normal persons, after addition of physiologic stimulators (isoproterenole, PGE, PGF, acetylcholine). The beta-adrenergic system shows a decreased stimulability and the cholinergic system an increased one depending upon the disease stage in comparison to controls.

Topics: B-Lymphocytes; Cyclic AMP; Cyclic GMP; Humans; Immunity, Cellular; Leukocyte Count; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Nucleotides, Cyclic; Reference Values; T-Lymphocytes

Topics: Adenoma; Cyclic AMP; Cyclic GMP; Humans; In Vitro Techniques; Neoplasm Metastasis; Theophylline; Thyroid Gland; Thyroid Neoplasms; Thyrotropin

The biochemical properties of cyclic nucleotide phosphodiesterases in a nonmetastasizing and a spontaneously metastasizing rat mammary carcinoma were compared. The phosphooiesterases in both tumors had a pH optimum of around 8.0 and preferentially hydrolysed cyclic purine nucleotides. The rate of hydrolysis of purine nucleotides in the nonmetastasizing tumor was two times higher than in the metastasizing tumor, but the rate of pyrimidine nucleotide hydrolysis was equal in both tumors. Theophylline, caffeine, and D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro20-1724) inhibited the enzyme activity in both tumors; the percent inhibition was the same by each inhibitor. The cyclic nucleotie phosphodiesterase activity in either tumor was stimulated by Mg++, Mn++, and Co++ and suppressed by Ca++, Zn,++, and Ni++. EDTA inhibited the activity below the basal level (activity in the absence of added cation), an this inhibition could be recovered up to the basal level by an equimolar quantity of either Mn++ or Mg++. Further stimulation of the enzyme activity with increasing concentrations of divalent cations was observed only with Mn++. Similar effects were observe with ethylene glycol bis(beta-aminoethyl ether)-tn,n-tetraacetic acid. The stimulatory cations affected both the low and high Michaelis constant (tkm) enzymes in these tumors by increasing the maximum velocity. In the low Km enzyme, the Km was also slightly increased. Neither guanosine 3',5'-cyclic monophosphate nor adenosine 3',5'-cyclic monophosphate had any effect on the hydrolysis of the other at physiologic levels.

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Caffeine; Calcium; Cobalt; Cyclic AMP; Cyclic GMP; Depression, Chemical; Edetic Acid; Egtazic Acid; Hydrogen-Ion Concentration; Magnesium; Manganese; Neoplasm Metastasis; Nickel; Purine Nucleotides; Pyrimidine Nucleotides; Rats; Theophylline; Zinc